KR820001994B1 - Process for preparing nitro compounds - Google Patents

Abstract

The title compds. (I; R3 = H, lower alkyl, aryl, heteroaralkyl; R4 = H, lower alkyl; Het = atoms required to complete a 5-6 membered ring; Z = S, O, CH2; m = 0-2; n = 2-3; m+n = 3-4), useful as histaminic H2 receptor antagonists, were prepd. by the reaction of II(X = QSO-, QSO2-, HS(CH2)nNH; Q = lower alkyl, aryl, aralkyl) and Het-(CH2)mY(Y = -Z(CH2)nNH2). Thus, 1.22 g 2-(3-chloro-2-pyridylmethylthio)etylamine dihydrobromide and 0.5 g nitropyrrole were reacted and refluxed for 10 days to give 2-[2-(3-choloro-2-pyridylmethylthio)ethylamino -3-nitropyrrole(m.p. 144-147≰C).

Description

[Name of invention]

Method for preparing nitro compound having histamine H ₂ -receptor antagonism

Detailed description of the invention

The present invention relates to a process for the preparation of nitro compounds having activity as histamine H ₂ -receptor antagonists. Many physiologically active substances exhibit their biological action by interaction with specific sites known as receptors. Histamine is just such a substance, and it has several biological actions.

This biological action of histamine, which is usually inhibited by a drug called "antihistamine", is transmitted through the histamine H ₂ -receptor. Representative examples of such antihistamines are mepyramine, diphenylhydramine, chloropheniramine.

However, other biological actions of histamine are these types of action of which is not inhibited by antihistamines prevented by the rim amide are histamine H ₂ - passing through the receptor known receptor and H ₂ -, but not the receptor is blocked by mepi lamin rim amide It is defined as the histamine receptor that is blocked by. Referred to as receptor antagonists - Histamine H ₂ - a compound to block histamine H ₂ receptors. The blocking of histamine H ₂ -receptors is of value in inhibiting the biological action of histamine that is not inhibited by antihistamines.

Histamine H ₂ -receptor antagonists are therefore useful, for example, as inhibitors of phase secretion, as anti-inflammatory agents, or as cardiovascular agents such as inhibitors of the effect of histamine on blood pressure.

The compound prepared by the present invention is a compound having the following structural formula (I).

Het is a 5- or 6-membered fully unsaturated heterocycle having at least one nitrogen atom and optionally substituted with lower alkyl, trifluoromethyl, hydroxymethyl, halogen, hydroxy, lower alkoxy or amino, or One heteroatom is a fully unsaturated five-membered heterocycle substituted with an R ¹ R ² NA- group with an oxygen or sulfur atom. Wherein R ¹ and R ² are the same or different and each is hydrogen, lower alkyl C ₃ -C ₆ cycloalkyl, lower alkenyl, arylalkyl, lower alkyl (lower alkyl) amino or di (lower alkyl) amino, substituted by lower alkoxy, Or R ¹ and R ² together with adjacent nitrogen atoms form a saturated 5- or 6-membered heterocycle.

A is a C ₁ -C ₆ alkanediyl group of straight or molecular chain, Z is sulfur, methylene or oxygen, m is 0,1 or 2 and n is 2 or 3 except m + n is 3 or 4. R ³ is hydrogen, lower alkyl, aryl, arylalkyl, all heteroarylalkyl and R ⁴ is hydrogen or loweralkyl.

Lower alkyl and lower alkoxy are used here to mean alkyl and alkoxy having 1 to 4 carbon atoms, each straight or branched chain and lower alkenyl refers to an alkenyl group having 3 to 6 carbon atoms which may be straight or branched chain. It was used to

Examples of nitrogen-containing heterocyclic compounds for Het include imidazole, pyridinethiazole, isothiazole, oxazole, isoxazole, 1,2,4-triazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole. The (CH ₂ ) m group is usually bonded to the carbon atom of the heterocycle Het adjacent to the nitrogen atom. Het, a heterocycle, is good for imidazole. In particular, Het may be 2- or 4-imidazole optionally substituted with lower alkyl (particularly methyl), halogen (particularly chlorine or bromine), trifluoromethyl or hydroxymethyl. Other suitable Het groups are lower alkyl (particularly methyl), lower alkoxy (particularly methoxy), halogen (particularly chlorine or bromine), amino or hydroxy optionally substituted 2-pyridyl; 2-thiazolyl; 3-isothiazolyl optionally substituted with chlorine or bromine; 3- (1,2,5) -thiadiazolyl or 2- (5-amino-1,3,4-thiadiazolyl) optionally substituted with chlorine or bromine. Specific examples of the Het group include 5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl, 3-methoxy -2-pyridyl and 3-hydroxy-2-pyridyl.

When Het is a heteroatom 5-membered heterocyclic ring, the (CH ₂ ) m group is preferably bonded to a heterocyclic carbon atom adjacent to the heteroatom. The R ¹ R ² NA-group is preferably bonded to another carbon atom of the heterocycle adjacent to the oxygen atom. R ¹ and R ² are hydrogen, lower alkyl (particularly methyl) phenyl (lower alkyl), wherein the phenyl group is optionally substituted by lower alkyl, lower alkoxy or halogen; or di (lower alkyl) amino (lower alkyl).

A is good for α, ω- straight chain alkylene group having 1-3 carbon atoms, especially methylene. Specific examples of such Het groups are 5- (4- (dimethylamino) butyl) -2-furyl and 5-((dimethylamino) methyl) -2-furyl. Preferred is 6, preferred m is 1 and n is 2.

R ³ is preferably hydrogen, methyl, aryl, arylmethylene or hetero arylmethylene. Examples of aryl groups for aryl or arylmethylene groups for R ³ include phenyl substituted with one or more lower alkyl, lower alkoxy, halogen, in particular 3- Methylphenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3-chlorophenyl, 5- or 6- (2,3-dihydro-1,4-benzodioxyyl) or 4- or 5- ( 1,3-benzodioxyl).

Examples of heteroaryl for R ³ are 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl and these groups are substituted by one or more lower alkyl or lower alkoxy and In particular 3-pyridyl, 6-methyl-3-pyridyl and 6-methoxy-3-pyridyl.

R ⁴ is methyl and better R ⁴ is hydrogen.

Examples of special compounds of the invention include 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -3-nitropyrrole, 2- [2- (5-methyl-4-imimi Dazolylmethylthio) ethylamino] -3-nitro-4-methylpyrrole, 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-4-benzylpyrrole, 2 -[2- (5-methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-4- (2-phenylethyl) pyrrole, 2- [2- (methyl-4-imidazolylmethylthio ) Ethylamino] -3-nitro-4-phenylpyrrole, 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-4-n-butylpyrrole, 2- [ (3-chloropyrid-2-yl) methylthio] ethylamino-3-nitropyrrole and 2- (5-dimethylaminomethyl-2-furylmethylthio) ethylamine.

Compounds of formula (I) are prepared according to the invention by reacting a compound of formula Het- (CH ₂ ) mY with a compound of formula (II). Where Y is -Z (CH ₂ ) n NH ₂ or mercaptan, eg halogen, trisubstituted phosphonium (eg triphenylphosphonium) or substituted sulfonyloxy (eg Free group which may be substituted by, for example, p-toluenesulfonyloxy, methinesulfonyloxy or trifluoromethanesulfonyloxy.

Wherein X is SO- or QSO _2- (where Q is lower alkyl, aryl or arylalkyl, or other free group which may be substituted by amine) when Y is -Z (CH ₂ ) n NH ₂ and Y is mer X is HS (CH ₂ ) n NH— when it is a free group which may be substituted by captan.

This reaction is usually carried out in the presence of a solvent, for example lower alkanol. Generally elevated temperatures are used, for example the boiling point of the reaction mixture. X is QSO- and Q is usually methyl or benzyl.

When R ¹ and R ² are hydrogen or lower alkyl substituted with (lower alkyl) amino, the amino group in the R ¹ R ² NA-substituent of the structural Het (CH ₂ ) m Y compound needs to be protected to prevent side reactions. I will understand that. The intermediate of Structural Formula (I) and Structural Formula (II), wherein X is QSO- or QSO ₂ , is a compound of Structural Formula (III), wherein H ₂ NCHR ⁴ COR ³ or Structural H ₂ NCHR ⁴ CR ³ (OR ⁵ ) ₂ compound ( Wherein R ⁵ may be prepared by reaction with aminoacetal or aminoketal of lower alkyl).

Wherein E is Het- (CH ₂ ) mZ (CH ₂ ) nNH- or Q ⁵ -and X ¹ is QSO- when QS- or E is QS-.

It will be appreciated that when E is Het (CH ₂ ) mZ (CH ₂ ) nNH and Het has a substituent containing a primary or secondary amino group, such amino groups should be protected during the reaction. When aminoketones are used the reaction is generally carried out under basic conditions such as, for example, sodium ethoxide in ethanol and directly produces compounds of formula (IV). When aminoacetals or aminoketals are used, the reaction is easily carried out under neutral conditions, for example in boiling ethanol and the product is cyclized under acidic conditions, for example in a solvent (e.g. with ether or lower alkanol hydrogen chloride). Bran A compound of formula IV is obtained.

The compound of formula IV wherein E is QS- may be converted to a compound of formula II wherein X is QSO- by reacting with one equivalent of hydrogen peroxide. It can be converted to a compound of formula II wherein X is QSO- by reacting with two equivalents of hydrogen peroxide.

Intermediates of formula (II), wherein X is HS (CH ₂ ) nNH-, may be prepared by reacting a compound of formula (II), wherein X is QSO- or QSO ₂ -with an amine of formula HS (CH ₂ ) nNH ₂ .

Structural formula (I) compounds block histamine H ₂ -receptors. That is, they block the biological action of histamine that is not inhibited by antihistamines such as mepyramine but is inhibited by burimamide.

For example, they block the release of gastric acid histamine excitation from the lumen-perfused stomach of rats anesthetized with urethane when dosed at a dose of 0.5-256 micromoles per kg. Their function as histamine H ₂ -receptor antagonists is also demonstrated by their ability to inhibit other actions of histamine that are not delivered by the histamine H ₁ -receptor.

For example, they inhibit the action of histamine in isolated guinea pig atriums and in isolated uterus. They also inhibit the basic secretion of gastric acid and the secretion of gastric acid that is excitated and secreted by pentagastrin or food. In conventional tests, such as blood pressure measurements in cats anesthetized with 0.5-256 micromolar semen to kg per kg, they inhibit the vasodilatation action of histamine.

The efficacy of these compounds is explained by an effective dose (less than 10 ⁻⁴ water) that inhibits gastric acid secretion by 50% in anesthetized states and 50% inhibits histamine-induced tachycardia in the atrium of isolated guinea pigs. The pharmacologically active compound for therapeutic use will usually be administered in a pharmaceutical composition comprising at least one compound in the form of a free base or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical ophthalmic diluent or carrier.

Such addition salts include salts of hydrochloric acid, bromic acid, iodic acid, sulfuric acid, and maleic acid, which salts can be reacted with an acid in lower alkanols or other addition salts directly from the base using ion exchange resins, for example. It can be easily formed from the corresponding base by standard methods such as forming the desired salt from.

The pharmaceutical carriers used may be solid or liquid and examples of solid carriers are lactose, white clay, scruce, talc, gelatin, transition, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.

When a solid carrier is used, the composition can be prepared in the form of tablets, capsules, troches or lozenges. The amount of solid carrier in unit dosage form is generally about 25 mg-300 mg. If liquid carriers are used, the compositions may be in the form of syrups, emulsions, soft gelatin capsules, sterile injections in ampoules, aqueous or non-aqueous liquid suspensions. This pharmaceutical composition may be prepared by conventional methods such as mixing, granulating, compacting or dissolving these ingredients in the desired form.

The composition of the present invention is preferably in unit dosage form containing sufficient active ingredient to block the histamine HH ₂ -receptor. Each unit dose should contain about 50 mg-250 mg of active ingredient. The histamine H ₂ -receptor can be blocked by administering the active substance of the present invention or a pharmaceutical composition containing the same. This active ingredient should be administered 1-6 times daily and the daily dosage range will usually be about 150-1005mg. Routes of administration may be administered orally or by injection.

The invention is illustrated by the following examples, where temperatures are shown in degrees Celsius.

Example 1

(a) (i) A solution containing 8 g (0.06 mol) of aminoacetaldehyde diethylacetal and 10 g (0.06 mol) of 1-nitro-2,2-bis-methylthioethylene in 100 ml of ethanol was refluxed for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column eluted with carbon tetrachloride / chloroform (7: 3) and the product was crystallized from propan-2-ol to give mp 73-73.5 ° of 1-nitro-2-methylthio-2. 8.7 ° (58%) of-(2,2-niethoxyethylamino) ethylene was obtained.

시간 동안 교반하고 용매를 진공제거시켜 황색유상잔사를 얻고 프로판-2-올로 적정 하여 mp 72-74°인 1-니트로-2-메틸티오-2-(2,2-디에톡시-에틸아미노)에틸렌 9.8g(49%)를 얻었다.(ii) A solution containing 11 g (0.08 mol) of aminoacetaldehyde diethyl acetal and 15 g (0.08 mol) of 1-nitro-2-methylthio-2-methylsulfinylethylene in 200 ml of methanol at room temperature

The mixture was stirred for an hour and the solvent was removed in vacuo to obtain a yellow oily residue which was titrated with propan-2-ol to give 1-nitro-2-methylthio-2- (2,2-diethoxy-ethylamino) ethylene having an mp 72-74 °. 9.8 g (49%) was obtained.

(b) 1-nitro-2-methylthio-2- (2,2-diethoxyethylamino) -ethylene 9.7 g (0.04 mol) was added to 250 ml of anhydrous ether for 3 hours at 5-10 ° for anhydrous hydrogen chloride gas. The mixture was passed through the stirred solution and the resulting mixture was poured into 300 ml of potassium carbonate solution and basified. The mixture was filtered to give a yellow solid, and the aqueous layer of the filtrate was separated and extracted with 2 x 150 ml of ether. The combined ether solutions were evaporated to give a residue, which was recrystallized from acetone-chloroform to give the residue and m. 2-methylthio-3-nitropyrrole 3.4 (54%) was obtained at p212-213 °.

Found: C, 38.1; H, 3.8; N, 17.7; S, 20.1; C ₅ H ₆ N ₂ O ₂ S

Calculated: C, 38.0; H, 3.8; N, 17.7; S, 20.3%

시간 동안 가열했다. 먼저 과산화물이 남아있지 않다는 것을 확인한 후 용매를 진공제거시키고 잔사를 프로판 2-올로부터 재결정시켜 m.p 162-164°인 2-에틸설피닐-3-니트로피롤 2.3g(85%)를 얻었다.(c) A solution of 2.5 g (0.016 mol) of 2-methylthio-3-nitropyrrole in 70 ml of glacial acetic acid and 2 ml of hydrogen peroxide (0.017 mol 100 vol) at 60 °

Heated for hours. After confirming that no peroxide remained, the solvent was removed in vacuo and the residue was recrystallized from propane 2-ol to give 2.3 g (85%) of 2-ethylsulfinyl-3-nitropyrrole, mp 162-164 °.

Found: C, 34.45; H, 3.4; N, 15.9; S, 18.3; C ₅ H ₆ N ₂ O ₃ S

Calculated: C, 34.5; H, 3.5; N, 16.1; S, 18.4%

(d) A solution containing 2 g (0.01 mol) of 2-methylsulfinyl-3-nitropyrrole and 2 g (0.01 mol) of 2- (5-methyl-4-imidazolylmethylthio) ethylamine in 50 ml of methanol was prepared. Reflux daily and evaporate to dryness. The residue was chromatographed on a silica gel column eluted with ethyl acetate, the eluate was evaporated to dryness and then recrystallized from propan-2-ol to give 2- [2- (5-methyl-4-imidazolylmethylthio) at mp 161-162 °. 0.96 g (31%) of ethylamino] -3-nitropyrrole was obtained.

Found: C, 46.9; H, 5. 45; N, 24.6; S, 11.0 C ₁₁ H ₁₅ N ₅ O ₂ S

Calculated: C, 47.0; H, 5.4; N, 24.9; S, 11.4%

Example 2

(a) 5.7 g (0.1 mol) of ground potassium hydroxide was refluxed in 100 ml of methanol with 9.3 (0.05 mol) of 1-nitro-2-methylthio-2-methylsulfinylethylene and 5.6 g (0.05 mol) of aminoacetone hydrochloride. The solution was added dropwise and reflux was continued for 5 minutes, then the mixture was cooled and the solvent was removed in vacuo. Water was added to the residue and the solid was recrystallized from chloroform / methanol / petroleum ether to give 1.45 g (16%) of 2-methylthio-3-nitro-4-methylpyrrole with m.p 216-216.5 °.

Found: C, 41.9; H, 4.6; N, 16.2; S, 18.8; C ₆ H ₈ N ₂ O ₂ S

Calc .: C, 41.85; H, 4.7; N, 16.3; S, 18.6%

(b) mp 161-162 ° (ethyl acetate) using an equivalent of 2-methylthio-3-nitro-4-methylpyrrole instead of 2-methylthio-3-nitropyrrole in Example 1 (c) Phosphorus 2-methylsulfinyl-3-nitro-4-methylpyrrole was obtained in 80% yield.

Found: C, 38.5; H, 4.4; N, 14.9; S, 16.9; C ₆ H ₈ N ₂ O ₃ S

Calculated: C, 38.3; H, 4.3; N, 14.9; S, 17.0%

(c) 2- in Example 1 (d), mp 172 ° using an iso-quantity of 2-methyl-sulfinyl-3-nitro-4-methylpyrrole instead of 2-methylsulfinyl-3-nitropyrrole. [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-4-methylpyrrole was obtained in 25% yield.

Found: C, 48.95; H, 6.0 N, 23.8; S, 10.8; C ₁₂ H ₁₇ N ₅ O ₂ S

Calculated: C, 48.8; H, 5.8; N, 23.7; S, 10.9%

Example 3

(a) A solution of sodium methoxide (1.9 mol, 0.084 mol) dissolved in 100 ml of methanol and 7.9 g (0.02 mol) of 1-amino-3-phenylpropane-2-silver hydrochloride in 100 ml of methanol were added simultaneously. 7.7 g (0.042 mol) of 1-nitro-2-methylthio-2-methylsulfinyl-ethylene was added dropwise to the stirred solution, and the mixture was maintained at about 60 ° for 25 minutes while the temperature was added. The solvent was removed in vacuo and the remaining dark red oil was chromatographed on silica gel. Elution and recrystallization were carried out with petroleum ether / ethyl acetate (7: 3) to give 2.95 (28.5%) of 2-methylthio-3-nitro-4-benzyl-pyrrole having an m.p of 190-192.5 °.

Found: C, 57.8; H, 4. 85; N, 11.35; S, 12.6; C ₁₂ H ₁₂ N ₂ O ₃ S

Calculated: C, 58.05; H, 4.9; N, 11.3; S, 12.9%

(c) mp 189-190 ° (ethyl acetate) using an equivalent of 2-methylthio-3-nitro-4-benzylpyrrole in place of 2-methylthio-3-nitropyrrole in Example 1 (d) 1.7 g (58%) of phosphorus 2-methylsulfinyl-3-nitro-4-benzylpyrrole was obtained.

Found: C, 54.3; H, 4.6; N, 10.7; S, 11.9; C ₁₈ H ₂₁

Calculated: C, 54.5; H, 4.6; N, 10.6; S, 12.1%

(c) mp 192.5-193 ° using the equivalent of 2-methylsulfinyl-3-phytro-4-benzylpyrrole in place of 2-methylsulfinyl-3-nitropyrrole in Example 1 (d) 1.08 g (52%) of 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-4-benzylpyrrole were obtained.

Found: C, 58.6; H, 517; N, 18.9; S, 8.5; C ₁₈ H ₂₁ N ₅ O ₂ S

Calculated: C, 58.2; H, 5.7; N, 18.85; S, 8.6%

Example 4

(a) 6.87 g (0.040 mol) of α-aminoacetophenone hydrochloride was mixed with 7.25 g (0,040 mol) of 1-nitro-2-methylthio-2-methylsulfinylethylene in 300 ml of anhydrous methanol and warmed to 60 °. . Sodium methoxide (0.92 g as sodium, 0.080 g atoms) was added dropwise in 25 ml of methanol for 10 minutes while stirring, and the mixture was stirred at 60 ° for 1 hour and filtered to give 2-methylthio-, which was mp 259-261 ° (decomposed). 5.66 g of 3-nitro-4-phenylpyrrole was obtained.

Found: C, 56.0; H, 4.3; N, 11.85; C ₁₁ H ₁₀ N ₂ O ₂ S

Calculated: C, 56.4; H, 4.3; N, 12.0%

(b) 3.00 g (0.013 mol) of 2-methylthio-3-nitro-4-phenylpyrone were suspended in 200 ml of glacial acetic acid, and 1.45 g (0.013 mol) of 30% hydrogen peroxide was added. The mixture was stirred at 80 ° for 5 hours, then evaporated to dryness and the residue was recrystallized from isopropanol to give 2.52 of 2-methylsulfinyl-3-nitro-4-phenylpyrrole, m.p 197 ° (decomposition).

Found: C, 52.5; H, 4.05; N, 11.3; C ₁₁ H ₁₀ N ₂ O ₃ S

Calculated: C, 52.8; H, 4.0; N, 11.2%

(c) 2.0 g (0.008 mol) of 2-methylsulfinyl-3-nitro-4-phenylpyrrole is partially dissolved in 150 ml of ethanol, and therein 2- (5-methyl-4-imidazolylmethylthio in a small amount of ethanol. ) Was added a solution in which 1.37 g (0.008 mol) of thylamine was added.

After refluxing the mixture for 7 days, the mixture was washed, chromatographed on silica gel and eluted with ethyl acetate to collect the desired product. The impure solid was recrystallized from 2-propanol to give 0.46 g of 2- [2- (5-methyl-4-imidazolylmethylthio) ethyl] amino-3-nitro-4-phenylpyrrole with m.p 182-184 °.

Found: C, 56.8; H, 5.5; N, 19.8; S, 8.7; C ₁₇ H ₁₉ N ₅ O ₂ S

Calculated: C, 57.1; H, 5.4; N, 19.6; S, 9.0%

Example 5

(a) mp 198-200 ° in Example 3 (a) using an equivalent equivalent of 1-amino-4-phenylbutan-2-one hydrochloride instead of 1-amino-3-phenylpropane-2-one hydrochloride 2-methylthio-3-nitro-4- (2-phenylethyl) pyrrole was obtained.

(b) mp 171.5-173 using an equivalent of 2-methylthio-3-nitro-4- (2-phenylethyl) pyrrole in place of the 2-methylthio-3-nitro-pyrrole in Example 1 (c) 2-methyl-sulfinyl-3-nitro-4- (2-phenylethyl) pyrrole was obtained at 75% yield.

(c) mp 186 using an equivalent of 2-methylsulfinyl-3-nitro-4- (2-phenylethyl) pyrrole in place of the 2-methylsulfinyl-3-nitropyrrole in Example 1 (d) 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-4- (2-phenylethyl) pyrrole is -187 ° in 31% yield.

Example 6

시간에 걸쳐 적가하고나서 증류수 500ml에 붓고 에테르층을 분리 건조시켰다. 에테르를 제거시켜 황색오일인 에틸-2-발레릴아세토아세테이트 142g을 얻었다.(i) Sodium hydride (50% in oil, 39.6 g) was added gradually to a solution containing 107.5 g of ethyl acetate in anhydrous ether under nitrogen stream and 100 g of valeryl chloride was added to the stirred suspension.

After dropping over time, the mixture was poured into 500 ml of distilled water, and the ether layer was separated and dried. The ether was removed to give 142 g of ethyl-2-valeryl acetoacetate as a yellow oil.

(ii) A solution containing 41.3 g of sodium citrite in water was added to a cooled solution by adding 118.7 g of ethyl 2-valeryl acetoacetate to 100 ml of acetic acid, and the temperature was maintained at 10 ° or less. 100 g of ice was added, 105.0 g of acetic anhydride was added thereto, and zinc powder (65.4 g in total) was added little by little while maintaining the temperature below 20 ° while stirring until the reaction was completed. The mixture was left at room temperature overnight, filtered and the replacement was washed with chloroform and the filtrate was extracted with chloroform. The chloroform extract was washed with sodium carbonate solution and dried. The solution was removed in vacuo and the residue was coagulated with petroleum ether (bp 60-80 °) / ethyl acetate to purify by column chromatography and no longer need to be purified ethyl-2-acetamido-3-oxoheptanoate 13.5 g was obtained.

(iii) 10.4 g of ethyl 2-acetamido-3-oxoheptanoate was hydrolyzed by reflux with 80 ml of 50% hydrochloric acid for 9 hours under reflux and the mixture was evaporated to dryness to give 1-amino-2- in dark red oil. Hexa obtained 5.8 g of hydrochloride.

(iv) 5.8 g of 1-amino-2-hexanone hydrochloride was dissolved in 100 ml of ethanol and mixed with a solution of 6.8 g of 1-methylthio-1-methylsulfinyl-2-nitroethylene in 100 ml of warm methanol. A solution of sodium methoxide (1.7 g as sodium) in methanol was added dropwise at 60 ° with stirring for 2 hours, and the mixture was evaporated to dryness. The residue obtained by titrating the residue with water was filtered and dried to obtain 3.9 g of 2-methylthio-3-nitro-4-n-butylpyrrole.

3.7 g of (V) 2-methylthio-3-nitro-4-n-butylpyrrole was suspended in 50 ml of glacial acetic acid and 1.62 g of 30% hydrogen peroxide was added. The mixture was heated to 80 ° for 7 hours and evaporated to give a brown oil. The crude product was eluted with benzene and chloroform, purified by column chromatography using silica gel, and left to crystallize. This was recrystallized from 2-propanol to give 1.6 g of 2-methylsulfinyl-3-nitro-4-n-butylpi, m.p 133-4 °.

(VI) 2.78 g of 2-methylsulfinyl-3-nitro-4-n-butylpyrrole was dissolved in ethanol, and 2.08 g of 2- (5-methyl-4-amidazolylmethylthio) ethylamine was added to 100 ml of ethanol. The solution was added and heated at reflux for 9 days. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column using chloroform and ethyl acetate to give 0.65 g of a crude product as a brown oil. This crude product was dissolved in 30 ml of isopropanol and reacted with a solution containing 0.5 g of maleic acid in 2-propanol. The mixture was warmed for several minutes in a steam poison and cooled to give 2- [2- (5-methyl-4-imidazolyl methylthio) ethyl] amino-3-nitro-4-n-butylpi, mp 94-95 °. 0.19 g of roll maleate was obtained as bright yellow crystals.

Example 7

1.22 g of 2- (3-chloro-2-pyridylmethylthio) ethylamine dihydrobromide were neutralized with aqueous sodium hydroxide solution and the free base was extracted with chloroform. Nitropyrrole was added to 0.5 g of ethanol solution. The mixture was refluxed for 10 days, evaporated to dryness and the residue was chromatographed on a silica gel column eluted with chloroform. The crude product was recrystallized from 2-propanol to give 2- [2- (3-chloro-2-pyridylmethylthio) ethylamino] -3-nitropyrrole which was m.p 144-147 ° (decomposition).

Found: C, 45.98; H, 4. 20; N, 17.57: C ₁₂ H ₁₃ N ₄ O ₂ SCl

Calculated: C, 46.08; H, 4. 19; N, 17.91%

Example 8

A solution containing 3 g (0.014 mol) of 2- (5-diethylaminomethyl-2-furylmethylthio) ethylamine and 2 g (0.011 mol) of 2-methylsulfinyl-3-nitropyrrole in 50 ml of ethanol was refluxed for 7 days. And evaporated to dryness. The residue was purified by elution in a silica gel column with ethyl acetate-petroleum ether (mp 60-80 °) (4: 1) to obtain 2-67- (5-dimethylaminomethyl-2-furylethylthio) ethyl, which is mp 67 °. Amino] -3-nitropyrrole was obtained.

Example 9-31

The following Example 9-31 compounds were obtained using the equivalents of the following (a)-(w) compounds instead of 2- (5-methyl-4-imidazolylmethylthio) ethylamine of Example 1, respectively.

(a) 2- (2-imidazolylmethylthio) ethylamine

(b) 2- (4-imidazolylmethylthio) ethylamine

(c) 2- (5-bromo-4-imidazolylmethylthio) ethylamine

(d) 2- (5-trifluoromethyl-4-imidazolylmethylthio) ethylamine

(e) 2- (5-hydroxymethyl-4-imidazolylmethylthio) ethylamine

(f) 2- (2-pyridylmethylthio) ethylamine

(g) 2- (3-methyl-2-pyridylmethylthio) ethylamine

(h) 2- (3-methoxy-2-pyridylmethylthio) ethylamine

(i) 2- (3-amino-2-pyridylmethylthio) ethylamine

(j) 2- (3-hydroxy-2-pyridylmethylthio) ethylamine

(k) 2- (3-isothiazolylmethylthio) ethylamine

(l) 2- (4-bromo-3-isothiazolylmethylthio) ethylamine

(m) 2- (3- (1,2,5) -thiadiazolylmethylthio) ethylamine

(n) 2- (4-chloro-3- (1,2,5) -thiadiazolylmethylthio) ethylamine

(o) 2- (5-amino-2- (1,3,4) -thiadiazolylmethylthio) ethylamine

(p) 2- (15-dimethylaminoethyl) -2-furyl) methylthio) ethylamine

(q) 2-((5-ethylaminomethyl) -2-furyl) methylthio) ethylamine

(n) 2-((5- (1-pyrrolidino) methyl) -2-furyl) methylthio) ethylamine

(s) 2-((5-methylethylaminomethyl-2-furyl) methylthio) ethylamine

(t) 2-((5-dimethylaminomethyl) -2-thienyl) methylthio) ethylamine

(u) 2-((5-methylaminomethyl) -2-thienyl) methylthio) ethylamine

(v) 2-((5- (1-pyrrolidino) methyl) -2-thienyl) methylthio) ethylamine

(w) 2-((5-methylethylaminomethyl-2-thienyl) methylthio) ethylamine

Example Number

9. 2- [2- (2-imidazolylmethylthio) ethylamino] -3-nitropyrrole

10. 2- [2- (4-imidazolylmethylthio) ethylamino] -3-nitropyrrole

11. 2- [2- (5-bromo-4-imidazolylmethylthio) ethylamino] -3-nitropyrrole

12. 2- [2- (5-trifluoromethyl-4-imidazolylmethylthio) ethylamino] -3-nitrolol

13. 2- [2- (5-hydroxymethyl-4-imidazolylmethylthio) -ethylamino] -3-nitrolol

14. 2- [2- (2-pyridylmethylthio) ethylamino] -3-nitropyrrole

15. 2- [2- (3-methyl-2-pyridylmethylthio) ethylamino] -3-nitropyrrole

16. 2- [2- (3-methoxy-2-pyridylmethylthio) ethylamino] -3-nitropyrrole

17. 2- [2- (3-amino-2-pyridylmethylthio) ethylamino] -3-nitropyrrole

18. 2- [2- (3-hydroxy-2-pyridylmethylthio) ethylamino) -3-nitropyrrole

19. 2- [2- (3-isothiazolylmethylthio) ethylamino] -3-nitropyrrole

20. 2- [2- (3-isothiazolylmethylthio) ethylamino] -3-nitropyrrole

21. 2- [2- (3- (1,2,5) -thiadiazolylmethylthio) ethylamino] -3-nitropyrrole

22. 2- [2- (4-chloro-3- (1,2,5) -thiadiazolylmethylthio) ethylamino] -3-nitropyrrole

23. 2- [2- (5-amino-2- (1,3,4) -thiadiazolylmethylthio) ethylamino] -3-nitropyrrole

24. 2- [2- (5-dimethylaminomethyl) -2-furylmethylthio) ethylamino] -3-nitropyrrole

25. 2- [2- (5-methylaminomethyl) -2-furylmethylthio) ethylamino] -3-nitropy roll

26. 2- [2- (5- (1-pyrrolidinomethyl) -2-furylmethylthio) ethylamino] -3-nitropyrrole

27. 2-2- (5-methylethylaminomethyl) -2-furylmethylthio) ethylamino] -3-nitropyrrole

28. 2- [2- (5- (dimethylaminomethyl) -2-thienylmethylthio) ethylamino] -3-nitrolol

29. 2- [2- (5-methylaminomethyl) -2-thimethylthio) ethylamino] -3-nitropyrrole

30. 2- [2- (5- (1-pyrrolidinomethyl) -2-thienylmethylthio) ethylamino] -3-nitrorrole

31. 2- [2- (5-methylethylaminomethyl) -2-thienylmethylthio) ethylamino] -3-nitropyrrole

Claims (1)

A method of preparing the following compound of formula (I) by reacting a compound of formula Het- (CH ₂ ) _m Y with a compound of formula II.

Het in the above formula is a fully unsaturated compound of 5- or 6 atoms containing at least one nitrogen atom and optionally substituted by lower alkyl, trifluoromethyl, hydroxymethyl, halogen, hydroxy, lower alkoxy or amino. Summoned or single heteroatoms containing one oxygen or sulfur atom and R ¹ R ² NA-group, wherein R ¹ and R ² are the same or different and each is hydrogen, lower alkyl, C ₁ -C ₆ cycloalkyl, lower alkenyl , Arylalkyl, or lower alkoxy, lower alkyl substituted with (lower alkyl) amino or di (lower alkyl) amino, or R ¹ and R ² together with the adjacent nitrogen atom form a saturated heterocyclic ring of 5- or 6-membered And A is a fully unsaturated 5-membered heterocycle substituted with a straight or molecular chain C ₁ -C ₆ alkanediyl group. Z is sulfur, methylene or oxygen, m is 0, 1 or 2, n is 2 or 3, but m + n is 3 or 4. R ³ is hydrogen, lower alkyl, aryl or hetero arylalkyl and R ⁴ is hydrogen or lower alkyl. Y is —Z (CH ₂ ) _n NH ₂ or when m is 1 or 2, for example halogen-trisubstituted phosphonium (eg triphenylphosphonium), substituted sulfonyloxy (eg P-toluenesul Free groups that can be substituted by mercaptans, such as phonyloxy, methanesulfonyloxy or trifluoromethane sulfonyloxy). X is QSO- or QSO _2- (where Q is lower alkyl, aryl or arylalkyl, or other free group which may be substituted by amine) when Y is -Z (CH ₂ ) NH ₂ and Y is substituted by mercaptan X is (HSCH ₂ ) n NH— when it is a free radical.