JPH0379354B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel thiophene derivatives. More specifically, the present invention provides a compound having the general formula (R ¹ in the formula is a hydrogen atom, a halogen atom, or an acyl group, and R ² and R ³ are each a hydrogen atom,
The present invention relates to a thiophene derivative represented by a lower alkyl group, an aryl group, or an aralkyl group, Y is alkylene, and n is 2 or 3, and a method for producing the same. The thiophene derivative of the general formula (1) of the present invention is a novel compound that has not been described in any literature, and exhibits a remarkable anti-itch effect on mammals including humans, making it extremely useful as a pharmaceutical for the prevention and treatment of gastric and duodenal ulcers. It is a useful compound. Thus, the present invention provides thiophene derivatives useful as pharmaceuticals, and also provides a method for producing the same. In the present invention, a halogen atom is a chlorine atom, a bromine atom, or an iodine atom, and an acyl group has two carbon atoms.
It is a group derived from ~7 aliphatic and aromatic carboxylic acids, and a lower alkyl group has 1 to 6 carbon atoms.
A straight-chain or branched alkyl group is a straight-chain or branched alkyl group, a lower alkoxyl group is a straight-chain or branched alkoxyl group having 1 to 6 carbon atoms, and an aryl group is a phenyl group, a substituted phenyl group. and other monovalent groups derived from aromatic hydrocarbons, and an aralkyl group is a lower alkyl group in which at least one hydrogen atom is substituted with an aryl group;
Alkylene is a divalent group derived from an aliphatic hydrocarbon having 1 to 8 carbon atoms, and acid residue is a halogen atom or an arylsulfonyloxy group such as a benzenesulfonyloxy group or a D-toluenesulfonyloxy group. It is a residue of an inorganic acid or an organic acid. The compound of general formula (1) of the present invention can be produced as follows. For example, the general formula (In the formula, R ¹ , R ² , R ³ , Y and n have the same meanings as above) and a thiophene amino alcohol derivative represented by the general formula The compound of general formula (1) can be produced by reacting with a carbonyl compound represented by (X in the formula is a chlorine atom or a 1-imidazolyl group). The thiophene amino alcohol derivative (2) used as a starting material in this production method is generally a new compound, but it can be produced by the following method. For example, the general formula (wherein R ¹ has the same meaning as above and Y′ is alkylene or a simple bond) or its reactive functional derivative; (R ² , R ³ and n in the formula have the same meanings as above) are reacted with an aminocarboxylic acid derivative represented by the general formula A thiophenamide carboxylic acid derivative represented by the formula (R ¹ , R ² , R ³ , Y' and n have the same meanings as above) is prepared, and this is treated with a suitable reducing agent such as aluminum hydride. It can be produced by reducing with Furthermore, a thiophenecarboxylic acid derivative of the general formula (4) or a reactive functional derivative thereof and a compound of the general formula (R ² , R ³ and n in the formula have the same meanings as above) are reacted with an amino alcohol derivative represented by the general formula A thiophenamide alcohol derivative represented by the formula (R ¹ , R ² , R ³ , Y' and n have the same meanings as above) is prepared and treated with a suitable reducing agent such as sodium acetoxyborohydride. It can be produced by reducing with etc. Furthermore, the general formula (R ¹ and Y′ in the formula have the same meanings as above,
A thiophene derivative represented by R ⁵ is a hydrogen atom or a lower alkyl group is reacted with an amino alcohol derivative (7), and the general formula (in which R ¹ , R ² , R ³ , R ⁵ , Y' and n have the same meanings as above) is prepared, and then treated with a suitable reducing agent such as sodium borohydride. It can be produced by reducing with etc. The thiophene amino alcohol derivative of the general formula (2), where n is 3, further has the general formula (R ¹ and Y in the formula have the same meanings as above)
The aminoalkylthiophene derivative represented by the general formula (R ² and R ³ in the formula have the same meanings as above,
Z′ is a halogen atom or a lower alkoxyl group, and R ⁶ is a lower alkyl group) is reacted with a malonic acid ester derivative represented by the general formula A thiophenamide carboxylic acid ester derivative represented by the formula (R ¹ , R ² , R ³ , R ⁶ and Y have the same meanings as above) is prepared and treated with a suitable reducing agent such as aluminum hydride. It can also be produced by reduction. The compounds used as starting materials in each of these production methods are generally known compounds and can be obtained as commercially available products or can be produced by methods described in literature. The thiophene amino alcohol derivative of general formula (2) produced in this way is generally an oily substance and can be purified by distillation under reduced pressure or recrystallization of an acid addition salt. It may be used without any particular purification. The compound of general formula (3), which is another starting material for the present production method, is a known compound and can be obtained as a commercially available product or can be produced by methods described in literature. In order to suitably carry out this production method, the thiophene amino alcohol derivative (2) produced by the above method is dissolved in an inert solvent such as benzene, toluene, etc., and an equimolar to slightly excess molar amount is dissolved therein. Add N,N'-carbonyldiimidazole,
React at 0-80°C for 3-20 hours. The reaction mixture is washed successively with dilute hydrochloric acid, an aqueous sodium bicarbonate solution, and water, and after drying, the solvent is distilled off under reduced pressure, and the resulting residue is purified by a conventional method to obtain the desired product.
Alternatively, thiophene amino alcohol derivative (2)
is dissolved in an inert solvent, such as benzene or toluene, and 2 to 5 equivalents of an organic tertiary amine, such as triethylamine, are added thereto, followed by equimolar to slightly excess molar phosgene, and the mixture is heated at 0 to 80°C.
Let it react for several hours. After the reaction is completed, the desired product is obtained by processing in the same manner as above. The compound represented by general formula (1) of the present invention further includes:
The thiophene amino alcohol derivative (2) in the above production method is represented by the general formula Z-COOR ⁴ (14) (in the formula, Z is a halogen atom or a lower alkoxyl group, and R ⁴ is a lower alkyl group). By reacting carbonate ester derivatives, the general formula (In the formula, R ¹ , R ² , R ³ , R ⁴ , Y and n have the same meanings as above) is prepared and then heated in the presence of a basic catalyst. It can be manufactured by Furthermore, the compound of the general formula (1) of the present invention has the general formula (R ¹ and Y in the formula have the same meanings as above,
A is an acid residue) and a thiophene derivative represented by the general formula It can also be produced by reacting a compound represented by the formula (in which R ² , R ³ and n have the same meanings as above). The compounds of general formulas (16) and (17) used as starting materials in this production method are all known compounds and can be obtained as commercially available products or can be produced by methods described in literature. In order to suitably carry out these production methods, the thiophene amino alcohol derivative (2) is mixed with an inert solvent,
For example, in a mixed solution of dioxane and water, in the presence of a basic substance such as sodium bicarbonate or sodium hydroxide, a slight molar excess to 5 times the molar amount of a carbonate derivative (14), such as ethyl chlorocarbonate, is reacted. An N-alkoxycarbonyl-N-hydroxyalkylaminoalkylthiophene derivative (15) is produced. This compound is then dissolved in an inert solvent such as toluene in the presence of a catalytic amount of a basic substance such as sodium methylate for 4 to 30 hours.
Reflux for an hour. At this time, if the alcohol produced by the reaction is removed from the reaction system, the reaction will proceed more favorably. After the reaction is complete, insoluble matter is filtered off, the solvent is distilled off under reduced pressure, and the residue is purified by a conventional method to obtain the desired product. In addition, in order to suitably carry out the production method by N-alkylation to the cyclic compound (17), a 2-oxazolidinone derivative or tetrahydro-2H-1,3-oxazin-2-one represented by the general formula (17) is used. The derivative is dissolved in an inert solvent such as N,N-dimethylformamide or tetrahydrofuran, and a basic substance such as sodium hydride or potassium carbonate is added thereto and stirred for a while. Next, equimolar to slightly excess molar amount of the compound represented by general formula (16) is added to this, and the mixture is reacted at 30 to 150°C for 3 to 20 hours. The reaction solution is concentrated under reduced pressure, an appropriate amount of water is added to the residue, and the mixture is extracted with a suitable solvent such as benzene, chloroform, methylene chloride, etc. The extract is washed with water, dried, and concentrated under reduced pressure, and the residue is purified by a conventional method to obtain the desired product. The compound of the general formula (1) of the present invention in which R ¹ is a halogen atom or an acyl group can be obtained by substituting the compound of the general formula ( ¹ ) with a hydrogen atom by halogen or acyl substitution. can also be manufactured. For example, by reacting a compound of general formula (1) in which R ¹ is a hydrogen atom with an equimolar to slightly excess molar amount of a halogenating agent, such as bromine, in an inert solvent, such as acetic acid, at 0 to 50°C. Compounds in which R ¹ is a bromine atom can be produced,
Alternatively, a compound of general formula (1) in which R ¹ is a hydrogen atom is dissolved in an inert solvent such as acetic acid in the presence of a Lewis acid such as boron trifluoride ether complex salt.
5 equivalents of an acylating agent, e.g. acetic anhydride and 0-50°C.
A compound in which R ¹ is an acetyl group can be produced by reacting with As the compound of general formula (1) of the present invention, for example, 3-
(2-thienylmethyl)-2-oxazolidinone,
3-[2-(2-thienyl)ethyl]-2-oxazolidinone, 3-[4-(2-thienyl)butyl]
-2-oxazolidinone, 3-[2-(5-bromo-2-thienyl)ethyl]-2-oxazolidinone, 3-[2-(5-acetyl-2-thienyl)ethyl]-2-oxazolidinone, 5-methyl -3
-[2-(2-thienyl)ethyl]-2-oxazolidinone, 5-ethyl-3-[2-(2-thienyl)ethyl]-2-oxazolidinone, 4-methyl-3-[2-(2-thienyl) ) Ethyl]-2-oxazolidinone, 4-ethyl-3-[2-(2-thienyl)ethyl]-2-oxazolidinone, 4,
4-dimethyl-3-[2-(2-thienyl)ethyl]-2-oxazolidinone, 4-n-propyl-3-[2-(2-thienyl)ethyl]-2-oxazolidinone, 4-isopropyl-3- [2-(2
-thienyl)ethyl]-2-oxazolidinone,
4-n-butyl-3-[2-(2-thienyl)ethyl]-2-oxazolidinone, 4-isobutyl-
3-[2-(2-thienyl)ethyl]-2-oxazolidinone, 4-sec-butyl-3-[2-(2-
thienyl)ethyl]-2-oxazolidinone, 4
-phenyl-3-[2-(2-thienyl)ethyl]
-2-oxazolidinone, 4-benzyl-3-
[2-(2-thienyl)ethyl]-2-oxazolidinone, 3-(2-thienylmethyl)tetrahydro-2H-1,3-oxazin-2-one, 3-
(3-thienylmethyl)tetrahydro-2H-1,
3-Oxazin-2-one, 3-[2-(2-thienyl)ethyl]tetrahydro-2H-1,3-oxazin-2-one, 3-[1-(2-thienyl)
ethyl]tetrahydro-2H-1,3-oxazin-2-one, 3-(5-bromo-2-thienylmethyl)tetrahydro-2H-1,3-oxazin-2-one, 3-(5-acetyl-2 -thienylmethyl)tetrahydro-2H-1,3-oxazin-2-one, 5-ethyl-3-[2-(2-thienyl)ethyl]tetrahydro-2H-1,3-
Examples include oxazin-2-one. Preferred among these compounds are, for example, 3-(2-thienylmethyl)-2-oxazolidinone, 3-[2-(2-thienyl)ethyl]-2-oxazolidinone, 5-bromo-3-
[2-thienyl)ethyl]-2-oxazolidinone, 4-isopropyl-3-[2-(2-thienyl)ethyl]-2-oxazolidinone, 3-(2-
thienylmethyl)tetrahydro-2H-1,3-
Examples include oxazin-2-one, 3-[2-(2-thienyl)ethyl]tetrahydro-2H-1,3-oxazin-2-one, and the like. The compound of general formula (1) of the present invention is a novel compound that has not been described in any literature, and is useful as an agent for treating ulcers in mammals including humans. The anti-inflammatory action of the compound of general formula (1) of the present invention is clearly demonstrated by the effect of suppressing the development of experimental ulcers using various experimental animals, and in particular against the expression of ulcers in aspirin-loaded pylorus-ligated rats.
50% at a dose of several mg to 100-odd mg per kg of body weight
It shows a certain degree of suppressive effect. Therefore, the general formula (1) of the present invention
The compound is extremely useful as a drug for the prevention and treatment of gastric and duodenal ulcers in mammals including humans. The content of the present invention will be explained in more detail with reference to the following reference examples and examples. Note that the melting points and boiling points of the compounds in each Reference Example and Examples are uncorrected. Reference Example 1 25.0 g of 2-thiophenecarboxylic acid and 56.7 ml of thionyl chloride were heated under reflux for 1 hour in 200 ml of benzene, and then concentrated under reduced pressure to obtain 2-thiophenecarbonyl chloride as an oil. 3-amino-1
−16.1g of propanol, 100ml of dioxane and water
Dissolved in 100ml of mixed solution, 49.1g of sodium bicarbonate
was added, and while stirring at room temperature, a solution of 2-thiophenecarbonyl chloride in 100 ml of anhydrous dioxane was added dropwise, and the mixture was allowed to react for 2 hours.
The reaction solution was concentrated under reduced pressure, the residue was extracted with methylene chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the oily N-(3-
25.5 g of (hydroxypropyl)-2-thiophenecarboxamide was obtained. Infrared absorption spectrum (liquid film) 3300cm ^-1 , 1620cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 1.6-2.0 (2H, m), 3.4-3.9 (5H, m), 6.9-7.6 (4H, m) 58.1 g of sodium borohydride was suspended in 300 ml of tetrahydrofuran, and while stirring under ice cooling, a solution of 82.3 g of acetic acid dissolved in 450 ml of tetrahydrofuran was added dropwise, and the mixture was allowed to react at room temperature for 1 hour. While stirring the reaction solution under ice-cooling, add N-
A solution of 25.4 g of (3-hydroxypropyl)-2-thiophenecarboxamide dissolved in 450 ml of tetrahydrofuran was added dropwise, and the mixture was heated under reflux for 1.5 hours. While stirring the reaction solution under ice cooling, a solution prepared by dissolving 100 g of sodium hydroxide in 500 ml of water was gradually added, and the mixture was concentrated under reduced pressure. Next, 100g of sodium hydroxide, 300ml of water and 500ml of ethanol
was added and heated under reflux for 14 hours. The reaction solution was concentrated under reduced pressure, the residue was extracted with methylene chloride, and then dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was distilled under reduced pressure to determine the boiling point.
13.8 g of 3-(2-thienylmethylamino)-1-propanol was obtained at 108-118°C/3 Torr. Elemental analysis value (as C ₈ H ₁₃ NOS) C% H% N% Calculated value 56.10 7.65 8.18 Actual value 56.20 7.87 8.37 Infrared absorption spectrum (liquid film) 3300cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 1.72 (2H, quint), 2.87 (2H, t), 3.10 (2H, s), 3.77 (2H, t), 3.98 (2H, s), 6.8~7.3 (3H, m) Reference example 2 Using the corresponding raw materials By performing substantially the same operation as in Reference Example 1, the following compound could be produced.

【table】

[Table] Reference Example 3 Dissolve 21.9 g of DL-Norvaline in a mixture of 190 ml of 1N aqueous sodium hydroxide solution and 200 ml of dioxane, and while stirring under ice-cooling, mix with a solution of 20.0 g of 2-thienylacetyl chloride dissolved in 50 ml of anhydrous dioxane. , 125 ml of 1N aqueous sodium hydroxide solution was added dropwise, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and hydrochloric acid was added to adjust the pH to 1.
The precipitated crystals were collected by filtration, washed with water, dissolved in ethyl acetate by heating, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from ethylbenzene acetate to give a melting point of 140-143.
N-(2-thienylacetyl)norvaline at °C
Obtained 27.6g. Elemental analysis value (as C ₁₁ H ₁₅ NO ₃ S) C% H% N% Calculated value 54.75 6.27 5.80 Actual value 55.01 6.31 5.85 Infrared absorption spectrum (KBr) 3350cm ^-1 , 1720cm ^-1 , 1600cm ^-1 Nuclear magnetic resonance spectrum (90MHz, _d6 -DMSO) δ: 1.85 (3H, t), 1.1~1.8 (4H, m), 3.73 (2H, s), 4.0~4.4 (1H, m), 6.85~7.4 (3H, m) , 8.30 (1H, d) 23.7 g of lithium aluminum hydride was suspended in 800 ml of tetrahydrofuran, 30.6 g of concentrated sulfuric acid was added dropwise while stirring under ice cooling, and the mixture was allowed to react for 4 hours. While stirring the reaction solution under ice-cooling, add N-(2-thienylacetyl)norvaline.
A solution of 27.5 g dissolved in 200 ml of tetrahydrofuran was added dropwise, and the mixture was reacted at room temperature for 17 hours and then heated under reflux for 1 hour. After 200 ml of a 5% aqueous sodium hydroxide solution was added dropwise to the reaction solution while stirring under ice-cooling, the solid was filtered off, water was added to the filtrate, and the mixture was concentrated under reduced pressure. The residue was extracted with methylene chloride,
After washing with water, it was dried over anhydrous magnesium sulfate.
After distilling off the solvent under reduced pressure, the residue was distilled under reduced pressure to obtain 13.4 g of 2-[2-(2-thienyl)ethylamino]-1-pentanol with a boiling point of 108-110°C/2 Torr.
I got it. Elemental analysis value (as C ₁₁ H ₁₉ NOS) C% H% N% Calculated value 61.93 8.98 6.57 Actual value 61.60 9.01 6.53 Infrared absorption spectrum (liquid film) 3300cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 0.7 ~1.05 (3H, m), 1.05 ~ 1.5 (4H, m), 2.14 (2H, s), 2.45 ~ 3.1 (5H, m), 3.26 (1H, dd), 3.59 (1H, dd), 6.7 ~ 7.15 (3H, m) Reference Example 4 The following compound could be produced by performing substantially the same operation as in Reference Example 3 using the corresponding raw materials.

【table】

[Table] Reference Example 5 Dissolve 7.76 g of 2-(2-aminoethyl)thiophene in a mixture of 100 ml of dioxane and 100 ml of water, add 10.3 g of sodium hydrogen carbonate, and while stirring under ice cooling, dissolve 2-ethoxycarbonylbutyryl chloride. A solution of 10.9 g dissolved in 30 ml of anhydrous dioxane was added dropwise, and the mixture was allowed to react at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 15.2 g of ethyl 2-[2-(2-thienyl)ethylcarbamoyl]butyrate having a melting point of 46 to 47°C as residual crystals. Infrared absorption spectrum (KBr) 3300cm ^-1 , 1735cm ^-1 , 1640cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 0.88 (3H, t), 1.20 (3H, t), 1.87 (2H, quint), 3.04 (2H, t), 3.13 (1H, t), 3.56 (2H, q), 4.20 (2H, q), 6.7~7.2 (4H, m) Suspend 10.6 g of lithium aluminum hydride in 500 ml of diethyl ether. 13.7 g of concentrated sulfuric acid was added dropwise while stirring under ice cooling, and the mixture was allowed to react for 1 hour. While stirring the reaction solution under ice-cooling,
2-[2-(2-thienyl)ethylcarbamoyl]
A solution of 15.1 g of ethyl butyrate dissolved in 50 ml of diethyl ether was added dropwise, and the mixture was allowed to react at room temperature for 17 hours. Water-containing diethyl ether, water, and an aqueous sodium hydroxide solution were sequentially added dropwise to the reaction solution, and then insoluble materials were filtered off and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was distilled under reduced pressure to obtain 2-[2-(2-thienyl)ethylaminomethyl]-1-butanol with a boiling point of 128-130°C/2 Torr.
Obtained 8.3g. Elemental analysis value (as C ₁₁ H ₁₉ NOS) C% H% N% Calculated value 61.93 8.98 6.57 Actual value 61.90 9.22 6.41 Infrared absorption spectrum (liquid film) 3290cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 0.8 ~1.9 (6H, m), 2.5 ~ 4.0 (10H, m), 6.8 ~ 7.3 (3H, m) Reference example 6 Add 70 ml of benzene to 5.0 g of 3-thiophenecarbaldehyde and 3.35 g of 3-amino-1-propanol. In addition, the mixture was heated under reflux for 19 hours while removing water from the reflux liquid using molecular sieves. After cooling, activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure to obtain 3-(3-tenylideneamino) as an oil.
7.5 g of -1-propanol was obtained. Infrared absorption spectrum (liquid film) 3300cm ^-1 , 1635cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 1.96 (2H, quint), 2.98 (1H, s), 3.7-4.1 (4H, m), 7.1 ~7.7 (3H, m), 8.32 (1H, s) Dissolve 7.4 g of 3-(3-tenylideneamino)-1-propanol in 50 ml of ethanol, and add 3.4 g of sodium borohydride while stirring under ice cooling. Thereafter, the mixture was allowed to react at room temperature for 20 hours. The reaction solution was acidified by gradually adding concentrated hydrochloric acid, concentrated under reduced pressure, and the residue was made alkaline by adding 10% aqueous sodium hydroxide solution, followed by extraction with methylene chloride. After washing the extract with brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain a boiling point of 106-108℃/
3-(3-thienylmethylamino)-1- at 1Torr
4.2 g of propanol was obtained. Elemental analysis value (as C ₈ H ₁₃ NOS) C% H% N% Calculated value 56.10 7.65 8.18 Actual value 56.26 7.77 8.09 Infrared absorption spectrum (liquid film) 3300cm ^-1 nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 1.66 (2H, quint), 2.85 (2H, t), 3.08 (2H, s), 3.7-3.9 (4H, m), 6.9-7.4 (3H, m) Reference example 7 2-acetylthiophene 6.3g, 3- Amino-1
-Propanol 7.5g, p-toluenesulfonic acid
A mixture of 1.0 g and 150 ml of toluene was reacted and treated in the same manner as in Reference Example 6 to obtain 3-[1-
9.1 g of (2-thienyl)ethylideneamino]-1-propanol was obtained. Infrared absorption spectrum (liquid film) 3350cm ^-1 , 1620cm ^-1 3-[1-(2-thienyl)ethylideneamino]
9.0 g of -1-propanol was reacted and treated in the same manner as in Reference Example 6 to obtain 8.3 g of 3-[1-(2-thienyl)ethylamino]-1-propanol as an oil. Infrared absorption spectrum (liquid film) 3280 cm ^-1 Reference Example 8 A mixture of 5.0 g of 2-thiophenecarbaldehyde, 6.74 g of 2-amino-3-phenyl-1-propanol, and 100 ml of benzene was reacted and treated in the same manner as in Reference Example 6. and as an oil, 3-phenyl-2-
(2-tenylideneamino)-1-propanol
Obtained 10.9g. Infrared absorption spectrum (liquid film) 3370cm ^-1 , 1630cm ^-1 3-phenyl-2-(2-tenylideneamino)-
10.8 g of 1-propanol was reacted in the same manner as in Reference Example 6 to form 3-propanol as a hydrochloride with a melting point of 122.5-124°C.
Phenyl-2-(2-thienylmethylamino)-1
-10.7 g of propanol hydrochloride were obtained. Infrared absorption spectrum (KBr) 3300cm ^-1 Example 1 Dissolve 13.8g of 3-(2-thienylmethylamino)-1-propanol in a mixture of 100ml of dioxane and 100ml of water, add 9.5g of sodium hydrogen carbonate, and stir at room temperature. 12.3g of chloroethyl carbonate
A solution prepared by dissolving . After the reaction solution was concentrated under reduced pressure, the residue was extracted with diethyl ether, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the oily N-(3-
19.3 g of ethyl (hydroxypropyl)-N-(2-thienylmethyl)carbamate was obtained. Infrared absorption spectrum (liquid film) 3450cm ^-1 , 1680cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 1.30 (3H, t), 1.5-1.9 (2H, m), 2.92 (1H, s), 3.3 ~3.7 (4H, m), 4.25 (2H, q), 4.68 (2H, s), 6.8 ~ 7.3 (3H, m) Ethyl N-(3-hydroxypropyl)-N-(2-thienylmethyl)carbamate 19.2 g and 0.6 g of sodium methylate were heated under reflux for 4 hours in 300 ml of toluene. After cooling, the reaction solution was treated with activated carbon, concentrated under reduced pressure, and the residue was dissolved in benzene.
Recrystallized from hexane with a melting point of 57.5-58.5℃
(2-thienylmethyl)tetrahydro-2H-1,
7.4 g of 3-oxazin-2-one was obtained. Elemental analysis value (as C ₉ H ₁₁ NO ₂ S) C% H% N% Calculated value 54.80 5.62 7.10 Actual value 54.89 5.71 7.17 Infrared absorption spectrum (KBr) 1690cm ^-1 Nuclear magnetic resonance spectrum (90MHz, d ₆ -DMSO) δ: 1.7-2.1 (2H, m), 3.28 (2H, t), 4.18 (2H, t), 4.60 (2H, s), 6.9-7.5 (3H, m) Example 2 1-[2-(2 -thienyl)ethylamino]-2
-9.6 g of propanol and 10.9 g of N,N'-carbonyldiimidazole were stirred in 150 ml of anhydrous benzene at room temperature for 16 hours. After the precipitated crystals were filtered off, the filtrate was washed successively with water, dilute hydrochloric acid, water, an aqueous sodium bicarbonate solution, and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from diethyl ether-hexane.
8.4 g of 5-methyl-3-[2-(2-thienyl)ethyl]-2-oxazolidinone with a melting point of 35-38°C was obtained. Elemental analysis value (as C ₁₀ H ₁₃ NO ₂ S) C% H% N% Calculated value 56.85 6.20 6.63 Actual value 57.02 6.16 6.75 Infrared absorption spectrum (KBr) 1730cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 1.40 (3H, d), 2.9-3.3 (3H, m), 3.4-3.7 (3H, m), 4.4-4.8 (1H, m), 6.8-7.3 (3H, m) Example 3 2-oxazolidinone 2.24g and potassium carbonate
4.85g to 50ml of anhydrous N,N-dimethylformamide
After stirring at room temperature, add a solution of 3.10 g of 2-chloromethylthiophene dissolved in 20 ml of anhydrous N,N-dimethylformamide.
The reaction was carried out at 100°C for 17 hours. After the reaction solution was concentrated under reduced pressure, the residue was extracted with methylene chloride, washed with water, and then dried over anhydrous magnesium sulfate.
After distilling off the solvent under reduced pressure, remove the residual oil.
Obtained 1.94g. This oily substance was purified by silica gel column chromatography (eluent: ethyl acetate-benzene) and then recrystallized from benzene-hexane. 3-(2-thienylmethyl)-2-oxazolidinone with a melting point of 58.5-59.5°C 0.44 I got g. Elemental analysis value (as C ₈ H ₉ NO ₂ S) C% H% N% Calculated value 52.44 4.95 7.65 Actual value 52.39 4.92 7.66 Infrared absorption spectrum (KBr) 1735cm ^-1 Nuclear magnetic resonance spectrum (90MHz, d ₆ -DMSO) δ: 3.3-3.7 (2H, m), 4.2-4.4 (2H, m), 4.59 (2H, s), 6.9-7.6 (3H, m) Example 4 3-(2-thienylmethyl)tetrahydro-2H
-1,3-oxazin-2-one 3.0g and acetic anhydride
1.79 g, 3.0 g of acetic acid, and 31.5 g of boron trifluoride ethyl ether complex salt were added, and the mixture was stirred at room temperature for 5 hours.
The reaction solution was poured into water, neutralized with sodium bicarbonate, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from benzene-hexane to give 3-(5-acetyl-2-thienylmethyl)tetrahydro-
2.8 g of 2H-1,3-oxazin-2-one was obtained. Elemental analysis value (as C ₁₁ H ₁₃ NO ₃ S) C% H% N% Calculated value 55.21 5.48 5.85 Actual value 55.19 5.40 6.00 Infrared absorption spectrum (KBr) 1670cm ^-1 , 1655cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 1.9~2.5 (2H, m), 2.62 (3H, s), 3.49 (2H, t), 4.40 (2H, t), 4.82 (2H, s), 7.18 (1H, d), 7.67 ( 1H, d) Example 5 3-(2-thienylmethyl)tetrahydro-2H
-1,3-oxazin-2-one 3.0g in acetic acid 60ml
A solution of 2.45 g of bromine dissolved in 10 ml of acetic acid was added dropwise while stirring under ice-cooling, and the mixture was allowed to react at room temperature for 5 minutes. The reaction solution was poured into water, extracted with chloroform, washed with water, and then
It was dried with anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from methylene chloride-hexane to give 3-(5-bromo-2-thienylmethyl)tetrahydro-2H- with a melting point of 95-96°C.
3.3 g of 1,3-oxazin-2-one was obtained. Elemental analysis value (as C ₉ H ₁₀ NO ₂ BrS) C% H% N% Calculated value 39.14 3.65 5.07 Actual value 39.29 3.59 4.99 Infrared absorption spectrum (KBr) 1685cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 1.9-2.3 (2H, m), 3.38 (2H, t), 4.29 (2H, t), 4.60 (2H, s), 6.87 (1H, d), 7.00 (1H, d) Example 6 Corresponding raw materials The following compounds were able to be produced by using substantially the same procedure as in each of the above Examples.

【table】

【table】

【table】

Claims (1)

[Claims] 1. General formula (R ¹ in the formula is a hydrogen atom, a halogen atom, or an acyl group, and R ² and R ³ are each a hydrogen atom,
A thiophene derivative represented by a lower alkyl group, an aryl group, or an aralkyl group, Y is alkylene, and n is 2 or 3. 2. The thiophene derivative according to claim 1, wherein n is 2. 3. The thiophene derivative according to claim 1, wherein n is 3. 4 General formula (R ¹ in the formula is a hydrogen atom, a halogen atom, or an acyl group, and R ² and R ³ are each a hydrogen atom,
a lower alkyl group, an aryl group, or an aralkyl group, Y is alkylene, and n is 2 or 3), and a thiophene amino alcohol derivative represented by the general formula A general formula characterized by reacting with a carbonyl compound represented by (X in the formula is a chlorine atom or a 1-imidazolyl group) A method for producing a thiophene derivative represented by the formula (R ¹ , R ² , R ³ , Y and n have the same meanings as above). 5 General formula (R ¹ in the formula is a hydrogen atom, a halogen atom, or an acyl group, and R ² and R ³ are each a hydrogen atom,
is a lower alkyl group, an aryl group, or an aralkyl group, Y is alkylene, and n is 2 or ³ ). or a lower alkoxyl group, and R ⁴ is a lower alkyl group) to form a compound represented by the general formula (In the formula, R ¹ , R ² , R ³ , R ⁴ , Y and n have the same meanings as above) is prepared and then ring-closed by heating. A method for producing a thiophene derivative represented by the formula (R ¹ , R ² , R ³ , Y and n have the same meanings as above). 6 General formula (In the formula, R ¹ is a hydrogen atom, a halogen atom, or an acyl group, Y is an alkylene, and A is an acid residue) and a thiophene derivative represented by the general formula (In the formula, R ² and R ³ are each a hydrogen atom, a lower alkyl group, an aryl group, or an aralkyl group, and n is 2 or 3.) formula A method for producing a thiophene derivative represented by the formula (R ¹ , R ² , R ³ , Y and n have the same meanings as above).