JPS606686A - Thiophene derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R1 is H, halogen, or lower acyl; Y is alkylene; R2 is H, or lower alkyl; X is simple bond, O, methylene, or alkylidene). EXAMPLE:N-[2-(2-Thienyl)ethyl]succinic acid imide. USE:A remedy and preventive for an ulcer such as gastric ulcer, doudenal ulcer, etc. PREPARATION:An aminoalkylthiophene derivative[e.g., 2-(2-aminoethyl)thiophene, etc.] shown by the formula II is reacted with a cyclic acid anhydride (e.g., succinic anhydride, etc.) shown by the formula III preferably in an inert solvent such as xylene, etc. under reflux by heating for 10-40hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel thiophene derivatives. More specifically, compounds useful as anti-inflammatory agents of the general formula (in the formula, lmo is a hydrogen atom, a halogen atom, or a lower acyl group, Y is an alkylene, and FuQ is a hydrogen atom or a lower alkyl group) and X is a simple bond, an oxygen atom, methylene or alkylidene) and a method for producing the same.

The compound represented by the general formula (1) of the present invention is a new compound that has not been described in any literature, and it exhibits a remarkable anti-inflammatory effect in mammals including humans, and can be used as a drug for the treatment and prevention of gastric and duodenal cancer. It is an extremely useful compound.

The present invention thus provides thiophene derivatives useful as pharmaceuticals, and also provides a method for producing the same.

In the VC8 of the present invention, the five halogen atoms are a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. A lower alkyl group is a saturated hydrocarbon group having 1 to 6 carbon atoms, and when it has 3 or more carbon atoms, it may be branched n-shaped or cyclic. A lower acyl group is an acyl group having 2 to 8 carbon atoms, and when it has 4 or more carbon atoms, it may be branched or cyclic. Alkylene is a saturated hydrocarbon chain having 1 to 8 carbon atoms, and when the number of carbon atoms is 2 or more, it may have a branch ny. An alkylidene is a methylane in which one hydrogen atom is replaced by a lower alkyl group. with acid residues.

is a residue of an inorganic or organic acid such as a chlorine atom, a bromine atom, an iodine atom, a benzenesulfonyloxy group or a p-toluenesulfonyloxy group.

The anti-alcoholic action of the thiophene derivative represented by the general formula (1) of the present invention varies depending on the bonding position and length of the alkylene, the type and size of the cyclic imide, etc. The bonding position of the alkylene is preferably the 2-position of the thiophene ring, and the length of the alkylene is preferably such that the chain connecting both cyclic compounds has 2 or 3 carbon atoms. Regarding cyclic imides, 5-membered ring succinimide derivatives tend to be somewhat stronger in both activity and toxicity than 6-membered ring diglyconylic imide or glutaric acid imide derivatives.

As the compound of general formula (1) of the present invention, for example, N-(2
-thenylmethyl)succinimide, N-[2-(2-
chenyl)ethylsuccinic acid ibad, N-[2-(3-
chenyl)ethylsuccinimide, N-[3-(2-
Chenyl]propyl]succinimide, 2-ethyl-N
,,L (2-(2-chenyl)ethylsuccinimide)", 2-methyl-N-(2-(2-chenyl)ethylsuccinimide, N-[2-(5-acetyl-2-chenyl]ethyl) ]Amber 51i <l”'b N-[2
-(5-7'rom-2-chenyl)ethylsuccinimide, N-[2-(2-chenyl)ethyl]glutarimide, 3-methyl-N-(2-(2-chenyl)ethyl]glutarihe)' , N-(2-f enylmethyl)
Examples include diglycolimide, N-[2-(2-chenyl)ethyl]diglycolimide, among which N-[2-(2-chenyl)ethyl anosuccinimide)', N -[3-(2-chenyl)furovir]succinimide, 2-ethyl-N-(2-(2-chenyl)ethylsuccinimide, 3-methyl-N-[2
-(2-chenyl)ethyl]glutarimide, N-[2
-(2-chenyl)ethylcocylicolimide.
is preferred.

The compound represented by the general formula (1) of the present invention is, for example,
An aminoalkylthiophene derivative represented by the general formula (in which It group and Y have the same meanings as above) and an aminoalkylthiophene derivative represented by the general formula (1 (in the formula, g and X have the same meanings as above)) It can be produced by reacting a cyclic acid anhydride with a cyclic acid anhydride.In this reaction Kj6, a compound of general formula (2) and a compound of general formula (3) are heated in an inert solvent such as xylene for 10 to 40 hours. By refluxing 1
The target compound can be obtained in the process. This method has the advantage of simplicity or ease of reaction and processing. Further, the compound of general formula (2) and the compound of general formula (3) are reacted in an inert solvent, for example, methylene chloride at room temperature, and the general formula (kite, R8, xg and Y in the formula have the same meanings as above) is prepared. (However, melon may be substituted at either the carboxyl group or the methylene to which the amide group is bonded) is prepared, and then this compound is dissolved in an inert solvent such as xylene. Middle l
The target product M can also be produced by heating and refluxing for 40 hours. This method is advantageous in terms of the purity of the final target product, since purification can be performed intermediately.

General formula (2) used as a raw material in this production method
The aminoalkylthiophene derivative is a known compound and can be easily produced by a known method. Such compounds include 2-aminomethylthiophene, 2-(2-aminoethyl)thiophene, 2-(3-aminopropyl)thiophene, 3=(2-aminoethyl)
Thiophene, 5-acetyl-2-(2-aminoethylfuthiophene, 2-(2-7minoethyl)-5-bromothiophene, etc.). ] The cyclic acid anhydride is also a known compound and can be produced by a known method.

Such compounds include succinic anhydride, methyl succinic anhydride, ethyl succinic anhydride, glutaric anhydride, 3-
Examples include methylglutaric anhydride and diglycolic anhydride.

The compound represented by the general formula (1) of the present invention further includes a compound represented by the general formula (in which UltO and Y have the same meanings as above, and A is an acid residue), A cyclic imide derivative represented by the general formula (in which R, g and X have the same meanings as above, and M is a hydrogen atom or an alkali metal) is reacted in the presence or absence of a basic substance. It can also be manufactured by For example, the general formula (
5) and a compound of general formula (6) in which M is a hydrogen atom are mixed in an inert solvent such as dimethylformamide in the presence of a basic substance such as potassium carbonate for 50 to
Alternatively, the compound of general formula (5) and the compound of general formula (6) in which M is an alkali metal, for example a potassium atom, are dissolved in an inert solvent, for example dimethyl 50 in formamide
The target compound can be produced by heating at ~120°C for 10 to 20 hours. The compounds of general formula (5) and general formula (6) used as raw materials in this production method are both known compounds and can be easily produced by known methods.

Compounds of the general formula (1) of the present invention in which ⇠ and ① are hydrogen atoms or lower sil groups can be prepared by adding a halogen atom to a compound of the general formula (1) in which ① is a hydrogen atom by a conventional method. It can also be produced by substitution or acyl substitution. For example, in the compound of general formula (1)
-t is a hydrogen atom in an inert solvent, for example, aqueous acetic acid, with 11 equivalent moles to a slight excess mole of bromine and 0 to 3
By reacting at 0° C., it is possible to produce a compound of general formula (1) in which the melon is a bromine atom. Alternatively, a compound of general formula (1) in which the cucumber is a hydrogen atom is added in an inert solvent, such as an acetic acid-chloroform mixed solvent, in the presence of a Lewis acid, such as boron trifluoride ether complex salt, in an equimolar to excess molar amount. By reacting with acetic anhydride at 0 to 30°C, the compound of general formula (1) is
Compounds in which is an acetyl group can be produced.

In order to suitably carry out the production method of the present invention, general formula (2)
An aminoalkylthiophene derivative represented by the formula (3) and an equimolar amount of the cyclic acid anhydride represented by the general formula (3) are heated under reflux for 1 to 40 hours in an inert solvent such as xylene. Concentrate the liquid under reduced pressure, dissolve the residue in a suitable organic solvent such as methylene chloride, wash successively with dilute hydrochloric acid, water, an aqueous solution of hydrogen carbonate 2 and water, dry over anhydrous magnesium sulfate, and remove the solvent. is distilled off under reduced pressure, and the residue is purified by an appropriate method to obtain the desired product.Alternatively, an aminoalkylthiophene derivative represented by general formula (2) and an equimolar amount of the aminoalkylthiophene derivative represented by general formula (3) are combined. The cyclic acid anhydride represented by the formula (4) is mixed with the cyclic acid anhydride represented by the general formula (4) in an inert solvent such as methylene chloride at room temperature for several hours. An amide carboxylic acid derivative is obtained. This is heated under reflux for 10 to 40 hours in a suitable inert solvent, such as xylene, and treated in the same manner as above to obtain the desired product.

Alternatively, a thiophene derivative represented by the general formula (5) and an equimolar amount of the cyclic imide derivative represented by the general formula (6) may be mixed in an inert solvent such as dimethylformamide at 50 to 120°C for 10 minutes. Heat for ~20 hours. At this time, when using a compound of general formula (6) in which M is a hydrogen atom, the reaction is carried out in the presence of a slightly excess basic substance, such as potassium carbonate, than the required amount. After the reaction is complete, the solvent is distilled off under reduced pressure, and a suitable solvent such as methylene chloride is added to the residue. After washing with water and drying, the solvent is distilled off under reduced pressure. The residue is purified by an appropriate method to obtain the desired product. get.

The compound represented by the general formula (1) of the present invention is a novel compound that has not been described in any literature, and exhibits a specific inhibitory effect on the occurrence of experimental calligrade in various animals. Particularly, it exhibits a suppressive effect of 50% on the expression of S in pylorus-ligated rats loaded with aspirin at several to several tens of thousands of days per body weight. Therefore, the compound represented by the general formula (1) of the present invention is extremely useful for the prevention and treatment of gastric and duodenal ulcers in mammals including humans. The present invention thus provides a novel thiophene derivative useful as a pharmaceutical, and also provides a method for producing the same.

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 Reference Examples and Examples are all uncorrected.

Reference Example Diethyl ethylideneconozoate 18.3. 150% of ethanol was added to 0.31% of 19% palladium on carbon, and hydrogen was added at normal pressure and room temperature. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain an oily product of diethyl ethylconolate 129
I got %.

Infrared absorption spectrum (liquid film): 17: (Ocm-” Nuclear magnetic resonance spectrum (90MHz, C1) C1,)
δ: 0.91 (3H, t), 1. n ~1.8 (81
-1, m) 12.3 to 2.9 (3H, m) * 4
．． 0-4.3 (4H,m) diethyl ethylsuccinate 12. Oy and 10y of sodium hydroxide to 50y of ethanol
It was dissolved in a mixture of - and 50 - of water and stirred at room temperature for 16 hours. . The reaction solution was made acidic with hydrochloric acid and then concentrated under reduced pressure. After dissolving the residue in acetone and filtering off insoluble matter, the filtrate was concentrated under reduced pressure to obtain 8.51 ethylconozoic acid with a melting point of 95-96°C.

Infrared absorption spectrum (KBr): 1710 crn-” nuclear magnetic resonance spectrum h (90 MHz, d, -1)
MS(J)δ: 0.86(3H,t)) 1. O~
1.8(2t(,m).

2.2-2.7 (3H, m) Ethylsuccinic acid 5.0. The mixture was heated under reflux for 1 hour in 910 ml of anhydrous vinegar. After concentrating the reaction solution under reduced pressure, the residual oil was distilled under reduced pressure to obtain a boiling point of 106-107°C/7'
J'orr's ethyl amber anhydride rljl 3.1 y
'l got it.

-Infrared absorption spectrum (liquid film): 1860crn-”, 1780crI!”Nuclear magnetic resonance,
X Heta)h (90MHz, CDCl, )δ
: 1.07(3H,t), 1.3=2.3(2H,m
).

2.5 S-3,4(:UH,m) Example 1 2-(2-"minoethyl)thiophene 5.01 and anhydrous amber #4, Oy'l"F'/L/7150
The mixture was heated to reflux in 11 J for 12 hours. After the reaction solution was concentrated under reduced pressure, the remaining crystals were dissolved in methylene chloride, washed successively with dilute acid, water, aqueous sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the remaining crystals were recrystallized from benzene to give N-(2-(2-4enyl)ethyl]cono-1 acid 4-mi)'3.81 with a melting point of 138-140°C. Obtained.

Elemental analysis value (C engineering.H1□No.8) 0% Hchi Nchi calculated value 57,39 5.30 6.69 Actual value 57
,54 5,19 6.67 Infrared absorption spectrum (K
Br): 1765 crn-', 17(10 crn-') Nuclear magnetic resonance spectrum (90 MHz, CDCl, ) δ: 2.
67 (4H, s), 3.14 (2H, t).

3.80 (2H, t), 6.8-7.2 (3H,
m) Example 2 6.8 ff of 2-(2-aminoethyl)thiophene and 6.11 ff of tomethylsuccinic anhydride were mixed with 150 IIll of methylene chloride.
After stirring for 17 hours at room temperature, add hydrogen carbonate)
Extracted with IJum aqueous solution. The aqueous layer was acidified with hydrochloric acid, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 100 yttl fi of cylene was added to the residue, followed by heating under reflux for 39 hours. Thereafter, the reaction solution was washed with an aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the remaining crystals were recrystallized from diethyl ether-hexane, with a melting point of 31.5-3.
7.21 of 2-methyl-N-[2-(2-chenyl)ethylsuccinimide was obtained at 2°C.

Elemental analysis value (as C, □I-1..NO, S) 0%
H-chi N-chi Calculated value 59.17 5,87 6.27 Actual value 58
．． 95 5,87 6.20 Infrared absorption spectrum (K
Br): 1765crn-", 1700crn-" Nuclear magnetic resonance spectrum (, -90MHz, d, -DMSO) δ:
1.18 (3H, d), 2.1-3.2 (5H,
rn) s3', 62 (2Hlt) + 6.8~
7.4 (3Hlrn) Example 3 2-(2-aminoethyl)thiophene 6.00. and ethyl succinic anhydride 6.04yY xylene 1 in 100d
The mixture was heated under reflux for 6 hours. From now on, the reaction solution will be hydrogenated)
After washing with IJum aqueous solution 8 and water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residual oil was distilled under reduced pressure to give a boiling point of 140-141'c/IT.
orr of 2-ethyl-N-[2-(2-thenyl)ethyl]conophosphate imide 8.21 y'l 4.

Elemental analysis value (as Cyu, H, 6NO, 8) C section 11
Ch ~φ Calculated value 6.0,73 6.37, 5.90 Actual value 60,96 6.41 5.94 Infrared absorption spectrum (liquid film): 1780 crn-", 1700 cm-" Nuclear magnetic resonance spectrum (90 MHz, CDCl, )δ: '
0.8 3 (3H1t) + 1.0~2.9
(5H, rrr).

3, (16 (211, t), 3.71 (2 + 1. t)
+ 6.7-7.15 (3H, m) Example 4 3.51 succinic anhydride was suspended in 22 me of methylene chloride, and while stirring at room temperature, 3-(2-aminoethyl)thiophene 4. 5Li/, methylene chloride 22m
A solution dissolved in A' was added and reacted for 1.5 hours.

The precipitated crystals were collected by filtration and 3-( with a melting point of 125-127.5°C
7.71 of 2-(3-chenyl)ethylcarbamoyl]furopionic acid was obtained.

Elemental analysis value (as C□.HlsNO,S) 0% 8%
N coefficient calculated value 52,84 5.77 6.16 Actual value 52
．． 62 5,71 6.11 Infrared absorption spectrum (K
Br): 3300crn-", 1690crn-", 1640C
rn-'Nuclear Magnetic Resonance System (90MHz, d
, -DMS(J) δ: 2.1-2.5 (48, m)
, 2.72(2I-1,t).

3.1 to 3.5 (2H, m), 6.9 to 7.6
(31-1,rn) +7.92(]ratiobr)
+ 12,0 (1(I Fl, -br-s)3-[
2”-(3-chenyl)ethylcarleno(moyl)propion e 7.5 y?24 in xylene 85m/!
The mixture was heated to reflux for an hour. After xylene was distilled off under reduced pressure and the remaining crystals were purified by silica gel column chromatography (eluent: chloroform), they were recrystallized from benzene-hegisan to give N-[2-(3-
Ceni IL, ) Ethylsuccinimide 4.31 was obtained.

Elemental analysis value (as C□.H1□NO,8) 0% 8%
N% Calculated value 57.39 5.3 (L 6.69 Actual value 5
7.09 5.23 6.70 Infrared absorption spectrum (
KBr): 1760CIn-", 1690crn-" Nuclear magnetic resonance spectrum (90MHz, CDCl5) δ: 2.64
(4H, s), 2.95 (2H, t).

3.80 (2H,t), -6,9-7,4(3
H, m) Example 5 2-7minomethylthiophene 5.0f1. Anhydrous Kono 1
After stirring 4.41 g of phosphoric acid in 1'00 m/i of methylene chloride at room temperature for 17 hours, the mixture was extracted with an aqueous sodium bicarbonate solution. The aqueous layer was acidified with hydrochloric acid, extracted with methylene chloride, washed with water, and dried over anhydrous magnasium sulfate. The solvent was distilled off under reduced pressure to a melting point of 131.
Obtain 3-(2-thenylmethylcarbamoyl)propionic acid at 3°C.

Infrared absorption spectrum (KBr): 3325crn-1, 1700crn-1, 1650z
-”Nuclear magnetic resonance spectrum (90Ml-1z, d6
-0M8(J)δ: 2.2~2.6(41-1, m
), 4.43 (2 ratio d).

6.8-7.5 (3H, m), 8.42 (IH, t
).

11.98 (lH, br, s) 3-(2-thenylmethylcarbamoyl)propionic acid was heated to reflux in 200 mm of xylene for 15 hours.

After the reaction solution was concentrated under reduced pressure, the residue was dissolved in methylene chloride, washed with an aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the remaining crystals were recrystallized from benzene-hexane to obtain 3.61% of N-(2-chenylmethyl)conolimide having a melting point of 100 to 101°C.

Elemental analysis value (as C, H, NO8) Cchi H N% Calculated value 55.36 4.65 7.17 Actual value 55
,73 4,66 7.17 Infrared absorption spectrum (K
Br): 1770cfn-", 1695m-" Nuclear magnetic resonance spectrum (90MHz, d, -DMS
U) δ: 2.68 (4H, s), 4.70 (2H
, s), 6.8-7.5 (3H, m) Example 6 Succinimide 2.55 and potassium carbonate 4.85. of? 2-chloromethylthiophene 3.10.Y anhydrous N,N = dimethylformamide 2.
A solution containing 0 ml of VC was added, and the mixture was reacted at 100° C. for 17 hours. The reaction solution was concentrated under reduced pressure, diluted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate.

After distilling off the solvent under reduced pressure, distillate 93 crystals were recrystallized from chloroform-diethyl ether-hexane to give N-(2
-thenylmethyl)succinimide 2,87. I got Y.

The physical properties of this product showed that it was the same as the compound obtained in Example 5.

Example 7 2-(3-aminopropyl)thiophene5. Qy and anhydrous co-liquid 51d: (,5y, methylene chloride 100m
After stirring overnight at room temperature in a vacuum cleaner with hydrogen carbonate)
Extracted with IJum aqueous solution. The aqueous layer was made acidic with hydrochloric acid, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7.7 y of 3-[3-(2-chenyl)propylcarbamoyl]propionic acid having a melting point of 87 to 88°C.

Infrared absorption spectrum (KBr): 3320ffi-”, 1695crn-”, 1630m
-”Nuclear magnetic resonance spectrum (90MH7, CDCl,
, ) δ: 1.82 (2H, quinl, 2.3-3.
(1 (6H, m) + 3.25 (2H, q), 6.5
0 (IH,br,).

6.7-7.2 (3H, m), 11.45 (IH, 5
)3-(3-(2-chenyl)furobylcarbamoyl]
Propion! 7.6. Add 150ml of xylene to the
The mixture was heated to reflux for 13.5 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in methylene chloride and diluted with hydrogen carbonate)
After washing with an aqueous IJum solution and water, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the remaining crystals were recrystallized from benzene-hexane to give a melting point of 85~
N-[3-(2-chenyl)propyl]cono-
3.21 of phosphoric acid imide was obtained.

Elemental analysis value (C,, H,, NO, 8 and poor) Cchi 8%
N% Calculated value 59.17 5,87 6.27 Actual value 59
,27 5,96 6.27 Infrared absorption spectrum (K
Br): 1770crn-', 1695crn-' nuclear magnetic resonance spectrum A, (90MHz, C1)CI, )'δ
: 2. +10 (2H, quin), 2.62 (4H
,S)+2.88(211,t),3.61(2
H,t).

6.75-7.15 (317 m) Example 8 N-[2-(2-chenyl)ethyl]cono\phosphoric acid imide (3.01 parts), acetic acid (15 parts, e1, chloroform (10 parts), acetic anhydride (4.7z), and three Boron fluoride ethyl ether complex salt 7,8me was added and stirred at room temperature for 28 hours. Pour the reaction solution into water! After stirring for 1 hour, the mixture was extracted with chloroform. Chloroform layer? : 01% hydrochloric acid aqueous solution, hydrogen carbonate) After sequentially reading with IJum aqueous solution and saline, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the remaining crystals were recrystallized from benzene-hexane to give N-[2-(5-
Acetyl-2-chenyl)ethyl]cono-1 phosphate imide 3
．． I got 31.

Elemental analysis values (C1, Hl, N (J, S, C) 8
% N% Calculated value 57.35 5,21 5.57 Actual value 57
．． 24 5.16 5.36 Infrared absorption spectrum (K
Br): 1760crn-", 1690crn-", 1650z
-”Nuclear magnetic resonance spectrum (90MHz, CDCl,
) δ: 2.53 (3H, s), 2.73 (4H, s
).

3.19 (2H, t), 3.86 (28, t).

6.94 (II-1, d), 7.57 (IH, d) Example 9 Dissolve 3,15 ff of N-[:2-(2L4enyl]ethyl]succinimide in a mixture of 601 acetic acid and 2511 Ll of water. A solution of bromine 2.46f dissolved in acetic acid ]0- was added dropwise while stirring under water cooling.After reacting at room temperature for 5 minutes, the reaction solution was poured into water, extracted with methylene chloride,
After washing with water, it was dried with anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the remaining crystals were recrystallized from benzene-hexane and heated to a melting point of io at 111 °C.
-(5-bromo-2-chenyl)ethylsuccinimide 3,90. I got it.

Elemental analysis value (C8゜H□.N (as J, B r S)
0% 8% N% Calculated value 41.68 3,50 4.86 Actual value 41
．． 85 3,27 4.94 Infrared absorption spectrum (K
Br): 1760 cm-", 169.0 Crn-" Nuclear magnetic resonance spectrum (90 MHz, C1) CI, ) δ: 2
．． 58 (4H, s), 2.96 (2H, t) s3.67
(2H, t), 6.54 (IH, d).

6.80 (IH, d) Example 10 5.01 of 2-(2-aminoethyl)thiophene and 4.51 of glutaric anhydride were stirred in 150 mJ of methylene chloride at room temperature for 24 hours, and then mixed with an aqueous sodium hydrogen carbonate solution. Extracted with. The aqueous layer was made acidic with hydrochloric acid, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the melting point was 61S-63.
4-[2-(2-chenyl)ethylcarbamoyl) at °C
Butyric acid s, 3. I got it.

Infrared absorption spectrum (KBr): 3320crn-", 1700crn-", 1640c
rn-” nuclear magnetic resonance spectrum (90MHz, d,
-DMSO) δ: 1.5 to 1.9 (2H, m), 2.
0-2.35 (4H.

m) s 2-92 (2H1t) + 3.32
(2H1q) s6.7-7.4 (3H, m), 7.9
Add 150 mJ of xylene to 8.3 g of 0(IH,t)4-[2-(2-fenyl)ethylcarbamoyl]butyric acid,
The mixture was heated under reflux for 39 hours. Thereafter, the reaction solution was washed with aqueous sodium bicarbonate solution S and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the remaining crystals were recrystallized from benzene-hexane to a melting point of 82 to 83.
．． 2.71 of N-(2-(2-chenyl)ethyl)glutaride epsilon at 5°C was obtained.

Elemental analysis value (as C,, H,, NO, S) Cchi 8%
N% Calculated value 59.17 5,87 6.27 Actual value 59
．． 20 5,78 6.23 Infrared absorption spectrum (K
Br): 1710CrIT-1,1670crn-”Nuclear magnetic resonance spectrum (90MHz, d, -DMS(J)δ
: 1.82(21-1,quin), 2.60(4
H,t).

2.93 (214, t), 3.88 (2H, t) s6.
8 to 7.4 (3H, m) Example 11 2-(2-aminoethylfuthiophene 6.9Ft3-
6.9 ff of methyl glutaric anhydride to 150 ml of methylene chloride
The mixture was stirred in rnl at room temperature for 17 hours, and then extracted with an aqueous solution of sodium bicarbonate. The aqueous layer was made acidic with hydrochloric acid, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure to obtain an oily product of 3-methyl-4-C2.
-<2--t-enyl)ethylcarbamoyl]butyric acid 1
4. I got ly.

Infrared absorption spectrum (liquid film): 3300crn-", l 705crn-", 1620
crIT-” nuclear magnetic resonance spectrum (90MMz, C
1) CI, )δ: 1.02 (3H,d) *
2.1-2.5 (5H, m).

3.05 (2H, t), 3.56 (2H, q).

6.57 (IH, t), 6.75-7.2 (3H,
m).

11.05(IH,5) 3-Methyl-4-[2-(2-chenyl)ethylcarbamoyl) Butyrm 14. Add xylene 15 to Oy,
The mixture was heated under reflux for 24 hours. From now on, the reaction solution will be hydrogenated)
After washing with IJJum solution and water, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the remaining crystals were recrystallized from benzene-hexane to give a melting point of 61~
3-Methyl-N-(2-(2-chenyl)ethyl)kultarimide 4.11 was obtained at 62°C.

Elemental analysis value (as C8, HlllNO, 8) 0% H
Chi Nchi Calculated value 60.73 6,37 5.90 Actual value 60
,80 6.39 5.65 Infrared absorption spectrum (K
Br): 1725 crn-", 1670 cm-" nuclear magnetic resonance spectrum (90 MHz, d, -1) MSO) δ:
0.93 (3H, d), 2.00-3.05 (7H.

m), 3.85 (2H, t), 6.7-7.4 (3H.

m) Example 12 2-(2-aminoethyl)thiophene 3.88. and diglycolic anhydride 3.55. 1 in 150 ml of xylene
The mixture was heated under reflux for 7 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in methylene chloride, washed successively with dilute hydrochloric acid, water, an aqueous solution of hydrogen carbonate, and water, and then dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the remaining crystals were subjected to silica gel column chromatography (elution solvent, ethyl acetate: Hensen =
After purification using 1:1), the product was recrystallized from benzene-hexane to obtain 3.13 ff of N-[2-(2-chenyl)ethyl cocylicolimide with a melting point of 117 to 119°C.

Elemental analysis value (as C8°H8, NO, S) 0% 8%
N% Calculated value 53.32 4,92 6.22 Actual value 53
,60 4,89 6.21 Infrared absorption spectrum (K
Br): 1735crn-", 1680crn-" Nuclear magnetic resonance spectrum (90MHz, d, -DMEO) δ: 3
．． 02 (2H, t), 3.92 (2H, t).

4.40 (4H,,s), 6.85-7.45
(3H,m) Example 13 2-7minomethylthiophene 5.65. and diglycolic anhydride 5.80. xylene 150WLl! Inside, 16
The mixture was heated to reflux for an hour. After concentrating the reaction solution under reduced pressure,
The residue was dissolved in methylene chloride, washed successively with dilute hydrochloric acid, water, hydrogen carbonate solution, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The remaining crystals were purified by silica gel column chromatography (elution medium: ethyl acetate: benzene = 'l: 1), and then recrystallized from benzene-hexane, with a melting point of 10.
N-(2-chenylmethyl)diglycolimide at 2-104°C, 5. Ox, was obtained.

Elemental analysis value (c, rt, No, s to L -c)C Hchi Nchi Calculated value 51.17 4.29 6.63 Actual value 51
,19 4,33 6.80 Infrared absorption spectrum (K
Br): 1730 crn-", 1675 cm-" Nuclear magnetic resonance spectrum l' (90 MHz, C1) CI, ) δ:'
4.35 (4H9S) + 5.10 (2H, s).

(5,8~7.3 (3H, m) patent applicant Kissei Pharmaceutical Co., Ltd. (C07D 413106 265:00.

333:00) 0 shots Akio Kitazawa 945 Yoshiyo Hirata, Matsumoto City 0 shots: Ryoji Yamamoto 3703-4, Oaza Kanbayashi, Matsumoto City 0 Inventor Hiroshi Harada 103 Oaza Hara, Matsumoto City

Claims (1)

[Scope of Claims] 1) General formula (wherein is a hydrogen atom, a halogen atom, or a lower acyl group, Y is alkylene and il), H is a hydrogen atom or a lower alkyl group, and X is a simple thiophene derivatives represented by a bond, an oxygen atom, methylene or alkylidene). 2) An aminoalkylthiophene derivative represented by the general formula (in the formula, R1 is a hydrogen atom, a halogen atom, or a lower acyl group, and Y is an alkylene), and an aminoalkylthiophene derivative represented by the general formula (in the formula, R1 is a hydrogen atom or a lower alkyl group) is the basis,
X is a simple bond, an oxygen atom, methylene or alkylidene. A method for producing a thiophene derivative represented by 3) A compound represented by the general formula (in the formula, R□ is a hydrogen atom, a halogen atom excluded, or a lower acyl group, Y is an alkylene, and A is an acid residue) and a compound represented by the general formula (the formula lζ in it is a hydrogen atom or a lower alkyl group,
X is a simple bond, an oxygen atom, a methylene chain or an alkylidene, and M is a hydrogen atom or an alkali metal. , the general formula (
A method for producing a thiophene derivative represented by the formula (1, -1X and Y have the same meanings as above).