KR870000450B1 - Process for preparing aminoalkyl furan derivatives - Google Patents

Abstract

Aminoalkyl furan derivs. of formula (I) were prepd. by reacting a (II) with nitroethene derivs. of formula H2NC(NHCH3)= CHNO2 in acidic or neutral condition, treating with reductant (sodium borohydride). The rxn. media is polar organic solvents e.g. methyl alcohol, ethyl alcohol, isopropanol. Nitroethene esp. 1-amino-1-methylamino-2- nitroethene was obtd. from reacting CH3SC (NHCH3)=CHNO2 with ammonia water. (I) are useful for treatment of gastric ulcer and dyspepsia.

Description

Method for preparing amino alkyl furan derivative

The present invention relates to a novel process for preparing amino alkyl furan derivatives of the following formula (I), which are known to be effective therapeutic agents for gastric ulcers and peptic ulcers.

The present invention prepares an imine derivative of formula (II) by reacting an aldehyde derivative of formula (III) with a nitroethene derivative of formula (IV), and immediately treating the imine derivative of formula (II) with a reducing agent to separate the object of formula (I). To prepare a compound.

~120℃의 온도범위에서 무수 조건을 잘 진행된다.Preparation of the imine intermediate of the formula (II) from the compounds of the formulas (III) and (IV) is carried out using a solvent having a relatively high boiling point such as alcohols such as ethanol and butanol or toluene and forming azeotropic mixture with water. It is preferable to distill off the water produced as it progresses. In this case, the reaction is carried out in the presence of an acid catalyst such as hydrochloric acid, acetic acid and p-toluenesulfonic acid.

In the temperature range of ~ 120 ℃ well proceeds anhydrous conditions.

The desired compound of formula (I) can be prepared from an intermediate of formula (II) prepared using an optional reducing agent such as sodium borohydride, potassium borohydride, cyanoborohydride and the like. The reaction proceeds well selectively in neutral to acidic conditions in polar organic solvents such as methanol, ethanol and isopropane.

The compound of formula (I) obtained by the novel production process of the present invention may be in free base form or may be separated into stable acid addition salts such as hydrochloride salts by conventional methods.

The 1-amino-1-methylamino-2-nitroethene of formula (IV) can be readily prepared using ammonia from known compounds containing suitable leaving groups such as methylthio.

The aldehyde derivative of formula (III), a new intermediate compound of the present invention, may be prepared by selective oxidation from an alcohol derivative of formula (VII), as shown in the following scheme, and contains a thiol group of formula (VI) Furan derivatives can be prepared by reacting with 2-halogenated ethanol.

Structural formula (V) and (VI) compounds used as starting materials are known compounds, which are easily prepared from 5- (dimethylamino) methyl-2-furanmethanol by British Patent No. 2075980, usually hydrochloride, hydrobromide, It is used as a stable acid addition salt such as oxalate.

The reaction for preparing the intermediate compound of formula (VII) using thioglycol is carried out in the presence of an inorganic acid such as hydrochloric acid from the perfuryl alcohol derivative of formula (V, R ₁ = OH).

Here, R ₁ = OH or a halogen atom such as Cl, Br

Here, R ₁ = OH or a halogen atom such as Cl, Br

It usually proceeds well at room temperature with water as a solvent, or from acid addition salts of halogen compounds of the formula (V) (R ₁ = C1 or Br), such as water, alcohols or mixed solvents such as It may be optionally carried out at a low temperature, preferably below room temperature, in the presence of a general inorganic base.

The reaction for preparing the intermediate compound of formula (VII) using 2-chloroethanol or 2-bromoethanol from the compound of formula (VI) is usually an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine. In the presence of organic bases, such as, it proceeds well in neutral to weak alkaline, and the solvent is a solvent containing a hydroxyl group such as mole, methanol, ethanol, isopropanol or a polar organic solvent such as N, N-dimethylformamide, acetonitrile or These mixed solvents are suitable.

The reaction for preparing the aldehyde compound of formula (III) from the alcohol derivative of formula (VII) may utilize general selective oxidation reactions, and in particular, the method using dimethyl sulfoxide as the oxidant may selectively proceed the reaction.

In this method, dimethyl sulfoxide is reacted at low temperature in a nonpolar organic solvent such as dichloromethane in the presence of oxaryl chloride or acetic anhydride trifluoride, and then treated with triethylamine and water to obtain an aldehyde compound. In particular, the reaction of the compound of formula (VII) with dimethyl sulfoxide in the presence of a tertiary base group such as acetic trifluoride and pyridine is carried out using dicyclohexylcarbodiimide as a dehydrating agent in anhydrous solvents such as benzene and toluene. desirable. The aldehyde compound of formula (III) thus prepared can be easily purified and separated by using an aqueous solution of a reagent such as sodium sulfite, and a conventional melting point of a 2,4-dinitrophenylhydrazone compound is obtained. You can check it by creating it.

The aldehyde compound of formula (III) may also be prepared using a suitable reducing agent from derivatives of organic acids, esters, nitriles and the like of formula (VII), as shown in the following scheme.

Here, R ₁ = OH or halogen atoms such as Cl, Br

Structural compounds used as intermediate compounds can be obtained by using thioglycolic acid or methyl or ethyl esters of thioglycolic acid from furan derivatives of the structural formula (V), and furan containing thiol groups of the structural formula (VI). It may also be prepared from a derivative using a reagent such as halogenated acetic acid, esters thereof or halogenated acetonitrile. These reactions proceed relatively well under similar reaction conditions to the preparation of alcohol derivatives of formula (VII).

The reaction for preparing the compound of formula (III) from the intermediate compound of formula (III) is carried out by a conventional reduction reaction in which organic acids or esters or nitrile derivatives are converted to aldehyde derivatives, in particular selection such as substituted hydrogenated metal derivatives. It is preferable to prepare a target compound by reacting in an organic solvent in anhydrous conditions using a conventional reducing agent and subjecting it to hydrolysis.

As described in detail above, the present invention utilizes a selective oxidation or reduction reaction of a structural formula (VII) or a compound (VII) which can be prepared from a suitable reagent containing a compound of formula (V) or (VI) and a thiol group or a halogen. There is provided a novel process for preparing an aldehyde compound of formula (III), from which the nitroethene derivative of formula (IV) and a reducing agent are continuously reacted to produce the final target compound of formula (I).

In order to better understand the production method of the present invention, the following examples are described, which do not limit the present invention.

Example 1

2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanol

~35℃에서 20시간 동안 교반시킨 후 10℃ 이하에서 클로로포롬 200ml로 1회, 100ml로 2회 추출한다. 활성탄 처리후 30℃ 이하에서 감압 농축하고 잔사를 아세톤 90ml에 녹여서 5℃ 이하에서 2시간 방치후 소량의 비용해 물질을 여과 제거한다. 여액을 감압 농축하여 표제화합물 50g을 얻는다.46.5 g of 5- (dimethylamino) methyl-2-furanmethanol is dissolved in 220 ml of concentrated hydrochloric acid, cooled, and 24.6 g of thioglycol is added dropwise at 5 DEG C or lower for 2 hours. 25 reaction solution

After stirring at ˜35 ° C. for 20 hours, the extract was extracted with 200 ml of chloroform once and 10 times under 10 ℃. After activated carbon treatment, the mixture was concentrated under reduced pressure at 30 ° C. or lower, and the residue was dissolved in 90 ml of acetone. The filtrate was concentrated under reduced pressure to obtain 50 g of the title compound.

Boiling Point: 135 ℃

Elemental analysis: C ₁₀ H ₁₇ NO ₂ S (215.31)

Theoretic value (%): C55.78, H7.96, N6.51

Found (%): C55.81, H7.89, N6.58

TLC: (silica gel / chloroform: isopropanol: 25%

Ammonia water = 10: 10: 1), Rf = 0.66

Example 2

2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] methanol

~5℃를 유지하면서 수산화칼륨의 10% 메탄올용액 480ml를 3시간 동안 적사히시킨다. 서서히 온도를 올려서 20

~25℃에서 1시간 더 교반한 후 40℃ 이하에서 감압 증류하여 메탄올을 회수한다. 고체와 액체가 혼합된 잔사에 물 200ml를 가한 후 디클로로메탄으로 추출한다. 실시예 1과 같은 방법으로 반응후 처리를 하여 동일한 표제화합물 72.3g을 얻는다.(a) 84 g of hydrochloride (1: 1) of 5- (dimethylamino) methyl-2-chloromethylfuran is dissolved in 320 ml of methanol, cooled to 0 ° C., and a solution of 31.3 g of thioglycol in 80 ml of methanol is gradually added. . 0

Maintain ˜5 ° C. and drop 480 ml of 10% methanol solution of potassium hydroxide over 3 hours. Slowly raise the temperature 20

After further stirring at ˜25 ° C. for 1 hour, methanol was recovered by distillation under reduced pressure at 40 ° C. or lower. 200 ml of water was added to the mixture of the solid and liquid, followed by extraction with dichloromethane. Post-reaction treatment was carried out in the same manner as in Example 1 to obtain 72.3 g of the same title compound.

(b) When hydrobromide (1: 1) of 5- (dimethylamino) methyl-2-bromomethylfuran is used as a starting material and reacted in the same manner as in (a), the same title compound is obtained in a yield of 89%. Get into.

Example 3

2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanol

(a) 143 g of 5- (dimethylamino) methyl-2--S-isothioureyl-methylfuran was dissolved in 550 ml of water, and 310 ml of potassium hydroxide 5N aqueous solution and 44.3 g of 2-chloroethanol were added at room temperature to 12 Reflux for time. Cool to room temperature and extract once with 300 ml of chloroform and three times with 150 ml. The combined extracts were washed with aqueous sodium bicarbonate solution and water, and then treated with 5 g of activated carbon and filtered. 150 ml of ethanol was added to the filtrate and concentrated under reduced pressure at 50 ° C. 91 g of the title compound are obtained as an oily liquid. It may be used directly in the next reaction without further purification.

(b) 2-bromo ethanol was reacted for 8 hours according to the method of (a), and then treated in the same manner to obtain the same title compound in a yield of 88%.

Example 4

Hydrochloride of 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanol (1: 1)

20:75 g of hydrochloride (1: 1) of 5- (dimethylamino) methyl-2--thiomethylfuran was dissolved in 120 ml of a 50% ethanol-water mixture, 20 ml of sodium hydroxide 10N aqueous solution and 8.85 g of 2-chloroethanol were added thereto. Reflux for 6 hours. About two-thirds of the total volume of the solution was distilled off to recover about 90% of ethanol, cooled and extracted once with 100 ml of benzene and twice with 60 ml. The oily residue obtained by concentrating the extract under reduced pressure was dissolved in 120 ml of acetone, and 18 ml of isopropanol containing 20% hydrochloric acid was gradually added. The mixture was cooled to 15 ° C. or lower, stirred for 2 hours, filtered, washed with 30 ml of acetone, and dried in vacuo at 40 ° C. to obtain 22.6 g of the title compound.

Elemental analysis: C ₁₀ H ₁₇ NO ₂ S.HCl (215.77)

Theoretic value (%): C47.71, H7.20, N5.56

Found (%): C47.66, H7.32, N5.51

Example 5

Hydrochloride of 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanol (1: 1)

52: 2 g of oxalate (1: 1) of 5- (dimethylamino) methyl-2--thiomethylfuran is dissolved in 250 ml of an aqueous solution of 35 g of sodium dithionite. 80 ml of potassium hydroxide 5N aqueous solution is slowly dripped at 20 degrees C or less. After stirring for 30 minutes, the mixture was extracted three times with 150 ml of dichloromethane at 15 ° C. or lower. The yellow oily liquid obtained by concentrating the solvent under reduced pressure was dissolved in 80% ethanol aqueous solution, and 20 ml of sodium hydroxide 10N aqueous solution and 27.5 g of 2-bromoethanol were refluxed for 4 hours. Post-reaction treatment was carried out in the same manner as in Example 4 to obtain 46.3 g of the same title compound.

Example 6

1-amino-1-methylamino-2-nitroethene

~35℃에서 12시간 동안 교반시킨 후 감압하여 개스를 제거한다. 용매를 감압 농축하여 얻은 황색고체를 아세톤 150ml에 넣어 실온에서 2시간 동안 세계 교반시킨 후 여과하고 아세톤 30ml로 2회 세척한다. 얻어진 미황색 결정을 50℃ 이하에서 건조시키면 표제화합물 30.8g을 얻는다.After dissolving 44.4 g of 1-methyl amino-1-methylthio-2-nitroethene in 220 ml of 95% ethanol, 250 ml of 28% ammonia water was added dropwise at room temperature for 2 hours. 25 reaction solution

Stir at ˜35 ° C. for 12 hours and remove the gas under reduced pressure. The yellow solid obtained by concentrating the solvent under reduced pressure was put in 150 ml of acetone, and the mixture was stirred at room temperature for 2 hours, filtered and washed twice with 30 ml of acetone. The resulting pale yellow crystals were dried at 50 ° C. or lower to obtain 30.8 g of the title compound.

Melting Point: 186 ℃ ~ 187 ℃

Elemental Analysis: C ₃ H ₇ N ₃ O ₂ (117.11)

Theoretic value (%): C30.77, H6.02, N35.88

Found (%): C30.71, H6.05, N35.93

TLC: (silica gel / chloroform: isopropanol: 25% aqueous ammonia = 10: 10: 10), Rf = 0.19

IR (KBr): 3350, 3250, 3200, 1610, 1425, 1225, 955, 770, 720, 665 cm ^-1

Example 7

[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -acetaldehyde

~30℃에서 20시간 동안 교반시킨 후 벤젠 200ml를 가하여 여과한 여액을 물150ml로 4회 추출한다. 분리한 물츨에 아황산수소나트륨 8.4g을 가하여 20℃에서 1 시간 교반후, 벤젠 100ml로 세척하고, 클로로포름 70ml로 3회 세척한다. 20℃ 이하에서 물층에 탄산수소나트륨 7.6g을 서서히 가하여 30분동안 교반한 후, 클로로포름 70ml로 3회 추출한다. 황산나트륨으로 건조하고 용매를 감압 농축시키면 표제화합물 3.5g을 얻는다.4.3 g of 2-[[[5- (dimethylamino) methyl-2--furanyl] methyl] thio] ethanol was dissolved in 70 ml of benzene, and 65 ml of dried dimethyl sulfoxide was added at room temperature. 1.7 ml of anhydrous pyridine, 0.8 ml of trifluoroacetic acid, and 12.4 g of dicyclohexylcarbodiimide are added in this order. 25 reaction mixture

After stirring at ˜30 ° C. for 20 hours, 200 ml of benzene was added and the filtrate was extracted four times with 150 ml of water. 8.4 g of sodium bisulfite was added to the separated water column, stirred at 20 ° C. for 1 hour, washed with 100 ml of benzene, and three times with 70 ml of chloroform. 7.6 g of sodium bicarbonate was slowly added to the water layer at 20 ° C. or lower, stirred for 30 minutes, and extracted three times with 70 ml of chloroform. Drying with sodium sulfate and concentration of the solvent under reduced pressure yields 3.5 g of the title compound.

Melting Point (2,4-dinitrophenylhydrazone derivative): 124 ° C

Elemental analysis: C ₁₀ H ₁₅ NO ₂ S (213.29)

Theoretic value (%): C56.31, H7.09, N6.57

Found (%): C56.38, H7.02, N6.61

Example 8

Hydrochloride (1: 1 of N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methyl-2-nitro-1,1-ethene diamine )

~30℃에서 15시간 교반 후 30분 동안 환류시킨다. 냉각하여 여과한 여액을 감압 농축하고 잔사를 문 20ml에 녹인다. 에테르 10ml로 2회 세척한 후 20℃ 이하에서 물층에 수산화나트륨 10% 수용액을 가하여 pH를 10.0으로 하여 30분 동나 교반시킨다.To 60 ml of 1-butanol, 1.8 g of 1-amino-1-methylamino-2-nitroethene and 3.2 g of [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] acetaldehyde were gradually added. Add 14 ml of ethanol solution containing 20% hydrochloric acid little by little. After stirring for about 30 minutes at room temperature, the solvent is distilled off with a water separator while gradually heating to reflux. After about 3 hours, cooled to pH 6 by adding 10% methanol solution of potassium hydroxide. The filtrate was concentrated under reduced pressure, and the residue obtained was dissolved in 20 ml of anhydrous ethanol. Then, 0.8 g of sodium borohydride was added thereto and 25

After stirring for 15 hours at ˜30 ° C., the mixture was refluxed for 30 minutes. The filtrate was cooled and concentrated under reduced pressure, and the residue was dissolved in 20 ml of moon. After washing twice with 10 ml of ether, 10% aqueous sodium hydroxide solution was added to the water layer at 20 ° C. or lower, and the mixture was stirred for 30 minutes at a pH of 10.0.

Extract three times with 10 ml of chloroform, wash with 10 ml of saturated aqueous sodium chloride solution, and then dry sodium sulfate. The residue of lactic acid obtained by concentrating the solvent under reduced pressure was dissolved in 25 ml of isopropanol and 1.2 ml of 35% hydrochloric acid was added thereto. After stirring for 12 hours, the mixture was cooled, filtered at 15 ° C., washed with 5 ml of isopropanol and 10 ml of acetone, and dried under reduced pressure at 50 ° C. or lower to obtain 3.95 g of the titled compound.

~ 141℃ (분해)Melting Point: 139

~ 141 ℃ (decomposition)

Elemental analysis: C ₁₃ H ₂₂ N ₄ O ₃ S.HCl (350.87)

Theoretic value (%): C44.50, H6.61, N15.97

Found (%): C44.46, H6.68, N15.94

TLC

(a) (Silica gel / toluene: methanol: diethylamine = 9: 1: 1) Rf = 0.11

(b) (silica gel / ethyl acetate: methanol: 25% aqueous ammonia = 1: 5: 1), Rf = 0.73

Claims (1)

Of the amino alkylfuran derivative of formula (I) characterized in that the aldehyde compound of formula (III) and the nitroethene derivative of formula (IV) are reacted under acidic conditions and then treated with an optional reducing agent such as sodium borohydride. Manufacturing method.