KR870000922B1 - Process for the preparation of a compound having antiulcer activity - Google Patents

Abstract

Furan derivs. of formul (I) and their salts and hydrates are prepd. by the reaction of II and III. In(I), R=hydroxy, halogen, dimethylamino or trimethylammonium iodide; X=O, S,-CH-NO2. (I) are anti-ulcer agents acting on histamine H1 and H2 receptors.

Description

Method for preparing a compound having antiulcer activity

The present invention relates to N- [2 [[[[5- (dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N '-(3,4-methylenedioxybenzyl) of formula (I) It relates to a process for producing 2-nitro-1,1-ethenediamine.

Reaction of 2-((2-aminoethyl) thio-methyl) -5- (dimethylaminomethyl) furan with 1-nitro-2-methylthio-2- (3,4-methylenedioxy benzylamino) ethene Compounds of the above formula (I), which have a high antiulcer activity and are virtually nontoxic, as compared to the method of Applicant's Italian Republic Patent Application No. 235464A / 81 described, can be obtained in high yield and high purity in the method of the present invention.

According to the most suitable embodiment of the present invention, 2- (dimethyl aminomethyl) -5- (R-methyl) furan of the following formula (II) is reacted with a compound of the following formula (III).

Wherein R is hydroxy, halogen, dimethylamino or trimethylammonium iodide and X is an O, S or CH-NO ₂ group.

When X is a CH-NO ₂ group, the compound of formula (I) is produced directly, whereas when X is O or S, the compound obtained by reacting the compound of formula (II) with the compound of formula (III) is nitromethane. To obtain a compound of formula (I).

Intermediates of formula (III), wherein X is CH-NO ₂ , may be selected from 1-nitro-2,2-bis (methylthio) ethene or 2- (nitromethylene) -thiazolidine according to the following reaction process. Can be used as starting material.

[Reaction Step 1]

In the reaction step, 1-nitro-2,2-bis (methylthio) ethene of formula (IV) reacts with 3,4-methylenedioxybenzylamine of formula (V) to form 1- of formula (VI). Nitro-2-methylthio-2- (3,4-methylenedioxybenzylamino) ethane is produced, which is N- (3,4-methylenedioxybenzyl) -1 of structural formula obtained by ammonia treatment. Addition of ethylene sulfide to nitroethenediamine produces intermediate (III).

Alternatively, the intermediate (III) can be obtained directly by reacting the compound of formula (VI) with cysteamine or 2-amino ethanethiol.

In the following reaction step (2), 1-nitro-2,2-bis (methylthio) -ethene of formula (IV) is treated with ammonia to give 1-nitro-2-amino-2-methylthio of formula (VII). -An ethene is obtained and reacted with ethylene sulfide to obtain 1-nitro-2-methylthio-2- (2-mercaptoethylamino) ethene of the structural formula (VIII), which is then 3,4 of the structural formula (V) The process of obtaining the intermediate of Structural Formula (III) by treating with methylenedioxy-benzylamine is shown.

[Reaction Step 2]

The compound of formula (VIII) reacts with one of the compounds of formula (II) to produce an intermediate of

This intermediate compound can produce compound (I) by reaction with 3,4-methylenedioxy-benzylamine (V).

Finally, according to reaction step 3, known compounds of formula (i), ie 2- (nitromethylene) -thiazolidine [French Patent No. 2,384,765, Federal Republic of Germany Patent Publication No. 2,734,070, S. ratio. S. B. Soloway et al., Pestic. Venom, Neuz. -15 ° C ongr. Entom. 1976, 153 (C.A. 89, 101812-1978) and Chem. Abstr. 99. 70613v] can be obtained much more simply and quickly by reacting 3,4-methylenedioxybenzylamine of formula (V).

[Reaction Process 3]

The intermediate of formula (III), wherein X is oxygen, reacts 3,4-methylenedioxybenzylamine of formula (V) with N, N-carbonyl-diimidazole by the following reaction step to Obtaining N- (3,4-methylenedioxybenzyl) imidazole-carbonylamide and reacting it directly with cystamine or 2-aminoethanethiol without recovery, the desired intermediate of formula (III) (X = O) Is generated.

In a similar manner, N- (3,4-methylenedioxybenzyl) imidazole-carbonylamide of formula (XI) is converted to cysteamine or 2,2'-dia of formula (XII) according to the reaction process below. Reaction with minodiethyl disulfide in a ratio of 2: 1 yields 2,2'-bis- (3,4-methylenedioxybenzylaminocarbonylaminoethyl) disulfide of the formula (XIII), which is With simple reduction with zinc and acetic acid, urea (III) can be produced in higher yields.

2 (XI) + H ₂ N-CH ₂ CH ₂ -SS-CH ₂ CH ₂ -NH ₂ →

On the other hand, an intermediate of formula (III) wherein X is S can be obtained by side-linking 3,4-methylenedioxybenzylisothiocyanate with cystamine.

Intermediates of formula (II) are known, and e. Subtle oil. E. W. Gill et al. (J. Chem. Soc. 1958, 4728) and o. It can manufacture by the obvious change of the well-known method described in the paper of O. Moldenhauer et al. (Ann. 580, 169, 1953).

According to one of the above methods for preparing compound (I), the compound of formula (III) in which R is chlorine or hydroxy can be converted to a compound in which R is SH. This compound is a compound of the following structural formula obtained by reacting compound (iii) or (iii) with ethylene oxide,

Can react with

According to the most suitable embodiment, the compound of formula (I) is formulated with 2- (dimethylamimethel) -5- (2-hydroxy) ethylthiomethyl-furan of formula (XIV) according to the following reaction fixation. It can be prepared by reacting 2-amino-2- (3,4-methylenedioxybenzylamino) -1-nitro-ethene (reaction step 1) in the presence of Raney nickel.

Compound (XIV) is optionally converted to the corresponding tosylate and then reacted with compound (iii).

Compound (XIV) and its tosylate are described in Italian Republic patent application 20461A / 82.

Hereinafter, the present invention will be described in more detail with reference to the following examples.

Example 1

a) 1-nitro-2- (3,4-methylenedioxybenzylamino) -2- (2-mercaptoethylamino) -ethyl [Structure Formula III (X = CH-NO)], Reaction Step 1)

1-nitro-2,2-bis- (methylthio) -ethene (33.05 g, 0.2 mol) is added to 1,1,2-trichloroethylene (200 mL) and the mixture is refluxed until complete homogenization I was. To this boiling solution was added 3,4-methylenedioxybenzylamine (15.1 g, 0.1 mol) dissolved in the same solvent (100 mL). The reaction solution was further refluxed for 90 minutes, and then the solvent was removed by distillation under reduced pressure, and the resin component was purified by silica gel column chromatography, which was first developed with petroleum ether and then with dichloromethane.

1-nitro-2-methylthio-2- (3,4-methylenedioxybenzylamino) ethene (formula VI) was crystallized in dichloromethane-ether. On analysis, 16.7 g (62% yield) of pure product were obtained. Melt 118 ° -119 ° C (not calibrated).

Schoeninger: calculated 11.95%, found 12.00%.

The compound (15.0 g, 0.056 mol) obtained above was added to concentrated ammonia (200 mL), and the reaction mixture was stirred at room temperature for about 48 hours. The mixture was evaporated under reduced pressure and the resulting crude product was used in the next step. 1-nitro-2-amino-2- (3,4-methylenedioxy benzylamino) -ethene (formula VII) was crystallized in alcohol, preferably 2-ftpanol. Yield 12.9 g (97% yield).

Mercaptoethylation of the compound is H. egg. It proceeded using ethylene sulfide according to the method described in H. R. Snyder et al. (J. Am. Chem. Soc. 69, 2672-1947).

1-nitro-2-amino-2- (3,4-methylenedioxy benzylamino) -ethene (11.8 g, 0.05 mol), toluene (50 ml) and ethylene sulfide (3.0 g, 0.05 mol) Mix in a vessel under pressure. After the vessel was sealed, the mixture was stirred and heated at 90 ° -100 ° C. for 24 hours. The reaction mixture was cooled and distilled under reduced pressure to obtain a crude product. Seed. Purification was carried out according to the method described in W. C. Still et al. (J. Org. Chem. 43, 2923-1978).

Elemental Analysis for C ₁₂ H ₁₅ N ₃ O ₄ S (297.33):

Calculated Value,%: C = 48.47, H = 5.07, N = 14.13, S = 10.78

Found,%: C = 48.62, H = 5.12, N = 14.10, S = 10.52

b) 2- (dimethyl aminomethyl) -5-chloromethyl-furan (formula II, R = Cl)

Lee, you. 2- (dimethylaminomethyl) -5-hydroxymethylfuran (15.6 g, 0.1 mol) prepared according to the method described in EW Gill et al. (J. Chem. Soc. 1958, 4728) was converted to dichloromethane. (100 mL), and the solution was treated with hydrochloric anhydride first in heterogeneous phase at room temperature and then phosphorus pentachloride. After about 4 hours, the chlorination reaction was complete. The resulting solids were collected and thoroughly washed with dichloromethane on a filter to remove the phosphorus halide. Pure alkaline with 20% aqueous sodium hydroxide solution gave the base, which was exported to dichloromethane. The organic solution was washed, dried over sodium sulfate (Na ₂ SO ₄ ) and evaporated to afford an oily residue (4.0 g, yield 80.6%). Chlorine nger: calculated 20.42%, found 20.77%.

c) N- [2-[[[5-[(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'- (3, 4-methylenedioxybenzyl) -2-nitro- 1,1-ethenediamine (formula I)

Fragments of sodium metal (1.15 g, 0.05 g.a.) were dissolved in anhydrous ethanol (200 mL) under nitrogen atmosphere. When all of the metal was dissolved, 1-nitro-2- (3,4-methylenedioxybenzylamino) -2- (2-mercaptoethylamino) ethene (14.8 g, 0.05 mol) was added. The mixture was heated to reflux for about 20 minutes, then left to cool, and 2- (dimethylaminomethyl) -5-chloromethyl-furan (8.7 g, 0.05 mol) in dry ethanol (50 mL) was added slowly under stirring. It was.

The reaction mixture was heated at 50 ° -80 ° C. for about 2 hours to complete the reaction and water was added until slightly cloudy at the same temperature. After the reaction mixture was cooled, it was left overnight in a cold place. Recovered 16.3 g (75%) of crystalline product at melting point 98 ° -102 ° C. (not calibrated).

Elemental Analysis for C ₂₀ H ₂₆ N ₄ O ₅ S (454.51):

Calculated Value,%: C = 55.29, H = 5.69, N = 12.90, S = 7.05

Found,%: C = 55.39, H = 6.02, N = 12.79, S = 7.10

The structure of the compound was confirmed by ¹ H-NMR spectrum (internal standard TMS, solvent DMSO) 2,1, s, 6H; 2.7, m, 4H; 3.4.s.2H; 3.7, d, 2H; 3.85, s, 2 H; 4.3, s, 2H; 6-7, m, 6H aromatic and CHNO 2; 8 and 10, s broad, 2H.

This compound was the same as was prepared by the method of Italian Republic patent application 23546A / 81.

Example 2

a) 1-nitro-2- (3,4-methylenedioxybenzylamino) -2- (2-mercaptoethylamino) -entene [Structure III (X = CH-NO ₂ ), reaction step 3]

2- (nitromethyl) thiazolidine (French Patent No. 2384765, German Federal Republic Publication No. 2734070, SB Soloway et al., Pestic. Veno m. Neurotoxic. 153, 1976 (See CA 89,1018 12) (7.3 g, 0.05 mol) was dissolved in a high boiling point nonpolar solvent, preferably toluene or xylene (100 mL). The mixture was refluxed under an inert atmosphere, and then 3,4-methylenedioxybenzylamine (15.1 g, 0.1 mol) was added dropwise over 30-40 minutes. After the addition, reflux was continued for about 12 hours, and then the reaction mixture was cooled and filtered, and then the filtrate was washed with water, an aqueous 10% dilute hydrochloric acid solution, water, an aqueous 5% sodium hydroxide solution, and then water again to give sulfuric acid. Dried over magnesium (MgSO ₄ ) and the solvent was evaporated in vacuo. The residue, consisting mainly of crude product, was purified by silica gel (70-230 mesh) column chromatography, which was developed with ethyl acetate-petroleum ether. Analysis gave 10.1 g (68% yield) of pure compound.

Elemental Analysis for C ₁₂ H ₁₅ N ₃ O ₄ S (297.33):

Calculated Value,%: C = 48.47, H = 5.08, N = 14.13, S = 10.78

Found,%: C = 48.53, H = 5.15, N = 14.08, S = 10.48

b) N- [2-[[[5-[(dimetalamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'- (2, 4-methylenedioxybenzyl) -2-nitro -1,1-Edendiamine (Formula I)

According to the same method as described in Example 1, the intermediate (III) prepared above was reacted to obtain the same compound as in Example 1. (72% yield)

Example 3

2,5-bis (dimethylaminomethyl) furan-mono-iodo methylate [Structure ^{Ⅱ, R = N + (CH} 3) 3 I -]

this. Subtle oil. 2,5-bis- (dimethyl aminomethyl) furan (9.9 g, 0.05 mole) prepared according to the method described in EW Gill et al. (J. Chem. Soc. 1958, 4728) was subjected to anhydrous athetonitrile. (100 mL). Iodomethane (7.1 g, 0.05 mol) was added dropwise to this solution. After about 30 minutes, the quaternary ammonium salt began to crystallize, which was collected and crystallized in alcohol, preferably ethanol. (12.1 g, 71% yield). Iodine (AgNO ₃ ): calculated 37.3%, found 36.9%.

b) N- [2-[[[5- (dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'- (3, 4-methylenedioxybenzyl) -2-nitro-1 , 1-Ethyldiamine (formula I)

Iodine methylate (6.8 g, 0.02 mole) obtained above was dissolved in dimethylformamide (80 mL). 1-nitro-2- (3,4-methylenedioxy benzylamino) -2- (2-mercaptoethylamino) ethene (5.9 g, 0.02 mol) prepared by the method of Example 2a) was added. The reaction mixture was stirred and heated at 80-120 ° C. under inert atmosphere for about 1 day. After cooling, the reaction mixture was poured into iced water to separate the rubbery solid, which was collected by decantation, washed again with water, and then crystallized in an aqueous ethanol solution (6.5 g, yield 72%), melting point 98 °- 102 ° C (not calibrated)

The resulting compound was the same as that prepared in Example 1.

Example 4

a). 2- (dimethyl aminomethyl) -5-chloromethyl-furan [Formula II (R = Cl)]

Five. 2,5-bis- (chloromethyl) furan (16.5 g, 0.1 mol) prepared by the method described in O. Moldenhauer et al. (Ann. 580, 169-1953) was added to ether (200 mL). It was dissolved and dimethylamine hydrochloride (8.1 g, 0.1 mol) was added. The reaction mixture was cooled to 0-5 ° C., and then kept at the same temperature, and anhydrous potassium carbonate (27.6 g, 0.2 mol) was added in small portions under vigorous stirring while being careful to stop gas generation with each addition. When the addition operation was completed, the temperature was raised to room temperature, and then the reaction mixture was further stirred for 2 hours.

The inorganic salt present was removed by filtration and the filtrate was distilled off under reduced pressure. Crude oil containing impurities of bis-substituents. Seed. Purification was carried out according to the method described in W. C. Still et al. (J. Org. Chem. 43, 2923, 1978).

The desired pure product was produced as a nearly colorless dark oil (12.4 g, 72% yield).

Chlorine: calculated 20.42%, found 20.33%.

b) N- [2-[[[5-[(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'- (3,4-methylenedioxybenzyl) -2-nitro- 1,1-ethenediamine (formula I)

According to the same method as in Example 1, the compound of the formula (I) similar to that of Example 1 was obtained (yield 81%).

Example 5

a). N- (2-mercaptoethyl))-N '-(3,4-methylenedioxybenzyl) urea (formula III, X = O)

3,4-methylenedioxy benzylamine (15.1f, 0.1 mol) and N, N'-carbonyldiimidazole (16.2 g, 0.1 mol) were dissolved in anhydrous chloroform (200 mL). This solution was stirred for about 30 minutes at room temperature, followed by addition of cysteamine or 2-aminoethanethiol (7.7 g, 0.1 mol) dissolved in anhydrous chloroform (50 mL). The reaction mixture was further stirred for 30 minutes and then filtered, the filtrate was washed with water, 10% aqueous hydrochloric acid solution, and then dried over magnesium sulfate (Mg SO ₄ ), and the solvent was evaporated. The resulting crude product was crystallized in ethanol-petroleum ether mixture to give analytical pure product (13.2 g, yield 52%).

Schoeninger: calculated 12.61%, found 12.44%

By using cystamine or 2,2'-diaminodiethyldisulfide (formula XII) instead of 2-amino ethanethiol, the same intermediate can be obtained in a similar manner, but the intermediate is obtained in higher yield (75-80%). I could get it). Then, N, N'-bis- (3,4-methylenedioxybenzyl) citamine (formula XIII) was seeded. F. Zinc and acetic acid were used to convert 2 moles of mercaptan by the method described in C. F. Allen et al. (Org. Synth.-coll. Vol. II. P. 580).

b). N- [2-[[[5-[(dimethylamino) methyl] 2-furanyl] methyl] thio] ethyl] -N '-(3,4-methylenedioxybenzyl) urea

Fragments of sodium metal (0.6 g, 0.025 g. A.) Were dissolved in anhydrous ethanol (100 mL). When the metals were all dissolved, N- (2-mercaptoethyl) -N '-(3,4-methylenedioxybenzyl) urea (6.35 g, 0.025 mol) prepared previously was added. The reaction mixture was stirred and heated for 15 minutes to cool, then 2- (dimethylamino-methyl) -5-chloromethylfuran (4.35 g, 0.025 mol) in anhydrous ethanol (20 mL) was added slowly. The reaction mixture was heated to 70 ° C. for about 2 hours, cooled, and then water was added to the extent that the reaction mixture became slightly cloudy. After overnight incubation, the crystals were collected (7.40 g, yield 75.8%) and used in the next step. Samples were recrystallized for elemental analysis.

Elemental Analysis for C ₁₉ H ₂₅ N ₃ O ₄ S (391.49):

Calculated Value,%: C = 58.29, H = 6.43, N = 10.73, S = 8.18

Found,%: C = 58.52, H = 6.25, N = 10.79, S = 8.10

c). N- [2-[[[5-[(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N '-(3, 4-methylenedioxybenzyl) -2-nitro-1, 1-ethenediamine (Formula I)

Nitromethane (3.5 g, 2.7 ml, 0.05 mole) and the urea derivative (19.5 g, 0.05 mole) prepared in the above were placed in a flask immersed in an ice-salt bath, and sodium hydroxide (2.1 g) dissolved in the same volume of water cooled beforehand. ) Aqueous solution was slowly added so that the temperature of the mixture did not exceed 10 ° -15 ° C. The precipitate produced during the addition was diluted with other methanol.

After stirring for 1 hour, dilute hydrochloric acid was added until neutral, and then water was added until the reaction mixture became slightly cloudy. After the reaction mixture was allowed to stand overnight in a cold place, crystals were collected. Since the purity was not sufficient, it was recrystallized in an aqueous ethanol solution. (16.9 g, yield 77.8%). Melting point 98 ° -102 ° C. (not calibrated). This compound was the same as obtained in Example 1.

Example 6

a). 3,4-methylenedioxybenzylisothiocyanate

A cold water solution (20 g, 0.5 mL) of carbon disulfide (38.1 g, 30.2 mL, 0.5 mol) and sodium hydroxide in water (45 mL) was placed in a flask immersed in an ice bath.

This mixture was added to 3,4-methylenedioxybenzylamine (75 g, 0.5 mL) at 10-15 ° C over about 30 minutes. The reaction mixture was further stirred for 30 minutes and then refluxed for about 2 hours. After the reaction mixture was cooled to 35 ° C., ethyl chlorocarbonate (54.2 g, 47.5 mL, 0.5 mol) was slowly added thereto, and further stirred at the same temperature for 30 minutes.

When the reaction mixture was cooled to room temperature, it was transferred to a separatory funnel, the supernatant was separated and dried over sodium sulfate (Na ₂ SO ₄ ), and the more volatile portion was then vacuumed at 35 ° -40 ° C. for use in subsequent steps. A product of sufficient purity was obtained. (73.5g, yield 76%)

b). N- (2-mercaptoethyl) -N '-(3,4-methylenedioxybenzyl) urea (formula III, X = S)

3,4-Methylenedioxyisothiocyanate (19.3 g, 0.1 mol) in dichloromethane (80 mL) was cooled to 5 ° C. 2-aminoethanethiol (7.7 g, 0.1 mol) diluted with dichloromethane (50 mL) was added. The addition was carried out slowly so that the reaction solution did not exceed 10 ° C. When the addition operation was completed, stirring was continued for 1 hour to raise the temperature to room temperature. The reaction solution was corrected in a separatory funnel, washed with 10% aqueous hydrochloric acid solution and water in that order, dried over magnesium sulfate (MgSO ₄ ), and then filtered and evaporated to obtain a crude product as a residue. J. Org.Chem. 43, 2923-1978). The product (18.4 g, yield 68%) had sufficient purity for use in the next step.

Schoeninger: calculated 23.71%, found 23.83%.

c). N- [2-[[[5-[(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N '-(3,4-methylenedioxybenzyl) thiourea

The thiourea prepared above was reacted with 2- (dimethyl aminomethyl) -5-chloromethyl-butane (II, R = Cl) in the presence of sodium ethoxide as described in Example 5b) to afford the title compound. (Yield 77%).

Elemental Analysis for C ₁₉ H ₂₅ N ₃ O ₃ S ₂ (407.55):

Calculated Value,%: C = 55.99, H = 6.18, N = 10.31, S = 15.73

Found,%: C = 60.11, H = 5.99, N = 10.29, S = 15.56

d). N- [2-[[[5-[(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N '-(3,4-methylenedioxybenzyl) -2-nitro-1, 1-erenediamine (formula I)

In the same manner as in Example 5c), the compound of formula (I) was obtained (yield 81%). This compound was the same as obtained in Example 1. Melting point 98 ° -102 ° C, melting point 98 ° -102 ° C.

Claims (4)

N- [2 of the following formula (I) characterized by reacting a compound of formula (II) with a compound of formula (III), and reacting the resulting compound with nitromethane when X is O or S -[[[5-[(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'- (3,4-methylenedioxybenzyl) -2-nitro-1,1-ethylenediamine Method of preparation.

Wherein R is hydroxy, halogen, dimethylamino or trimethylammonium iodide and X is an O, S or CH-NO ₂ group. The method of claim 1, wherein R in the compound of formula II is Cl. The method of claim 1 wherein R in the compound of formula II is OH. The method of claim 1, wherein R in the compound of formula (II) is (CH ₃ ) ₂ N- or (CH ₃ ) ₂ N ⁺ I ⁻ .