JPH0346465B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to aziridine derivatives and methods for producing the same.

formula() The furan derivative represented by is known as ranitidine and has been shown in British Patent No. 1,565,966 as an effective and selective _H2 -antagonist.

The present invention provides the formula () in which R ₁ R ₂ N is an ethyleneimino group. An aziridine derivative represented by the formula () N-methyl-α-(nitromethylene)-
The present invention provides 1-aziridine-methanamine and a method for producing the same.

The compound in the present invention is important in the production of the furan derivative represented by formula ().
Accordingly, the following description is made from this perspective.

The furan derivative represented by the formula () is given by the formula () The thiol represented by and the formula () [However, in the formula, R ₁ is a -CH ₂ CH ₂ L group (however,
L is a leaving group) and R ₂ is a hydrogen atom, or R ₁ and R ₂ together with the nitrogen atom bonded thereto form an ethyleneimino group]. It can be manufactured by

An example of a suitable leaving group L is a halogen atom,
Chlorine is preferred.

This method is a new and useful method for producing the compound ranitidine.

When R ₁ is a -CH ₂ CH ₂ L group and R ₂ is a hydrogen atom, the process can be carried out using a suitable solvent such as water, aqueous tetrahydrofuran, dimethylformamide, an alkanol (e.g. methanol) or a ketonic solvent such as acetone (optionally). (addition of water). The reaction is preferably carried out using a base such as an inorganic base (such as an alkali metal carbonate or hydroxide such as potassium carbonate or potassium hydroxide or sodium hydroxide), an alkoxide (such as sodium methoxide) or a tertiary amine (such as triethylamine). ) in the presence of a suitable temperature e.g.
It is carried out within the range of 80℃. The reaction is preferably
It is carried out in an inert atmosphere, for example nitrogen. In a variant of this method, thiols of formula In a two-phase system, it is reacted with an alkylating agent ().

Particularly useful conditions for carrying out the alkylation reaction are in the presence of an alkali metal hydroxide (e.g., potassium hydroxide) and water, or in the presence of potassium carbonate using aqueous tetrahydrofuran as the solvent. (wherein R ₁ is a -CH ₂ CH ₂ C1 group and R ₂ is a hydrogen atom) includes treating a thiol represented by the formula () with an alkylating agent represented by the following. Advantageously, the reaction is carried out at room temperature under an atmosphere of nitrogen.

When R ₁ and R ₂ together with the nitrogen atom attached to them form an ethyleneimino group, the reaction is carried out in the presence or absence of a solvent. Suitable solvents include water, alkanols (e.g. methanol)
or dimethylformamide. The reaction is preferably carried out under an inert atmosphere, such as nitrogen, with heating, for example 100°C.

Thiols () can be used directly or generated in situ from acid addition salts such as oxalates.
On the other hand, when the reaction is carried out in the presence of a base, the thiol () is generated in situ from the isothiourea () or a salt thereof such as bismaleate under the basic conditions of the reaction.

A thiol of formula () can be prepared by combining thiourea with formula () in the presence of a concentrated acid e.g. concentrated hydrochloric acid. to form an isothiourea (), which is then reacted with a base such as sodium carbonate or 5N sodium hydroxide, preferably in the presence of an antioxidant such as sodium dithionite or sodium metabisulfite. The treatment converts it into a thiol represented by formula (). Once isolated, the free base so formed is converted into a stable acid addition salt by treatment with a suitable acid, especially oxalic acid, preferably in a solvent such as tetrahydrofuran.

If it is desired to isolate the isothiourea (), it is also preferably isolated in the form of a stable salt, such as the bismaleate, by treatment with a suitable acid, preferably in a solvent such as tetrahydrofuran.

Compounds of formula () in which R ₁ is a CH ₂ CH ₂ L group (wherein L is a halogen, e.g. chlorine) and R ₂ is a hydrogen atom, are preferably haloalkylamines in the form of salts, e.g. hydrochlorides. For example, chloroethylamine and the formula () (In the formula, L' is a leaving group such as a methylthio group.) The reaction is carried out in a suitable solvent, such as water, in the presence of a base, such as triethylamine, and preferably at an elevated temperature, such as about 100°C.

A compound represented by the formula () in which R ₁ R ₂ N is an ethyleneimino group is a compound represented by the formula () (wherein L'' is a leaving group such as a C _1-4 alkoxy group or a C _1-4 alkylthio group, preferably a methylthio group) and is produced by the reaction of nitroethenamine with ethyleneimine.
The reaction is carried out in a suitable aprotic solvent such as acetonitrile.

Acid addition salt of thiol represented by formula (),
Compounds represented by formula () in which R ₁ R ₂ N is an ethyleneimino group, i.e., formula () The compound represented by formula (), the isothiourea represented by formula (), and its acid addition salt are all new compounds.

Although thiols of formula () and isothioureas of formula () are not particularly stable, it is known that they can be stabilized by converting them into acid addition salt form. Examples of this stable acid addition salt are hydrochloride, sulfate, alkyl sulfonate,
Aryl sulfonates, acetates, fumarates,
Contains maleate and benzoate. formula()
A preferred acid addition salt of the thiol represented by is the oxalate salt, and a preferred acid addition salt of the isothiourea () is the bismaleate salt.

The invention is illustrated by the following example.

Note that Production 4 below is an example of producing N-methyl-α-(nitromethylene)-1-aziridine-methanamine according to the present invention, and Reference Example 3 below is a production example of N-methyl-α-(nitromethylene)-1-aziridine-methanamine according to the present invention. This is an example of the production of ranitidine from (nitromethylene)-1-aziridine-methanamine.

Production example 1 1-[[[5-[(dimethylamino)methyl]-2-
Furanyl]methyl]thio]methanimidamide,
Maleate salt (1:2) 5-[(dimethylamino)methyl]-2-furanmethanol (3.1 g) was added slowly to a solution of thiourea (1.53 g) in concentrated hydrochloric acid (5 ml). After standing at room temperature for 18 hours, the solution was heated to 98-100° for 30 minutes. Cool the solution and add tetrahydrofuran (100
ml) and excess anhydrous sodium carbonate;
After 30 minutes the mixture was filtered. A solution of maleic acid (4.65g) in anhydrous tetrahydrofuran (40ml) was added to the liquid and the solid that separated was filtered and washed with tetrahydrofuran and ether to give the title compound (8.1g) mp 144-145°. .

Production Example 2 5-[(dimethylamino)methyl]-2-furanmethanethiol, oxalate (1:1) 5-[(dimethylamino)methyl]-2-furanmethanol (7.76 g) was dissolved in concentrated hydrochloric acid (12.5 g). ml) of thiourea (3.81 g). After 18 hours, the solution was heated at 98-100° for 30 minutes to evaporate and reduce the weight. A solution of sodium hydroxide in water (50ml) and sodium dithionite (10g) were added and after 1 hour the solution was extracted with ether (6 x 50ml). Boric acid (35g) was added to the aqueous portion and the suspension was extracted with ether (4 x 50ml). Sodium dionite (2 g) to the combined ethereal extracts
and excess anhydrous sodium carbonate were added. After 3 hours, dry tetrahydrofuran (60 ml) of the mixture
The mixture was filtered through a solution of oxalic acid (6.3 g). The solid that separated was filtered, washed with tetrahydrofuran, and dried to give the title compound (5.84 g), mp 116.5.
−118° was obtained.

Production 3 N-(2-chloroethyl)-N'-methyl-2-
Nitro-1,1-ethenediamine N-methyl-(1-
Methylthio)-2-nitroethenamine (5.93g)
and 2-chloroethanamine hydrochloride (18.56g)
Triethylamine (24 ml) was added to the solution.
The mixture was stirred for 10 minutes at 98-100° and applied vacuum (12-20 mm) for 50 minutes. Water (8ml) was added and the mixture was heated under reduced pressure at 98-100° for 20 minutes. Acetone (200ml) and excess anhydrous magnesium sulfate were added to the residue and the suspension was refluxed for 45 minutes. The solids were removed and washed with hot acetone (3 x 50ml). The combined liquid and washing liquid were cooled and the resulting crystalline precipitate was separated. The liquid was concentrated to 100 ml, the separated solid was removed, the liquid was evaporated to a reduced volume and chromatographed (silica/acetone). The appropriate eluate was evaporated in vacuo and the residue suspended in ethyl acetate:ether (1:4) and filtered to give the title compound (2.8g) mp 113-115°. tlc silica: 2-butanone: Rf0.4.

Preparation 4 (Example) N-Methyl-α-(nitromethylene)-1-aziridine-methanamine Ethyleneimine (0.47 g) and N-methyl-(1-methylthio) in acetonitrile (5 ml)
-2-Nitroethenamine (1.48g) solution
The mixture was stirred at room temperature for several days. The suspension was evaporated under reduced pressure at room temperature and the residue was extracted with hot ethyl acetate (100ml).
Evaporation of the extract under reduced pressure gave a residue, which was suspended in ethyl acetate (50ml) and filtered. The liquid was evaporated to approximately 5 ml and chromatographed (silica/ethyl acetate). The appropriate eluent [TLC (silica/ethyl acetate) Rf 0.28] was evaporated under reduced pressure to give the title compound (0.33g) mp 118-119°.

Preparation 5 5-[(dimethylamino)methyl]-2-furanmethanethiol oxalate (1:1) Potassium carbonate (83.5 g), sodium metabisulfite (22.9 g) in water (140 ml) and ether (160 ml) ) and 1-[[[5-[(dimethylamino)
Methyl]-2-furanyl]methyl]thio]methanimidamide maleate (1:2) (26.73g)
The mixture was stirred for 24 hours at room temperature under nitrogen atmosphere. After adding anhydrous sodium carbonate (10 g) and stirring for an additional 2 hours, the ether portion was separated and water (60 g) was added.
ml) of sodium metabisulfite (5 g) and potassium carbonate (8 g). The ether extract was dried (Na ₂ SO ₄ ) for 1 hour and filtered into a solution of oxalic acid (7.6 g) in tetrahydrofuran (100 ml). The separated solid (13.33g) was crystallized from tetrahydrofuran to give the title compound (12.20g), mp 116.5-119°.

Reference example 1 N-[2-[[5-[(dimethylamino)methyl]-
2-Furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine N-(2-chloroethyl)-N'-methyl-2-
Nitro-1,1-ethenediamine (0.9g), 5-
A mixture of [(dimethylamino)methyl]-2-furanmethanethiol oxalate (1:1) (1.3 g) and potassium carbonate (2.7 g) in water (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 5 days. Stir under nitrogen. The suspension was evaporated under reduced pressure, the residue was mixed with water (40 ml) and the suspension was dissolved in ether (2x
30ml). The aqueous portion was evaporated under reduced pressure and the residue co-evaporated with ethanol (2x10ml).
Tetrahydrofuran (20ml), MgSO ₄ and decolorizing charcoal were added and after 1 hour the mixture was filtered. The liquid was evaporated to obtain an oil (1 g), which was chromatographed (silica/methanol: 0.88 ammonia 79:1).
I put it on. The appropriate eluate was evaporated and the oily residue (0.66g) extracted with hot isopropyl acetate.
Filtration of the separated solid yielded the title compound (0.4
g), with a melting point of 65-68°, which is claimed in British patent no.
Even when mixed with the sample prepared by the method of Example 15 of No. 1565966, there was no decrease.

Reference example 2 N-[2-[[5-[(dimethylamino)methyl]-
2-Furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine Water (10ml) and tetrahydrofuran (10ml)
1-[[[5-[(dimethylamino)methyl]-2
-furanyl]methyl]thio]methanimidamide maleate (1:2) (2.23 g), N-(2-chloroethyl)-N'-methyl-2-nitro-1,1
- A mixture of ethenediamine (0.9 g) and potassium carbonate (3.46 g) was stirred for 5 days at room temperature under nitrogen. The suspension was evaporated under reduced pressure and the residue was dissolved in water (5 ml).
and extracted with ether (2 x 40ml). The aqueous portion was evaporated under reduced pressure and magnesium sulphate and tetrahydrofuran (100ml) were added.
After 18 hours, the mixture was filtered and the liquid was evaporated to give a semi-solid which was chromatographed (silica/methanol). Evaporation of the appropriate eluate under reduced pressure afforded the title compound (0.3 g), which had the same nmr as that of the product made according to Example 1 above.
It had

Reference example 3 N-[2-[[5-[(dimethylamino)methyl]-
2-furanyl-methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine 5-[(dimethylamino)methyl]-2-furanmethanethiol oxalic acid in water (0.4 ml) Salt (1:1) (0.156g), sodium dionite (0.05g) and anhydrous sodium carbonate (0.15g)
To the mixture was added ether (15ml) and excess sodium carbonate. The mixture was filtered and the liquid was evaporated under reduced pressure. To the residue N-methyl-α-(nitromethylene)-1-aziridinemethanamine (0.072g) and methanol (2ml) were added and the solution was evaporated to dryness. The residue was heated at 98-100° for 1.25 hours and the product was chromatographed (silica/methanol:0.88 ammonia, 79:1). Evaporation of the appropriate eluate under reduced pressure afforded the title compound (0.113g), which was similar to the product of the example above.
It had the same nmr as nmr.

Reference example 4 N-[2-[[5-[(dimethylamino)methyl]-
2-Furanylmethyl[thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine 5-[(dimethylamino)methyl]-2-furan in water (20 ml) at 45° under nitrogen atmosphere. Methane-thiol oxalate (1:1) (1.31 g) and N
To a stirred mixture of -(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (1.08g) was added a solution of potassium hydroxide (1.04g) in water (3ml). . The solution was stirred for 2.5 hours at 45° and then for 15 hours at room temperature. The solution was then evaporated under reduced pressure, the residue was dissolved in water and a stream of air was passed through the mixture for 15 minutes. Pour the mixture into ether (2 x 15
ml) and the aqueous portion was evaporated under reduced pressure. To the residue was added tetrahydrofuran (70ml), excess anhydrous sodium carbonate and decolorizing charcoal. 1 hour later
The mixture was filtered, the liquid was evaporated under reduced pressure and the oily residue was dissolved in 8 ml of 4-methyl-pentan-2-one. The solid that separated was filtered and washed with 4-methylpentan-2-one to give the title compound ( 0.72g),
A melting point of 63-66° was obtained, which did not decrease when mixed with a sample made according to the method of Example 15 of GB 1565966.

Reference example 5 N-[2-[[5-[(dimethylamino)methyl]-
2-Furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine 1-[5 in water (20 ml) at 45° under an atmosphere of nitrogen
-[(dimethylamino)methyl]-2-furanylmethyl]thio]methanimidodiamide maleate (1:2) (2.23 g) and N-(2-chloroethyl)-N'-methyl-2-nitro-1, To a stirred solution of 1-ethenediamine (1.08 g) was added water (3
A solution of potassium hydroxide (1.68g) in ml) was added. After 40 hours at room temperature, the solution was dissolved in ether (2 x 50
ml) and the aqueous phase was evaporated under reduced pressure. Tetrahydrofuran (70ml), decolorizing charcoal and excess anhydrous sodium carbonate were added to the residue and the mixture was refluxed for 30 minutes. After 3 hours, the mixture was filtered and the liquid was evaporated under reduced pressure to obtain a semi-solid, which was dissolved in a mixture of methanol and acetone and chromatographed (silica:methanol:acetone 1:1).
Evaporation of the appropriate eluate under reduced pressure gave the title compound as an oil (0.37 g), a portion of which was crystallized from 4-methylpentan-2-one (melting point 68-70°), which is described in British Patent No. 1565966. It did not decrease even when mixed with a sample prepared according to the method of Example 15.

Claims (1)

[Claims] 1 N-methyl-α-(nitromethylene)-1-aziridine-methanamine. 2 Ethyleneimine and the formula () _{N -} methyl-
A method for producing α-(nitromethylene)-1-aziridine-methanamine. 3. The method according to claim 2, wherein L'' is a methylthio group.