JPH0812658A - Production of sydnones - Google Patents

Abstract

PURPOSE:To efficiently obtain sydnones useful as a medicine in a short time by reacting N-nitro-2-amino acids with a haloiminium salt. CONSTITUTION:This method for producing sydnones of formula III (R<3> and R<4> are each H or an organic group) is to react a compound of formula I with a compound of formula II [R<1> and R<2> are each a lower alkyl; X is a halogen; Y is a halogen or a hexafluorophosphate; (n) is 2 or 3] as a dehydrating agent, as necessary, in a solvent (e.g. dichloromethane) in the presence of a base (e.g. triethylamine). When the compound of formula II is used as the dehydrating agent, the compounds of formula III are obtained under nearly neutral mild conditions. The compounds of formula III are useful as a medicine having physiological activities such as antimicrobial, antitumor, analgesic and diuretic actions.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing sydnones, and more specifically, it uses a special haloiminium salt to produce N.
-A method for industrially producing sydnones from nitroso-α-amino acids.

[0002]

BACKGROUND OF THE INVENTION Cydonones include many compounds useful as pharmaceuticals having physiological activities such as antibacterial action, antitumor action, analgesic action and diuretic action [Adv. Hete
rocyclic Chem. , 19 , 3 (197
6)].

Conventionally, several methods for producing sydnones have been reported, one of which is N-
A method based on a ring closure reaction of nitroso-α-amino acids is known. As this method, 1) a method using acetic anhydride [J. Chem. Soc. , 899 (193
5); Chem. Soc. , 307 (194
9)], 2) Method using thionyl chloride [J. Che
m. Soc. , 1542 (1950)], 3) Method using phosgene (British Patent 832).
001), 4) Method using N, N'-diisopropylcarbodiimide (British Patent 83)
2001), 5) Method using trifluoroacetic anhydride [J. Chem. Soc. , 1542 (1950)] and the like are known.

However, in the method 1) using acetic anhydride, a large amount of reagents must be used because acetic anhydride is used as a solvent, and a long reaction time is required at room temperature, and a reaction time is long when heated. Although shortened, the reaction conditions are severe, and thus alkylsydnones having a functional group on the side chain have a drawback that a considerable decomposition reaction proceeds during the reaction. Further, the methods of 2) and 3) using thionyl chloride or phosgene cannot be applied to N-nitroso-α-amino acids having a functional group weak to acid because the reaction system is strongly acidic, or the yield is low. It has a drawback that it requires a special reaction vessel when it is carried out on an industrial scale because it generates hydrogen halide that is low and is highly corrosive and phosgene gas that is highly toxic. are doing. In addition, 4) N, N'-
In the method using diisopropylcarbodiimide, the reagent is accompanied by strong skin irritation, and at the end of the reaction, sparingly soluble N,
Since a large amount of N'-diisopropylurea is produced, there is a problem in separation and purification, and the method of 5) using trifluoroacetic anhydride is not commercially available as a reagent for industrial use, resulting in high production cost and industrial usefulness. It had the drawback of low sex.

[0005]

Therefore, the object of the present invention is not affected by the properties of the raw materials, and a method for industrially advantageously producing sydnones from N-nitroso-α-amino acids under mild conditions. To provide.

[0006]

Under these circumstances, the present inventor has conducted diligent research to find out a new method for producing sydnones, and as a result, the haloiminium salt represented by the following general formula (1) was used as a dehydrating agent. As a result, they have found that sydnones can be produced from N-nitroso-α-amino acids under mildly neutral conditions, and completed the present invention.

The method of the present invention is shown by the following reaction formula.

[0008]

Embedded image

[In the formula, R ¹ and R ² are the same or different and each represents a lower alkyl group, X is a halogen atom,
Y represents a halogen atom or hexafluorophosphate, and n represents an integer of 2 or 3. R ³ and R ⁴ are the same or different and each represents a hydrogen atom or an organic group, and B represents a base]

That is, the present invention is a method for producing sydnones (4) by reacting N-nitroso-α-amino acids (2) with a haloiminium salt (1).

The haloiminium salt used in the present invention is represented by the general formula (1). In the formula, the lower alkyl group represented by R ¹ and R ² is a methyl group, an ethyl group, an n-propyl group, Isopropyl group, n-butyl group,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as an isobutyl group. Further, examples of the halogen atom represented by X and Y include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among them, a chlorine atom and a bromine atom are particularly preferable. Specific preferred examples of the haloiminium salt (1) include 2-chloro-1,3-dimethylimidazolinium chloride and 2-chloro-1,3-dimethyl-
3,4,5,6-Tetrahydropyrimidinium chloride, 2-bumoro-1,3-dimethylimidazolinium bromide, 2-bromo-1,3-dimethyl-3,4.
5,6-Tetrahydropyrimidinium bromide, 2-
Chloro-1,3-dimethylimidazolinium hexafluorophosphate and the like can be mentioned.

This haloiminium salt (1) can be obtained by, for example, adding an oxalyl halogenide, a phosphorus trihalide, a phosphorus pentahalide or an oxyhalogen to a compound represented by the general formula (5) which is known as an easily available solvent. It can be easily obtained by reacting a halogenating agent known per se such as phosphorus bromide, phosgene, trichloromethyl chloroformate and the like. In this reaction, either compound (5) or a halogenating agent is dissolved in a suitable solvent such as carbon tetrachloride,
The other is added little by little to this, and the reaction is further carried out at room temperature to 70 ° C. for several hours to several tens of hours. The haloiminium salt (1) thus obtained can be isolated, but the reaction solution can also be used in the reaction of the present invention without isolation.

When Y is hexafluorophosphate, the hexafluorophosphate salt of the haloiminium salt is a haloiminium salt obtained by reacting the compound represented by the general formula (5) with a halogenating agent. Is dissolved in a suitable solvent, and an aqueous solution of an alkali salt of hexafluorophosphate is added thereto, whereby salt exchange proceeds and a hexafluorophosphate salt of a haloiminium salt can be easily obtained.

N- which is a starting compound used in the method of the present invention
In the nitroso-α-amino acids (2), R ³ and R
Examples of the organic group represented by ⁴ include an alkyl group which may have a substituent, an alkenyl group, an aromatic group and a heterocyclic group. The substituent may have a substituent containing an ether bond, an olefin bond, or the like.

Examples of the base represented by B include 2,6-lutidine, pyridine, triethylamine and tributylamine.

To carry out the method of the present invention, about 1 mol of the haloiminium salt (1) and about 2 mol of the base (3) are added to 1 mol of the N-nitroso-α-amino acid (2), and the temperature is around room temperature. You can react with. Although a reaction solvent may not be used, a solvent that does not participate in the reaction, such as a halogenated hydrocarbon such as dichloromethane or dichloroethane, a hydrocarbon, an ether, an aromatic hydrocarbon, or the like can be used. Further, even when the reaction apparatus is carried out on an industrial scale, it is possible to use an ordinary stainless steel reaction kettle instead of a special reaction kettle such as glass lining. In the method of the present invention, the haloiminium salt (1) is changed to the water-soluble compound (5), so that separation and purification are easy. Therefore, isolation of the desired sydnones from the reaction mixture can be conveniently carried out by a conventional method such as distillation or recrystallization.

[0017]

EFFECTS OF THE INVENTION According to the method of the present invention, sydnones useful for pharmaceuticals can be efficiently produced in a short time from N-nitroso-α-amino acids under mildly neutral conditions.

[0018]

The present invention will be described in more detail below with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 Preparation of 2-bromo-1,3-dimethylimidazolinium bromide: Oxalyl bromide 2 in 100 ml of benzene.
5.0 g (0.12 mol) and 1,3-dimethyl-2-
After dissolving 15.8 g (0.14 mol) of imidazolidinone and stirring at room temperature for 18 hours, it was further added with 24-55.
The mixture was heated and stirred at ℃ for 3.5 hours. After cooling, the precipitated crystals were collected by filtration, washed with benzene and n-hexane, and dried under reduced pressure to obtain 10.2 g (yield 34%) of the title compound. This was a yellow granular crystal having hygroscopicity.

Mp; 120.1-122.7 ° C. IR; ν _max ^KBr (cm ^-1 ) 1605, 1520, 140
0, 1310, 1280, 1105, 930. ¹ H-NMR; (60 MHz, CDCl ₃ -MeOH-d ₄ ) δ 3.33 (6 H, s, CH ₃ × 2), 4.22 (2 H,
s, CH ₂ × 2).

Reference Example 2 Preparation of 2-bromo-1,3-dimethyl-3,4,5,6-tetrahydropyrimidinium bromide: benzene 1
25.0 g (0.12 mol) of oxalyl bromide in 00 ml
And 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidinone 17.8 g (0.14 mol)
Was dissolved and stirred at room temperature for 48 hours. The precipitated crystals were collected by filtration, washed with benzene and n-hexane and dried under reduced pressure to give the title compound (31.5 g, yield 100%). This was a light brown granular crystal having hygroscopicity.

Mp; 100.1 ° C. (decomposition) IR; ν _max ^KBr (cm ^-1 ) 1635, 1560, 141
0, 1320. ¹ H-NMR; (60 MHz, CDCl ₃ -MeOH-d ₄ ) δ 2.19 (2H, quintet, J = 6 Hz, -CH
_{2 CH 2 CH 2 -),} 3.16 (6H, s, CH 3 × 2),
3.53 (4H, t, J = 6Hz, - CH 2 CH 2 CH 2
−).

Example 1 Preparation of 3-phenylsydnone: 3.0 g (17 mm) of N-nitroso-N-phenylglycine in 50 ml of methylene chloride.
ol) and 3.4 g (20 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride, 4.0 g (40 mmol) of triethylamine was slowly added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. Next, water was added to the reaction solution and extracted with methylene chloride. The extract solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.1 g.
A crystalline residue of was obtained. The residue was washed with n-hexane to obtain 2.5 g of the title compound (yield 93%). IR; ν _max ^KBr (cm ^-1 ) 1750.

Example 2 Preparation of 3-phenylsydnone: 1.6 g (9 mmo) of N-nitroso-N-phenylglycine in 50 ml of methylene chloride.
l) and 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate 3.0 g (11 mmol)
2.2 g of triethylamine (22 mmo
l) was slowly added dropwise, and the mixture was further stirred at room temperature for 17 minutes.
Thereafter, the same operation as in Example 1 was repeated to give 1.
5 g (yield 100%) was obtained.

Example 3 Preparation of 3-phenylsydnone: 1.0 g of N-nitroso-N-phenylglycine (6 mmo in 30 ml of methylene chloride).
l) and 1.7 g (7 mmol) of 2-bromo-1,3-dimethylimidazolinium bromide were added thereto, 1.3 g (13 mmol) of triethylamine was slowly added dropwise thereto, and the mixture was further stirred at room temperature for 2 hours. Next, water was added to the reaction solution and extracted with methylene chloride. The extract solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.1 g.
A crystalline residue of was obtained. The residue was purified by silica gel column chromatography (solvent: chloroform) to obtain 0.6 g of the title compound (yield 64%).

Example 4 Preparation of 3-phenylsydnone: 1.1 g of N-nitroso-N-phenylglycine (6 mmo in 30 ml of methylene chloride).
l) and 2-bromo-1,3-dimethyl-3,4,5,
2.0 g of 6-tetrahydropyrimidinium bromide
(7 mmol) was added to which 1.5 g of triethylamine was added.
(15 mmol) was slowly added dropwise. Thereafter, the same operation as in Example 3 was carried out to give 0.4 g of the title compound (yield: 40
%)Obtained.

Preparation of 3-benzyl-4-methylsydnone: 10.5 g (59 mmol) of N-benzyl-N-nitrosoalanine and 2-chloro-in 200 ml of methylene chloride.
1,3-Dimethylimidazolinium chloride 10.3
g (61 mmol) was added to which triethylamine 1 was added.
4.2 g (141 mmol) was slowly added dropwise, and the mixture was further stirred at room temperature for 25 minutes. Thereafter, the same operation as in Example 3 was carried out to obtain 3.1 g of the title compound (yield 55%). IR; ν _max ^KBr (cm ⁻¹ ) 1735.

Claims (1)

[Claims] 1. N-nitroso-α-amino acids are represented by the following general formula (1): [In the formula, R ¹ and R ² are the same or different and each represents a lower alkyl group, X represents a halogen atom, Y represents a halogen atom or hexafluorophosphate, and n represents 2
Or an integer of 3] is used as a dehydrating agent, and the reaction is carried out using a haloiminium salt.