Process for preparing derivatives of 1-acyl-2-cyanoaziridines or their salts

专利摘要:
1-Acyl-2-cyanoaziridines of the formula <IMAGE> wherein R is an acyl radical of a carboxylic, sulphonic, sulphinic, sulphenic, phosphonic or phosphoric acid, exhibit immune-stimulating and cancerostatic activities.
公开号:SU1077565A3
申请号:SU782631500
申请日:1978-07-04
公开日:1984-02-29
发明作者:Бергер Херберт；Галл Руди；Кампе Вольфганг；Бикер Уве；Кун Рольф
申请人:Берингер Маннхайм Гмбх (Фирма)；
IPC主号:

专利说明:

or lower dialkoxyphosphoryloxy or dialkoxyphosphonyl residue, or residue
-.-
-8 - $ - CHi
CR
/ A-riii
or group v
A-r
in which the residues A-Rj are the same or different; A is a valency sign, carbonyl-thiocarbonyl, or —CO — CH j group} Rg is hydrogen, nitrile, aryl, lower straight linear or branched saturated or unsaturated alkyl group which, in appropriate cases, can be single or multiple substituted by halogen, aryl the remainder
- "(" "-" - UJ.
OR
SC -,
in appropriate cases, aryl-substituted lower alkoxy, lower alkylmer, pto-, alkylsulfonyl-ac, or ac-sulfonyl; appropriate cases with a substituted aromatic haterocycle, aryl or lower alkyl group, aryl merc-apto, arylsulfini or arylsulfonyl group, aryloxy or cycloalkyl group, or in the corresponding cases of substituted aromatic or non-aromatic heterocycle, and aryl in all listed groups in appropriate cases can be substituted once or repeatedly by halogen, nitrile, nitrosulfamoyl, in appropriate cases N-alkylated carbamoyl, trifluoromethyl, phenyl, phenoxy methylenedioxy, lower alkyl, gshkoxy-, acyl-, acyloxy-, ashkoxycarbonyl-, alkylmercapto-, alkylsulphinyl-, alkylsulphonyl-, phenylsulphonyl, single or multiple substituted by alkyl, phenyl, acyl by an amino group or a residue st.,
yy
or R is, in appropriate cases, a substituted aromatic or a non-aromatic heterocyclic residue.
or R (- aryl residue, single or multiple substituted by halogen, nitrile, trifluoromethyl-, sulfamoylj, substituted with halogen, alkyl, alkoxy, or residue in appropriate cases

-W tl o
phenyl, phenoxy or & fenilsulfrN1 group, a lower alkyl group methylenedioxy, in cases sootvetstvukschih substituted carbamoyl, lower alkoksikarbonilalkoksi-, acyloxy, alkilaminokarboniloksi--H, I-alkoxycarbonyl-amino or acylamino And, lower alko, ksi-, acyl -, acyloxy, alkyl mercapto, alkoxycarbonyl, alkylsulfinyl or alkylsulfonyl, amino, substituted alkyl, aryl, acyl, alkoxycarbonyl, or in appropriate cases substituted by alkyl or aryl rows cases N-alkylated carbamoyl group or the residue
moreover, Z is oxygen or sulfur;
R. and Re are the same or different and are hydroxy, piperi DINO-, anilino, N-alkoxycarbonylamino, phenyl, phenoxy, lower alkyl or alkoxy, or a residual current
with
or R and R are also an alkylenedioxy group, or R is a 3-camphor, abietic or 6-acetamidopenicillanic acid residue, all of these aromatic and nonaromatic heterocyclic residues are substituted in the appropriate cases with single or multiple halogen, nitro, phenyl, lower acyl, acyloxy, alkyl, hydroxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl or amino groups that are substituted once or several times by alkyl, aryl or acyl, and N-containing heterocycles can be oxidized,
or salts thereof, characterized in that the 2-cyanoaziridine is reacted with compounds of the general formula
R - X
where R has the indicated meanings;
X is hydroxy, halogen, azide, lower alkoxy, alkoxycarbonyloxy, phenoxycarbonyloxy or the residue —OR, and R residues may be the same or different in an inert solvent in appropriate cases in the presence of a bonding water or acid condensing agent followed by separation target product in free form or in salt form.
The invention relates to the production of new derivatives of 1-acyl-2-cyanoaziridines, which have biological activity and can be used in medicine. Methods are known for the preparation of amidone from acid chlorides and amines or from acids and amines in the presence of carbodiimide Ij. The purpose of the invention is to develop, using a known method, a method of obtaining new compounds possessing valuable pharmaceutical properties. The goal is achieved: by the method of preparation; 1-acyl-2-cyanoaziridines of the general formula R is a -CR residue, moreover, Hj is hydrogen, carbs1-moyl, nitrile, lower alkoxycarbonyl or acyl residue, saturated or unsaturated cycloalkyl group, in corresponding cases one or many times substituted by halogen, nitrile , aryl, aryloxycarbonyl group with a lower alkoxy, acyloxy group, lower alkoxycarbonyl group, in appropriate cases with a substituted lower m, H-diyshkylamino group, lower alkyl group, in appropriate cases with a substituted ureido, lower acylamino or acyloxy group upa, an amino group, a substituted carbamoyl, alkoxycarbonyl or acyl group, or a —cil and C residue or, in appropriate cases, is fused with phenyl, or may contain hydrocarbon bridges containing 1–3 carbon atoms, or an oxygen bridge, a straight line or branched saturated residue whether a non-palatable alkyl residue containing 2–18 carbon atoms is straight, branched or branched, saturated or unsaturated hydrocarbon chain, single or multiple substituted by nitrile, by halogen, nitro, aryl-, ryloxy-, arylmercapto group, in appropriate cases with a substituted heteroaryl mercapto group, a saturated or unsaturated cycloalkyl group, which in appropriate cases can be attached through 1–3 carbon atoms, in appropriate cases with an N-alkylated carbide, lower alkoxycarbonyl group, in some cases x overlaid H.N-dialkylamino group, in appropriate cases, a substituted N-alkylated sulfamoyl group, in appropriate cases, an N-alkylated urethane group; lower acyl, acyloxy, alkylsulfonyl or alkylsulfinyl group, or lower alkyl mercapto or alkoxy groups which, in appropriate cases, may be replaced by phenyl or —C-HI and cai, or in appropriate cases, by substitution with aromatic or non-aromatic heterocyclic ring either by a group of HD, or by a lower dialkoxyphosphoryloxy or dialkoxyphosphonyl residue or a residue of -4-S-I-CHi „vL to or by group A – I, in which the residues A – Rj. the same sludge is different. A is the sign of the valence, carbonyl, thiocarbonyl or -CO-CH group and R2 is a hydrogen, nitrile, aryl, lower or linear or branched, saturated or unsaturated alkyl group, which in appropriate cases may be substituted once or several times for tax, aryl, residue-co-cn. i (cHj-co-n I) CMI in appropriate cases, substituted aryl lower alkoxy, lower alkylmercapto, alkylsulfinyl or alkylsulfonyl, in cases oootvetszhu boiling mono- or multiply substituted phenyl, heteroaryl, lower alkyl, or alkilsulfonilatsilamidokarbimidoil- atsnlgruppoy amino group, n-methylene amino residue, substituted in appropriate cases with a substituted aromatic heterocycle, aryl or lower alkyl group, aryl mercapto, arylsulfine yl or arylsulfonyl group, aryloxy or cycloalkyl group, or in soo corresponding cases is a substituted aromatic or non-aromatic heterocycle, and aryl in all of the listed groups may be substituted by single or multiple halogen, nitrile, nitro, sulfamoyl, in appropriate cases N-alkylated carbamoyl, trifluoromethyl, phenyl -, phenoxy, methylenedioxy, lower alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, alkylmercapto, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, single or multiple substituted by alkyl, phenyl, acyl, amino C-1g1 And cn or E - in appropriate cases, a substituted aromatic or non-aromatic heterocyclic residue, or n - aryl residue, or several times substituted by halogen, nitrile, trifluoromethyl, sulfamoyl, in corresponding cases, substituted by halogen, alkyl, alkoxyl, x-alkoxy, sulphamoyl, in corresponding cases, substituted by halogen, alkyl, alkoxoxy, sulphamoyl; or the residue of yy, phenyl, phenoxy or phenylsulfonyl group, methylenedioxy group, lower alkyl group, in accordance with HUHCHI 4C cases of substituted carbamoyl, lower alkoxycarbonyl, alkoxy, acyloxy, N-alkylaminocar bonyloxy, N-alkoxycarbonylamino or N-acylamino, lower alkoxy, acyl, acyloxy, alkyl mercapto, sshkoxycarbonyl, alkylsulphinyl or alkylsulphonyl, amino, substituted by alkyl, aryl, acyl, ac-, ole- cases substituted with an alkyl or aryl carbamoyl group, or in appropriate cases N-alkylated carbamoyl. by a group or residue of -c-c and CN or a residue of -CHpN or R is the residue 8 (0), - B, or 1; E3 CR Yulinear or branched, saturated or non-branched alkyl group, which in appropriate cases can be substituted once or several times by halogen, cycloalkyl or in appropriate cases substituted by phenyl, halogen, nitro, lower alkyl, alkoxy, alkyl mercapto or alkyl sulfonyl group aryl residue or in appropriate cases a substituted heteroaromatic residue or R is a residue 302-K3, and Rj is in appropriate cases an N-alkylated amino group, a straight line or a branch en, saturated or unsaturated alkyl group, which in appropriate cases can be mono- or multi-substituted by halogen or N-acylamino, cycloalkyl or substituted alko C 1 -, phenoxy - or phenyl group, phenyl group, naphthyl or in appropriate cases substituted het roaromatic residue, or H residue 2 I m. T. ". D with Z being oxygen or sulfur, B and Rj may be the same or different and represent hydroxy piperidino, anilino, N-alkoxycarbonylamino, phenyl, phenoxy -, lower alkyl or alkoxy, and and the residue / 1 CN or Rij and RS is also an alkylenedioxy group, or k is a residue of 3-camphor abietic or B-acetamidonenicilanic acid, all of which are aromatic and non-aromatic heterocyclic residues in each case substituted by one or more halogen, nitro -, phenyl, lower acyl, acyloxy, alkyl, alkoxy, alkyl mercaptoalkyl sulfinyl, alkylsulfonyl or amino, which is once or repeatedly substituted for alkyl, aryl or acyl, and N-containing heterocycle can be oxidized, or their salts, 2-cyanoaziridine subject t reacted with compounds of the general formula wherein R is as defined above; X is hydroxy, halogen, azide, lower alkoxy, alkoxycarbonyloxy, or phenoxycarbonyloxy or the residue is OR, and the residues R may be the same or different in an inert solvent, in the presence of a condensing agent that binds water or acid, followed by isolation of the target product in free form or as a salt. As an inert solvent, for example, tetrahydrofuran, methylene chloride, dimethylformamide, dioxane can be used. dstilfir, pyridine and water. It is advisable to use dicyclohexylcarbodiimide or carbonyldiimidazole in a molar ratio or with a slight excess as a condensing agent for the case when the reagents are free acids. In the case when acid chlorides or acid anhydrides are used in the reaction with 2-cyanoaziridine such as, for example, triethylamine or other tertiary organic amines. In many instances, inorganic bases such as sodium hydroxide, calcium hydroxide or carbonates of alkali or alkaline earth metals, such as potassium carbonate or calcium carbonate, can also be used. When carrying out the reaction in an aqueous medium, it is preferable to add an organic solvent which is not compatible with water, such as, for example, benzene, sufire, ethyl acetate. Compounds of general formula I having the appropriate acidic or basic groups can be converted by the action of inorganic or organic acids or bases to pharmacologically compatible salts. The invention further relates to all stereoisomers of the compounds of formula I, which are formed, for example, as a result of the presence of asymmetric carbon atoms or due to cistransomerism. The separation present in the mixture of products occurs by known methods. By 1-acyl-2-cyanoaziridines of the general formula I, we should understand the new aci-jpane compounds, the acyl residues of which belong to carboxylic, sulfonic, sulfonic, sulfenic, phosphonic or phosphoric acids. Unless otherwise indicated, the alkyl group of the substituents R, R, R, Hg, R and Rg is alone or in combination, for example, alkoxy, alkoxycarbonyl, acyl, acyloxy, N-alkylamino, N, K-dialkylamino, alkylsulfonyl, alkylsulfinyl , alkyl mercapto, dialkoxyphosphoryloxy or dialkoxyphosphonyl, a lower alkyl group containing 1-6, preferably 1-4 carbon atoms, which may be straight, branched or cyclic, saturated or unsaturated, but primarily methyl or ethyl. Example 1. 1-l-Methoxybenzoyl-2-cyanoaziridine.
1.52 g of ti-methoxybenzoic acid is dissolved in 20 ml of dioxane, a solution of 0.68 g of 2-cyanoazyridine in 3 ml of dioxane is added to the solution, then a solution of 2.06 g of dicyclohexylcarbodiimide in 4 ml of dioxane is added, stirred for 2 hours while, the crystals formed are filtered off with suction (2 g of 1,3-dicyclohexyl urea, mp. 225-230 0). The filtrate is evaporated in vacuo, the semi-solid residue after evaporation (3.88 g) is triturated with 3 ml of abs. the ether. The resulting crystals (0.6 g) are filtered off with suction, the filtrate is evaporated in vacuo, the residue after evaporation (2.45 g) is triturated again with 3-4 ml of ether, filtered off with suction. 0.59 g of the required BeiiecTBa is obtained. . 81-83 ° C; after re-evaporation and trituration with ether, an additional 0, 18 g of the desired substance is recovered.
Example 2. 1- (2-Methylmercaptobenzoyl) -2-cyanoaziridine.
1.86 g of 2-methyl mercaptobenzoyl chloride is dissolved in 14 ml of abs. ether, then this solution is added | dropwise at room temperature to a solution of 0.68 g of 2-cyanoaziridine in 8.6 ml of aqueous 2N. of a solution of CU and 20 ml of water, stirred for 2 hours, the ether phase is separated, evaporated, the residue (1.72 g) is triturated with 4 ml of isopropanol. Obtain 1.35 g of the desired substance with so pl. 67-69 s,
Example 3. 1- (Pyridine-2carbonyl) -2-cyanoaziridi n,
2.96 g of pyridine-2-carboxylic acid are refluxed. Jumins 54 ml of tiochloride The excess thionyl chloride is evaporated in vacuo, abs is poured to the residue after evaporation. the ether, separated by insoluble particles (1.2 g) by filtration, a clear ether filtrate containing crude pyridine-2-carboxylic acid chloride, is added to a solution of 0.84 g of 2-cyanoaziridine and 1.45 g of triethyl | ishna and 60 ml abs The ether is stirred for 1 hour at room temperature, the resulting HC1 salt is filtered off with suction on the filter (1.9 g) and the ether filtrate is evaporated. The residue after evaporation of the ether (2.1 g) was triturated twice with ether (each time with 3 ml), the resulting crystals were sucked off from the filter and they were obtained: a total of 0.76 g of the desired substance with mp. 124-127®C, slightly contaminated with monochlorinated pyridine ring product.
Example 4. 1- (2-Furoyl) -2 cyanoaziridine.
To a solution of 0.7 g of 2-cyano-airadi and 1.22 g of triethylamine in 10 ml
abs under ether cooling, a solution of 1.3 g of 2-furoyl chloride in 5 ml is added under ice cooling. abs ether, stirred for 1 h, the precipitated precipitate (salt with HC1 is sucked off on the filter, the ethereal mother liquor is evaporated, the residue after evaporation is triturated with 2 ml of ether and thus obtained 0.99 g of substance with mp 73-76 ° C, from which after repeated trituration with ether (2 ml), 0.75 g of the desired substance is isolated. mp t.P-78 ° C.
Example 5. 1-Acryloyl-2-cyanoaziridine.
To a solution of 1.4 g of 2-cyanoaziridine and 2.42 g of triethylamine in 30 ml of abs. ether solution is added dropwise a solution of 1.6 ml of acrylic acid chloride in 1Q ml of ether, stirred for 1 h, the precipitated salt with HCl is sucked off on the filter and the ether mother liquor is evaporated, yielding 2.26 g of a yellow oil. The oil is subjected to chromatographic purification on a column with silica gel about 25 cm long (50 g Cl 1) with elution with chloroform and the fractions obtained from the column are purified according to thin-layer chromatography (fractions with silica gel upon elution with chloroform are collected. front solvent), and after evaporation, 1.07 g of the desired substance is obtained in the form of a yellow oil.
Found,%: C 58,32; H 4.98; , K 22.54.
CfeHgHjO
&Num;%: G 59.02; H 4.92 K 22.95.
The data of the mass and PMR spectra are consistent with the proposed structure.
Example 6. 1- (3-Carbethoxyacryloyl) -2-cyanoaziridine,
To a solution of 1.2 g of 2-cyanoaziridine and 2.2 g of triethylamine in 60 ml of abs. slowly added dropwise with a solution of 2.87 g of trans-3-ethoxycarbonylacryloyl chloride (b.p. 85C / 13) in 20 ml of ether, stirred for 1 hour at 0 ° C, then for 24 hours at. room temperature. The precipitated salt with HC1 is dsacted on the filter, the ether is evaporated, after evaporation 2.28 g of solid are obtained. The resulting product is triturated with ether (2-3 ml) and receive 1 g of the desired substance with so pl. 54-56 ° C
Example 7. 1st-Butylmer-X-100-acetyl-2-cyanoaziridine.
To a solution of 0.74 g of I-butylmercaptoacetic acid and 0.34 g of 2-cyanoaziridine in 15 ml of ether is added with a solution of 1.03 g of dicyclohexylcarbodiimide in 5 ml of ether, stirred for 1 hour at room temperature and for 2 hours, the precipitated dicyclohexymethyl is sucked off on the filter (1.08 g), the ether filtrate is extracted twice with 5 ml of water, the ether phase is dried and evaporated. So, about 8, g of the desired substance is obtained in the form of a viscous oil.
The same substance is obtained by adding dropwise a solution of 0.99 Hz -butylmercaptoacetyl chloride in 10 ml of abs. ether to a solution of 0.73 triethylamine and 0.42 g of 2-cyanoaziridine in 20 ml of ether, followed by stirring for 1 h, sucking on the filter with the HCl salt, evaporation of the ether phase and re-extraction with water. The ether phase, after drying, is evaporated to give 0.87 g of the desired substance as a viscous oil.
Found,%: C 54.31; H 7.07; N 14-, 00
 N203 (198)
Calculated,%: C 54.55; H 7.07; N 14.14.
Example 8. 1- (H-Chlorobenzoyl-aminoacetyl) -2-cyanoaziridine,
4.27 g of N-chlorobenzoylglycine (m.p. 147-148c) is dissolved in 36 m of pure tetrahydrofuran, 1.36 g of 2-cyanoaziridine is added and after cooling to 0 ° C, 4.3 g of dicyclohexylcarbodiimide is stirred for 2 hours at the precipitated dicyclohexyl urea is filtered off on the filter, the filtrate is evaporated in vacuo, the residue after evaporation is dissolved in ethyl acetate, petroleum ether is added until the precipitate is evaporated. The oil is separated from the solvent, re-triturated with a fresh portion of petroleum ether and left overnight under a layer of petroleum ether. Thus, 2.1 g of the desired substance is obtained, which is slightly contaminated with dicyclohexyl urea, mp. 65-68c.
Example 9. 1- (4-Benzamido 7. butyryl) -2-cyanoaziridine.
2.07 g of 4-benzoylaminobutyric acid (m.p. 85-86 ° C) is dissolved in 13 ml of dioxane, a solution of 0.68 g of 2-cyanoaziridine in 2 ml of dioxane is added, added dropwise at 10 -15 ° C. A solution of 2.06 g of dicyclohexylcarbodiimide in 10 ml of dioxane, the solution is stirred for 30 minutes at 10-15 ° C and then left for overnight at room temperature, sucked on a filter and formed by cyclohexylurea (2.48 g) , washed with dioxane and the filtrate evaporated in vacuo. The oily residue after evaporation was triturated with ether and thus 1.8 g of the desired substance was obtained with a mp of 114-116 ° C and a slightly contaminated dicyclohexyl urea.
Example 10, l- (f -Haftoylamidoacetyl) -2-cyanoaziridine,
To suspension of 2.29 g | -naphthoylglycine. and 0.68 g of 2-cyanoaziridine in 18 ml of tetrahydrofuran at 0 ° C. add 2.15 g of dicyclohexylcarbodiimide in portions with maze, stir for 2 hours at 0 ° C, filter on the filter and wash with tetrahydrofuran and ether to form dicyclohexylmethyol in 10 h, wash with filter and wash with tetrahydrofuran and ether to form dicyclohexylmethylamine, and add a mixture of dicyclohexylmethylamine to the mixture. 18 g, t, mp, 228 ° C),
the filtrate is evaporated in vacuo, the oil triturated three times with ether and obtain 1.3 g of the desired compound with t, mp, 116-118 ° C,
Example 11, analogously to example 10, from 1.93 g of phenylacetylglycine (m, mp, 144g146 s) and 0.68 g of 27 Cyanoaziridine using dicyclohexylcarbodiimide (2.15 g) are obtained
1.7 g of 1-phenylacetamido-acetyl-2-cyanoaziridine with so pl. 114-116 ° C.
Example 12. Analogously to the primer 10 of 1.85 g of cyclohexylcarbonylglycine (mp. 150-152 ° C) and 0.68 g
2-cyanoaziridine with 2.15 g of dicyclohexylcarbodiimide after stirring for 3 hours, yielding 0.95 g of l- (cyclohexylcarbonyl-amidoacetyl) -2-cyanoaziridine with
m.p. 101-102 ° C I
Example 13. 1-Cyclohexyl acetamido-acetyl-2-cyanoaziridine.
Analogously to Example 10, from 1,98 g of crude cyclohexyl acetamidoacetic acid (m, mp, 52 ° C) and 0,68 g of 2 cyanoaziridine with 2.15 g of dicyclohexylcarbodiimide after 3 hours of stirring to obtain 1 g of the desired compound with mp, 133 g -135 ° C, which is dissolved in 100 ml of ethyl acetate at 50 ° C for further purification, the insoluble portion is separated by filtration and the filtrate is clear at room temperature and evaporated in vacuo. From the solid residue after evaporation, after trituration with ether, 0.8 g of the desired compound are obtained, m.p. 135-136 ° C,
Cyclohexyl acetamidoacetic acid used as starting material is obtained in the following manner. For approximately 10 minutes at 10 ° C, 3.21 g of cyclohexylacetyl chloride is added to a mixture of 2.5 g of glycine and 2 g of anhydrous soda in 20 ml of water and 0.8 g of NaOH, stirred for 2.5 h at, extracted twice with ether, with cooling
Approximately 8 MP conc., HC1 is acidified with ice and the oily product that gradually hardens is precipitated. It is sucked off on the filter, washed
ice water, cold ether, obtained 1.98 g of cyclohexyl acetylglycine. Example 14. Similarly, with 10 of 2.09 g of phenoxyacetylglycide (mp 121-123c) and 0.68 g of 2-cyano aziridine using 2.15 g of dicyclohexylcarbodiimide, after 3 hours of stirring at-0 ° C, 1.3 1-phenoxyacetate-acetyl-2-cyanoaziridine with so pl. 72-74 ° C. The phenoxyacetylglycine used as the starting compound is prepared analogously to the description of the synthesis and the starting material in Example 13. Thus, out of 2.5 g of glycine and 3.41 g of phenoxyethyl chloride, 3.4 g of phenoxyacetylglycine is obtained. Example 15. 1- (2,4-dichloro benzamidoacetyl) -2-cyanoaziridine. In the same way as Example 10 of 2.48 g of 2,4-dichlorobenzoylglycine (mp. 16 174 ° C) and 0.68 g of 2-cyanoazirn: Dine, using 2.15 g of dicyclohexylcarbodiimide, the desired compound is obtained in the form of a viscous oil with a yield of 1.4 Found,%: C 48.82 H 3.37; N 13.60 (298). Calculated,%: C 48.30; H 3.02; S14.10 The mass and PMR spectra are consistent with the indicated structure of the desired compound. Example 16. 1- (2-Benafuryl amidoacetyl) -2-cyanoaziridine. Analogously to Example 10 and 2.19 g of 2-Renzofuroylglycine (mp. 189190c) and 0.68 g of 2-cyanoaziridinone Psi dvu 2.15 g of dicyclohexylcarbrdiimide after 3 hours of stirring with 2.07 g of the desired substance in the form of crystals with m.p. 133-134 ° c. The 2-beisofuroylglycine used as the starting material is obtained from 2.5 g of glycine and coumaric acid chloride to yield 4 g (similar to the preparation of the starting compound described in Example 13). Example 17. 1- (Thiophene-2carbonylamidoacetyl) -2-cyanoairIr This substance is prepared as in Example 10 of 1.85 g of thiofe2-2carbonylglycine (mp. 170-171 C) and 0.68 g of 2-cyanoazir Idin with 2, 15 g of dicyclohexylcarbodiimide after 3 hours of stirring at a yield of 2 g as a viscous oil (containing a small amount of dicyclohexylurea. Data of elementary anyoshiz. (S, H, N, S), mass and pMR spectroscopes confirm the structure of this compound. Example 18. 1- (L-Succinimidoacetyl) -2-cyanoaziridine. This substance is obtained analogously to Example 10 from 1.57 g of N-succ Nimoacetic acid (mp. 111-113 ° C) and 0.68 g of 2-cyanoaziridine using 2.15 g of dicyclohexylcarbodiimide with a yield of 1.4 g (mp. 146-150 s), and after treatment with a saturated solution sodium bicarbonate in water gives a dicyclohexyl urea-free substance Example 19. 1-c-Methylphenylsulfinyl-2-cyanoaziridine. To a solution of 2.1 g of 2-cyanoaziridine and 3.66 g of triethylamine in 50 ml of ether, a solution of 5, is added to the solution, 23 g of crude H-toluenesulfinic acid chloride in 10 ml of abs. ether, stirred for 1 h, the precipitated salt with HCl is sucked off on the filter, the ether solution is evaporated, after which 3.66 g of the substance remain. This precipitate after evaporation is dissolved in a small amount of ether, twice: extracted with 5 ml of water. The ether phase is dried and evaporated, the residue (4.58 g) is triturated under ice-cooling with a small amount of ether, the undissolved crystals are sucked off on a filter, and thus 1.05 g of the desired compound is obtained with m.p. 102104 C. After rubbing, some more of the required substance is extracted from the mother liquor. Example 20. 1-Methylsulfonyl-2-cyanoaziridine. To a solution of 1.4 g of 2-cyanoaziridine and 2.42 g of triethylamine in 30 ml of fat, a solution of 1.6 ml of methanesulfonic acid chloride in 10 ml of abs is slowly added with cooling. ether, transfer for 1 h, filter the resulting salt with 10S1 on the filter, evaporate the ether filtrate, evaporate the residue after evaporation (2.7 g), column chromatography (150 g silica gel, bed height 35. cm, elution with chloroform), On a thin-layer chromatogram (on a plate with silica gel) with elution with chloroform, two spots were observed: one near the start, the second near the solvent front. CocVipa fractions corresponding to the lower spot (near the start), evaporated in vacuo and thus receive 1 g of the desired substance in the form of oil. Found,% s C 32,82; H 4.07; S 21.70. C.HgNjOS (146) CalcdT1o,%: C 32.88; H 4.11; N, 21.92. The mass and PMR spectra are consistent with this structure of the desired compound.
Example 21. (3-Chloropropionamido) -propionyl -2-cyanoaziridine.
Example 10 From 0.9 g of 3- (p-chloropropionylamino) -propiionic acid and 0.34 g of 2-cyanoaziridine with g of dicyclohexylcarbodimide, after 3 hours stirring at 10-15 ° C, 0.93 g of the desired compound is obtained (t 60–72c), a little contaminated with dicyclohexyl urea i
The 3 - (} - chloropropionamido) propionic acid used as the starting compound is obtained from 2.94 g of 3-aminopropionic acid and 2, 3-chloropropionic acid chloride (similar to the synthesis of the starting compound described in Example 13) with a yield of 1.2 g (t mp 110112 C). Since after acidification conc. “Cl, the desired product does not precipitate, in this case the aqueous phase is again extracted with ethyl acetate, the combined ethyl acetate extracts are evaporated in vacuo to a volume of about 200 ml, then neutralized by shaking with solid sodium bicarbonate and, finally, the filtered clear solution in ethyl acetate is evaporated vacuum.
Example 22. 1-Diphenylacetyl2-cyanobiridine.
To a solution of 1.06 g of diphenylacetic acid in 10 ml of ether was added with a solution of 0.34 g of 2-cyanoaziridine in 1 ml of ether and a solution of 1.03 g of dicyclohexylcarbodiimide in 4 ml of ether, stirred for 1 hour at and 2 hours at room temperature, Sucked on a filter of 1.06 g of the formed dicyclohexyl urea (m.p. 22 bs), the ether filtrate is evaporated, the residue is shaken twice with 4 ml of water, the ether phase is separated and 0.97 g of the desired compound is obtained as a yellowish viscous oil.
Data from elemental analysis, as well as mass and PMR spectra, confirm the structure of the required compound.
This compound can be obtained by another method of 1.15 g of diphenylacetyl chloride in 5 ml of abs. ether was added dropwise at 0 ° C to a solution of 0.35 g of 2-cyanoaziridine and 0.6 g of triethylamine in 15 ml of ether, stirred for 1 hour at and 2 hours at room temperature, the precipitated HC1 salt (0.7 g the filtrate is evaporated to a volume of about 10 ml and shaken twice with 5 ml of water.After evaporation of the ether phase, 1.13 g of the desired substance remain.
Example 23. 1-Methoxymalonyl-2-cyanoaziridine.
5.9 g of malonic acid ester monomethyl of 3.4 g of 2-cyanoaziridine and
10.8 g of didiclohexylcarbodiimide are dissolved under cooling in 60 ml of tetrahydrofuran. The mixture was stirred for 45 minutes, the precipitated dicyclohexyl urea was filtered off and the filtrate was evaporated. Obtain 2.8 g of crude product, which is recrystallized from boiling ether, t, p. 48-50s
Example 24. 1- (DL-1-3TOKCH2-ethylmalonyl) -2g-cyanoaziridine.
To 3.2 O monoethyl ether of DL ethylmalonic acid and 1.36 g of 2 cyanoaziridine in 32 ml of ether, 4.3 g of dicyclohexylcarbodiimide was added under ice-cooling. The mixture is kept for 2 days at room temperature, the dicyclohexyl urea filters are separated. The filtrate is evaporated, the oily residue is purified by chromatography on a column of silica gel, eluted with a mixture of heptane methyl ethyl ketone. Get 2.2 g of colorless, not containing impurities according to thin-layer chromatography of oil,
. Example 25. 1-MethoxisuccineNIL-2-cyano-eiridine,
2.64 g of succinic acid monomethyl ester, 1.36 g of 2-cyanoazyridine and 4.3 g of dicyclohexylcarbodiimide are condensed into 25 ml of ether and treated in the same way as described in Example 24. This gives 1.75 g of a colorless oil. Chromatography column chromatography eluent 5: 5: 1, chloroform-acetone-cyclohexane
Example 26. 1- (C1, -O-Acetylactoyl) -2-cyanoaziridine.
2, 64 g of DL-Acetyl lactic acid is dissolved in 26 ml of ether. While cooling with ice, 1.36 g of 2-cyanoaziridine and 4.3 g of dicyclohexylcarbodimimide are added and stirred for 2 hours. After processing and purification in the same manner as described in Example 25, 2.2 g of a yellowish oil are obtained.
Example 27. 1-Succinamoyl-2 cyanoaziridine.
1.85 g of succinic monoamide is suspended in 35 ml of tetrahydrofuran. Under ice cooling, 3, .4 g of dicyclohexylcarbodiamide and 1 g of 2-cyanoaziridine are added. The mixture was incubated overnight at room temperature, the dicyclohexyl urea was filtered off and the filtrate was evaporated. Get 0.35 g of substance with so pl. 68-72 ° C.
Example 28. 1- (2-Acetoxy-4-acetaminobenzoyl.) - 2-cyanoaziridine. 4.5 g of OH-O-diacetyl-I-aminosalicylic acid, 1.3 g of 2-cyanoaziridine and 4.1 g of dicyclohexylcarbodia. The guide is reacted in 45 ml of tetrahydrofuran. After separation of the dicyclohexylurea, filtration of the evaporation of the filtrate and crystallization of the residue with ether give 1.4 substances with a mp. 118-120s. Example 29, 1- (6-Chlorpyrid azin-3-carbonyl) -2-cyanoaziridine. 1.1 g of b-chloropyridazine-3-carboxylic acid are suspended in 11 ml of tetrahydrofuran and 0.47 g of 2-cy. Anaziridine and 1.5 g of dicyclohexylcarbodiimide are added with cooling. After 1 hour of stirring at room temperature, filter out the dicyclohexyl urea and crystallize the desired product with ether. N Yield 0.7 t; m.p. 109-115 ° C. Example 30. 1- (n-acetylglycine 2-cyanoaziridine. 5.85 g of N-acetylglycine, 3.4 g of 2-cyanoaziridine and 10.8 i dicyclohexylcarbodiimide are stirred for 2 hours at room temperature in 60 ml of tetrahydrofuran. Then the precipitated dicyclohexylurea is filtered off well, the filtrate is evaporated and the residue is entrapped with ether to give 5.2 g of crude product. The product can be recrystallized from a mixture of ether and methanol and melted at 102-104 ° C. Example 31 "1-HYPPURIL-2 cyanoaziridine. 3.6 g hippuric acids and 1.36 2-cyanoaziridine are dissolved in 36 ml of tetrahydrofuran and cooled 4.3 g of dicyclohexyl carbodiimide are added with ice. After 2 hours, dicyclohexylurea is filtered off and the filtrate is evaporated. The residue is recrystallized from methylene chloride-ligroin mixture and 1.35 g of substance are obtained with a melting point of 78-8lc. Phthalimido atyl) -2 cyanoaziridiNa Jaoluchan} t similarly from 4.1 g of phthalylglycine, alchod - 3.3 g, m.p., 126-128 0. Example 33. 1- (Pb-L-Acetyl aminopropionyl) -2-cyanoaziridine Get similar to KS 3.9 g of acetylanine. The product is a water soluble oil. Example 34, 1 (L-L-AcetalYlamino-phenylacetyl) -2-cyanoaziridine Prepared analogously from 4.2 g of H-acetyl-OV-B-phenylglycine. The mixture is stirred at room temperature, then it is subjected to conventional processing. 1.3 g of substance are obtained with m.p. 96-102 0. Example 35. 1- (DL-L-Acetylamino-p-phenylpropionyl) -2-cyanoazir din. It is obtained analogously from 2.1 g of N-acetyl-Pb-phenylalanine. The residue after evaporation is crystallized from ether. Yield 1.25; bp 97-109 ° C. Example 36. 1-Benzyloxycarbonylglycyl-2-cyanoaziridine. Receive similarly from 4 g of carbobenzoxyglycine. After the usual treatment, 3.7 g of oil is isolated, Example 37, 1- (Nn-tosylglycyl) -2-cyanoaziridine. It is obtained similarly from 4.6 g of y-tosylglycine. The residue after evaporation is triturated with ether, 4.1 g of substance are obtained with m.p., 124-128 ° C, Example 38, 1- (n-Trifluoroacetylglycyl) -2-cyanoaziridine. It is obtained similarly from 3 g of s-trifluoroacetyl-glycine, 3.7 g of an oil was isolated, PRm.per 39, 1- (H-Acetyl-Pleucyl) -2-cyanoaziridine, 3.4 g of I-acetyl-DL-leucine are suspended in 34 ml of tetrahydrofuran, 1.36 g of 2-cyanoaziridine is added, cooled and 4.4 g of dicyclohexylcarbodiimide are added with stirring. the mixture was vortexed for 2 hours in an ice bath, then overnight at room temperature. After that, dicyclohexyl urea is filtered off and the filtrate is evaporated. The residue is triturated with ether, get 2.89 g of white crystals with t, mp, 112-11b with, PRI me R 40, 1- {Bb-Acetal in the ethoxymalonyl) -2-cyanoaziridin, 3.8 g The monoethane ester of acetamidomalonic acid is suspended in 40 ml of ether, 1.35 g of 2 cyanoaziridine and 4.3 g: dicyclohexnylcarbodiamide are added and the mixture is stirred for 2 hours in an ice bath. Thereafter, the filter is: ary dicyclohexyl urea and, after evaporation of the filtrate, 0.5 g of white crystals are isolated with m.p., 124-1270s, Example 41, 1- {2-Pyrrolidone-1-methylcarbonyl) -2-cyanoaziridine, 2.2 - g 2 -pyrrolidone-1-acetic acid is suspended in 44 ml of tetrahydrofuran and 1.04 g of 2-cyanoaziridine and 3.3 g of dicyclohexylcarbodiimide are added with stirring and ice-cooling, after 2 hours (O C) and dicyclohexylmobinuate is filtered off at 2 hours, the filtrate is evaporated and after triturating the residue with ether, 2.5 g of crystalline product are obtained with t, pl. 86-90s (foaming), Example 42, 1- (4-Methylbenzamidoacetyl) -2-dianoziridin. Analogously to example 10 of 0.96 g of fl-cholyl glycine (t, mp, 161-1b2 C) and 0.34 g of 2-cyanoaziridine in 10 ml of tetrahydrofuran with the addition of 1.08 g of dicyclohexylcarbodiimide (at 10-15 ° C), stirring for 30 minutes at 10-15 ° C and 2 hours at room temperature, filtering the cyclohexylurea (mp. 228 ° C) and evaporating the filtrate in vacuo to obtain the crude desired substance. This substance is dissolved in ethyl acetate, the resulting solution is extracted with saturated aqueous pacTBOpioM sodium bicarbonate, the organic phase is dried and evaporated. The residue after evaporation is triturated twice with ether, thus obtaining 0.95 g of the desired substance with-mp. 92-94 0.
Example 43. 1- (3,4-Methylenedioxy-benzoyl) -2-cyano-eiridine.
To a solution of 0.68 g of 2-cyanoaziridine and 1.2 g of triethylamine in 100 ml abs. At 0 ° C. a solution of 1.85 g of 3,4-methylenedioxybenzoyl chloride in 80 ml is added. ether, stirred for 1 h at 0 ° C and 1 h at room temperature, sucked on; filter, the precipitated salt with HC1, ether, is evaporated, the residue after evaporation is triturated with 45 ml of ether, the resulting crystals are sucked off on the filter, 1.75 g of the desired substance is obtained with so pl. 95 ° -97 ° C.
Example 44. 1- (n-Formylglycyl) -2-cyanoaziridine.
2.06 g of N-pharmylglycine are suspended in 20 ml of tetrahydrofuran, 1.36 g of 2-cyanoaziridine and 4.3 g of dicyclohexylcarbodiimide are added under ice-cooling and stirred for 2 hours. After the usual treatment, 0.85 g of soluble water with crystals is obtained. square 51-56 ° C.
Example 45. 1- (C-Acetyl-cmethylglycyl) -2-cyanoaziridine.
It is obtained similarly from 2.6 g of M-acetyl sarcosine. Yield 1.7 g of substance as yellowish oil.
Note 46. 1- (c-Acetylglycyl-Glycyl) -2-cyanoaziridine.
5.05 g of acetylglycyl-glycyl are dissolved in 60 ml of N, N-dimethylphoramide and 2 g of 2-cyanaziridine and 6.3 g of dicyclohexylcarbodiimide are added under ice-cooling. After 2 h (). and dicyclohexyl urea is filtered off at room temperature for 2 hours, the filtrate is evaporated in vacuo and after redissolving the residue in ethyl acetate, 1.4 white, E (water-soluble crystals, mp. 70-76 ° C are obtained,
I; .
Example 47. 1- (n-Ethoxycarbonylglycyl) -2-cyanoaziridi n.
Prepared in the same way as in the example 45 from 2.94 g of N-ethoxycarbonylglycine. Yield 2.6 g, water-soluble crystals, m.p. 55sa c.
Example 48. 1- (5-Acetylhydantoyl) -2-cyanoaziridine ..
3 g of 5-acetylhydantoic acid are suspended in 30 ml of tetrahydrofuran, 1.28 g of 2-cyanoaziridine, and also 4 g of dicyclohexylcarbodiimide are added under ice-cooling and. stirring. The mixture is stirred for 4 hours in the cold, then kept at room temperature for 5 hours, dicyclohexylurea is filtered off and the filtrate is evaporated. After trituration with ether, a crystalline residue (2 g) is obtained with a mp. 11810/122 ° С ..
Example 49. 1- (OH-2n-Acetylglutaminyl) -2-cyanoaziridine.
The required product is obtained analogously from 3.8 g of N-acetylglutamine, 5 1.36 g of 2-cyanoaziridine and 4.4 g of dicyclorexylcarbodiimide in 38 ml of tetrahydrofuran as an oil.
Example 50. 1-Gadantoyl-2 cyanoaziridine.
Q 2.36 g of hydantoic acid, while carrying out a similar reaction, give 2 g of a substance with so pl. llO-ll C.
Example 51. 1- (N-Benzenesulfonyl-K-I-propylglycyl) -2-cyanoazi25 ridine,
2.6 g of H-benzenesulfonyl-N-n-propyl glycine is dissolved in 26 ml of ether, 0.68 g of 2-cyanoaziridine is added and 2.16 g of dicyclohexylcarbodiimide is added with ice-cooling. After the usual treatment, 2.3 g of substance are obtained in the form of an oil.
Example 52. l (N-f-Chloropropionylglycyl) -2-cyanoazir Idin.
It is obtained analogously from 3,3 chloropropionylLglycine in 33 ml of tetrahydrofuran. Output 1.4 g, so pl. N-12 ° C. .
I. PRI me R 53. l- (DL-2-N-acetyl linocyccinamoyl) -2-cyanoaziridine. 0
It is obtained analogously from 4.5 g of N-acetyasparagin. The output of 1.2 g of water-soluble amorphous product.,
Example 5-4. 1- (H-Lethyl-Valanyl) -2-cyano-Bb-aziridine.
. If the replacement used in example 33 is racemic N-acetylanine by K-acetyl-B-alanine, / ci / J
 +64, then after separation of the dicyclohexylurea, a mixture of diestereomers is obtained, from which two possible isomers can be isolated by repeated recrystallization from ether:
5 Isomer A: mp. 109-111 С (from
ether), chromatographically pure,, 6 (С Ij СН, ОН),
Isomer B: mp. 87-89 0 (from a mixture of acetone-ligroin 1: 1), chromatographic, pure, oil ° -166.0 (C If
CHjOH),. -h
Example 55. 1- (N-Phenoxycarbonylglycyl) -2-cyanoaziridine. Get similar from 3.9 g
5 K-phenoxycarbonylglycine in 40 ml
the ether. Yield 2 g, the substance in the form of oil.
Jrimer 56. 1- (o6-acetylaminoisobutyryl) -2-cyanoaziridine.
The substance in the form of an oil is obtained in a similar way from 5.4 g of oL-acetyl aminoisobutyric acid in 50 ml of tetrahydrofuran. The product is purified by chromatography on a column of silica gel using the solvent indicated in Example 25. i
Prlmer 57. 1- (CC-Phthalimidopropionyl) -2-cyanoaziridnn.
It is obtained in a similar way from 2.5 g of o6-phthalimidopropionic acid in 25 ml of tetrahydrofuran. Purify by column chromatography, washing with a mixture of heptane-methyl ethyl ketone 2: 1, obtain 1.4 g of substance in the form of oil.
Example 58. 1- (c-Acetyl-Nphenylglycyl) -2-gziyanoaziridin.
A similar manner is obtained from 3.86 g of i-acetyl-H-phenylglycine in 40 ml of tetraxy-shfuran. Output 3 g of white crystals with so pl. 69-75 C.
Example 59. 1- (L-Acetyl-Nbenzylglycyl) -2-cyanoaziridine,
It is obtained analogously from 4.14 g of N-acethyl-N-benzylglycine in 40 ml of tetrahydrofuran. 3.9 g of substance is obtained in the form of an oil.
Example 60 1- (c-methoxy-acetylglycyl) -2-cyanoaziridine.
2.94 N-methoxyacetylglycine is dissolved in 29 ml of tetrahydrofuran, while stirring under ice-cooling, 1.36 g of 2-cyanoaziridine and 4.3 g of dicyclohexylcarboxylic acid are added. imimide and stirred for 2 hours. After separation of the dicyclohexylurea / from the filtrate, 2.8 g of crystals are separated, which are dissolved in ethyl acetate for purification and precipitated with ligroin, m.p. 70-72c.
Example 61. 1- (p-Acetylaminopropionyl) -2-cyanoaziridine. Prepare similarly from 2.6 g of 5-acetylalanine. Yield 1.7 g of substance as a water-soluble oil.
Example 62. 1- (4-Acetaminobutyryl) -2-cyanoaziridine.
The analogous images are obtained from 4.4 g of 4-acetaminobutyric acid :. The crystalline product (3.8 g) is recrystallized from a mixture of ether and methylene chloride, so pl. 72-75 0.
Example 63. 1- (6-Acetylaminohexanoyl) -2-cyanoaziridine.
3.46 g of 6-acetylaminocaproic acid, 1.36 g of 2-cyanoaziridine and 4.3 g of dicyclohexylcarbodiimide are condensed and treated in the usual manner in 35 ml of tetrahydrofuran. 1.1 g of substance are obtained with a mp.
74-77 0 (recrystallization from ethyl acetate ligroin).
Example 64. 1-Cyclohexylacetyl-2-cyanoaziridine.
In a solution of 0.68 g of 2-cyanoaziridine II 1.2 g of triethylamine in 30 ml of abs. ether is added dropwise with a solution of 1.6 g of cyclohexyl acetyl chloride in 10 ml of abs. ether, stirred for 1 hour at and 1 hour at room temperature, the precipitated CH1 salt (1.38 g) is sucked off on the filter, the filtrate is evaporated, the residue after evaporation (dissolved in a small amount of ether) is treated three times with 5 ml of water, 5 The ester phases are dried and evaporated to give 1.62 g of the desired material as an oil. The results of the elemental analysis and the PMR-mass spectral data confirm the structure of the required 0 compound.
Example 65. 1- (2,4-Dichlorobenzoyl) -2-cyanoacidine.
Prepared analogously to Example 64 from 2.09 g of 2,4-dichlorobenzoyl chloride 5 (in 10 ml of ether) and 0.68 g of 2-cyanoazyridine, as well as 1.2 g of triethylamine (in 50 ml of abs. Ether), without treatment with water. From 2.2 g of a semi-solid reaction product (after trituration, with 4 ml of ether, 1.14 g of the desired substance is obtained with mp 95-97 s.
Example 66. 1-Cyclohexylcarbonyl-2-cyanoaziridine.
Prepared analogously to Example 64. From 1.46 g of cyclohexane 5 carboxylic acid chloride, g of 2-cyanoaziridine and 1.2 g of triethylamine 1.45 g of the desired substance is in the form of an oil, and the mass and PMR spectra are consistent with its structure.
Example 67. 1- (N- -Methoxybenzamidoacetyl) -2-ayanoaziridine.
1.04 g of N- -methoxybenzoylglycine - (mp. 173-175 0) is suspended in
 10 ml of dry tetrahydrofuran, 0.34 g of 2-cyanoaziridine is added and then at 10-15 ° C 1.08 g of dicyclohexylcarbodimide, the mixture is stirred at this temperature for 4 hours, filtered, washed on a filter with tetrahydrofuran and ether (wash liquids combined with filtrate). The solid thus obtained (1.1 g; mp. 224j227c) is 1,3-dicyclohexyl5 urea. The filtrate is evaporated in vacuo and the residue after evaporation is dissolved in ethyl acetate. This solution is shaken with a saturated aqueous solution of sodium bicarbonate, the organic phase is separated, dried
and evaporated (in vacuo). The residue after evaporation is again dissolved in ethyl acetate (15 ml), petroleum ether is added until the oil precipitates,
5 liquid decanty, oil twice
triturated with petroleum ether and get 0.85 g of the desired substance; m.p. 117-120 ° C.
Example 68 1-Carbamoyl Acetyl-2-Dianoziridine.
2.15 g of dicyclohexylcarbohydlimide is added in portions at 0-5 ° C to a suspension of 1.08 g of carbamoyl acetic acid and 0.68 g of 2-cyanoaziridine in 13 ml of tetrahydrofuran, stirred for 1 hour at and 2 hours at room temperature, filtered, washed with tetrahydrofuran and ether, combining the washings with the filtrate and thus obtain 2.2 g of dicyclohexyl urea {mp. 226-228 The filtrate is evaporated in vacuo, the residue is triturated with ether and in the end get 1.3 g of the desired substance with so pl. 115-119c.
Example 69. 1- (2-Thiophene carbonyl) 2-cyanoaziridine.
Analogously to Example 4, of 1.47 g of thiophene-2-carboxylic acid chloride and 0.68 g of 2-cyanoaziridine after 1 hour of stirring at 0 ° C and 30 minutes of stirring at room temperature (1.3 g of ammonium salt), followed by By evaporation of the mother ether solution, 1.45 g of substance is obtained in the form of an oil, from. which after chromatographic purification on a column of silica gel (150 g of silica gel; elution with chloroform) obtain 1.1 g of the desired substance in the form of an oil. The latter at a longer one hundred scientific research institutes hardens.
Example 70. 1- (3- (2-Furyl) acryloyl) -2-cyanoaziridine.
To a solution of 0.68 g of 2-cyanoaziridine and 1.2 triethylamine in 30. ml abs. ether added dropwise
with a solution of 1.56 g of p-furyl chloride (2) -acrylic acid in 10 ml of abs. ether, stirred 1 with OS and 1 hour at room temperature, the precipitated triethylamine salt is sucked off on a filter (1.28 g), the ether filtrate is evaporated to a volume of approximately 10 ml, shaken three times with 4 ml of water, the ether phase is dried and evaporated, 1.56 g of a dark brown oil is obtained which is purified by chromatography on a column of silica gel (150 g of silica gel; elution with chloroform), and thus 0.83 g of the desired substance is obtained in the form of an oil, which solidifies during longer periods of time.
The same substance can be obtained in another way: 2.1 g of dicyclohexylcarbodiimide (dissolved in 10 ml of ether) at 0 ° C is added to
"A solution of 1.38 g (i- (2-furyl} acrylic acid and 0.68 g 2-cyanoaziridi
30 ml of ether, stirred for 2 hours at 0 ° C and kept overnight at room temperature, 2.2 g of dicyclohexylurea are filtered off, the ether filtrate is shaken three times with 4 ml of water, dried and evaporated, after a similar purification on a column silica gel gives 0.9 g of an oil, which solidifies on standing for several days. After rubbing with petroleum ether, so pl. 59-61 S.
Example 71. 1- (3-Chloropropionyl) -2-cyanoaziridine.
Analogously to example 70, from 1.27 g of p-chloropropionic acid chloride and 0.68 g of 2-cyanoaziridine or from β-chloropropionic acid and 2 cyanoaziridine using cyclohexylcarbodimide without purification, on a silica gel column, 0.94 g of the desired substance is obtained as a yellowish oil ( the data of elemental analysis, PMR and mass spectra are consistent with its structure).
Example 72. 1-Stearoyl-2 cyanoaziridine.
 To a solution of 0.34 g of 2-gtsianoazirchg dina and 0.6 g of triethylamine in 30 ml of abs. ether is added with a solution of 1.51 g of stearic acid chloride in 10 ml of abs. ether, stirred for 1 hour and 1 hour at room temperature, the separated product is filtered off with suction, stirred with 100 ml of ethyl acetate, filtered off with suction (0.65 g of triethylamine salt) and the ethyl acetate filtrate is evaporated with ether. After trituration of the residue with ether, 1.2 g of the desired material is obtained after evaporation. 85-88 ° C. .
Example 73. 1-Prypionil-2 cyanoaziridine.
To a solution of 0.68 g of 2-cyanoaziridine and 1.2 g of triethylamine in 40 ml of abs. ether, a solution of 0.92 g of propionyl chloride in 40 ml of abs is added dropwise during about 15 minutes. ether, stirred for 1 h at 0 ° C and 2 h at room temperature, the precipitated salt is sucked off on the filter, washed with ether, combined with the filtrate, the filtrate is rubbed. in vacuum, get 1.44 g of oil. The oil is dissolved in ethyl acetate, shaken with a saturated sodium bicarbonate solution and, after drying, the ethyl acetate solution is evaporated in vacuo. Obtain 1.14 g of the desired substance in the form of a light oil, the data of elemental analysis, mass and PMR spectra confirm its structure. The substance is slightly polluted with water.
Example 74. 1-Pheno-6-acetyl-2-cyanoaziridine. Analogously to Example 73, 1.45 g of this substance is obtained, m.p., 92-94 from 1.7 g of phenoxy-acetic acid chloride and O, 68 g and 2-cyano-azirid. The substance is pressed on the filter (2.4 d) triturated with 70 ml of ethyl acetate, the remaining triethylamine salt (1.2 is sucked off on the filter, the ethyl acetate solution is evaporated in vacuo and the residue after evaporation is triturated with ether. Thus, 0.85 g of the desired substance is obtained. mp. 92-94c, the remaining 0.6 g of this substance (m.p. 92-94c) is obtained by evaporation of the first ether filtrate and subsequent trituration. ether 75. 1-Phenylacetyl-2-cyanoaziridine. 1.28 g of this substance (mp. 76-78 s) was prepared as in Example 73, from 1.54 g of phenyl acetic acid chloride and 0.68 g of 2-cyanoaziridine, moreover, after separation of the salt of triethylamine from HC1 and evaporation of the ether filtrate, the resulting residue is triturated with ether, resulting in the desired product is obtained in crystalline form Example 76. 1- (4-Methylbenzoyl) -2-cyanoaziridine. This substance (oil; 1.8) was obtained analogously to example 73 from 1.54 g of P-methylbenzoyl chloride and O, -68 g of 2 cyanoaziridine. It contains a small amount of ethyl acetate and water. The data of elemental analysis, PMR and mass spectra are consistent with its structure. Example 77. 1- (2-Benzofuroyl) -2-11 dianoaziridine. Obtain 1.3 g of this substance (so pl. 92-E4 ° C) analogously to example 75 of 1.8. g benzofuran-2-carbonyl chloride and 0.68 g 2-cyanoaziridine. Example 78. 1- (1-Methyl-3ipiopyrazole-4-carbonyl) -2-cyanoaziridine. A solution of 1.89 g of 1-methyl-3-nitropyrazole-4-carboxylic acid chloride in 20 ml of abs. ether and Yu ml abs. tetrahydrofuran is added dropwise at O - to a solution of 0.68 g of 2-cyanoaziridine and 1.2 g of triztilamine in 15 ml of abs. the ether is stirred for 2.5 hours at 0 ° C, this solution is decanted from the formed oil and evaporated in vacuo, the oily residue obtained after evaporation is dissolved in ethyl acetate, the separated oil is triturated with this ethyl acetate solution, insoluble triethylamine hydrochloride is sucked off, shaken An ethyl acetate solution with an aqueous solution of sodium bicarbonate, dried and the organic phase was evaporated in vacuo to give 2.1 g of an oil. This oil is triturated twice with ether and then with isopropanol, and a viscous oil is formed, which is then held overnight in isopropanol. This produces 1.1 g of the desired substance. 66-72 ° C, which is slightly contaminated with its isomer (with an open aziridine cycle). Example 79. l- (N-Ethoxycarbonyl-N-methyl-α-aminopropionyl) 2-cyanoaziridine. 3.5 g of AND-ethoxycarbonyl-n-methyl-pc1 / 1-inopropionic acid is dissolved in 35 ml of tetrahydrofuran, added. Under stirring and ice-cooling. 1.3.3 g of 2-cyanoaziridine and 4.3 g of dicyclohexylcarboxylate and stirred for 2 hours. Next The precipitated cyclohexylurea is separated and, after usual treatment, 3.7 g of the desired substance is obtained in the form of an oil. Example 80. 1- (| 3-Phthalim) 9dopropionyl) -2-cyanoaziridine. 2.5 g of | 3-phthalimidopropionic acid is dissolved in 25 ml of dimethylformamide and 2.46 g of dicyclohexylcarbodiimide and 0.78 g of 2-cyanoaziridine are added with stirring and ice-cooling. Stirring time: 2 hours in an ice bath, 4 hours at room temperature. After separation of the dicyclohexyl urea, the crude product is obtained, which is then recrystallized from ethyl acetate. Output 1 g, so pl. 168-170 0 .. Example 81. Succinyl-8is- (2 cyano-1-aziridine) 1.18 g of succinic acid and 4.3 g of dicyclohexylcarbodiimide are dissolved in 50 MP of tetrahydrofuran, after which precipitation occurs after a short time. 1.36 g of 2-cyanoEyridine was added and stirred for 2 hours in an ice bath. After separation of the dicyclohexylurea, the residue after evaporation crystallized with ether and thus obtained 0.65 g of substance with m.p. 139144 ° C. Example 82. Decandiol-bis (2diano-1-aziridine). 4 g of sebacic acid are similarly reacted with 2.7 g of 2-cyanoaziridine. 1 g of the substance is obtained. 11-Q2 ° C (recrystallization from ethyl acetate-ligroin). Example S3. Ethanphosphono (2-cyano-2-aziridine). 1.36 g of 2-cyanoaziridine and 2.78 ml of triethylglycin are dissolved in 15 ml of abs. the ether. While stirring and cooling with ice, a solution of 1.47 g is added dropwise to this solution.
ethanephosphonic acid dichloride in 15 ml a.b. the ether. After allowing to stand overnight, the mixture is filtered, the residue is washed with ethyl acetate, and after evaporation of the filtrate and trituration of the residue with ether, 0.85 g of water-soluble crystals are obtained. .
PRI me R 84. DL- (2-Y-Acetylaminosuccinyl) -, 4-6is- (2-cyano-1 aziridine).
A suspension of 4.5 g of H-aCetilasparatinic acid in a solution of 3.5 g of 2-cyanoaziridine and 11.1 g of dicyclohexylcarbodimide in 45 ml of tetrahydrofuran is stirred for 2 hours in an ice bath and treated in the usual manner. The oily product after evaporation is subjected to chromium. A graphical purification on a column of silica gel as in Example 25 and obtain 0.6 g of a water-soluble amorphous product.
Note 85. 2-1 ano-1- (diethoxyphosphoryl) -aziridine.
Solution 2, .5 g of chlorine ng ID reed diethylphosphoric acid in 12 ml of abs. ether, while cooling with ice, is added dropwise to a solution of 1.45 g; 2-cyanoaziridine and 3 ml of triethylamine in 14 ml of abs, ether. After 2 h, the precipitated salt is filtered off, washed with ether, the filtrate is filtered, the residue is purified on a silica gel column as in Example 25. 1.5 g of a colorless oil are thus obtained.
Example 86. 1- (3-Chlorocyridazine-6-mercapto-acetyl) -2-cyanoaziridine,
To a solution of 2.28 g of 3-hlorpiridazin6-mercaptoacetic kislty and 0.76 g of 2-tsianoaziridina in 25 ml tetragidrofuratsa added under ice-cooling, 2.4 g of dicyclohexylcarbodiimide and stirred for 2 hours. Poslevyderzhivani mixture overnight at room temperature the precipitated dicyclohexylurea is suctioned on the filter, the filtrate is evaporated in vacuo and the residue is dissolved in ethyl acetate. Then filter them with the addition of carbon, again evaporated and triturated with ether. Thus, 0.65 g of substance is obtained with m, pl, 104–107 ° C.
Example 87, 1- (4-Ethoxycarboylbenzoyl) -2-cyanoaziridine,. To a solution of 0.68 g of 2-cyanoaziridium and 1.2 g of triethylamine in VO ml of ether are added dropwise with a solution of 2.18 gC-Ztoxycarbonylbenzoyl chloride in 20 ml of ether, stirred for 1 hour at 0 ° C and 1 hour at room temperature the temperature of the precipitated triethylamine salt is filtered off on the filter, the filtrate is evaporated, the residue after evaporation is triturated with yfir, 1.45 g of crude product is obtained (m, mp 8286 C), from which, after purification by silica gel 5, (elution with ethyl acetate; 110 g silica gel) isolated 1.3 g of the desired substance with a melting point of 89-9-1s.
This substance is obtained by
0 by the following method: to a mixture of 0.97 g of Sh-e-syc arbonylbenzoic acid and 0.34 g of 2-cyanoaziridine in 15 ml of ether, a solution of 1.1 g of dicyclohexylcarbodischide in
5 5 ml of ether, stirred at this temperature for 2 hours and 1 hour at room temperature, injected dicyclohexylurea (1.13 g) is filtered off with suction, the filtrate is evaporated
Q and the residue is ground with about
3 ml of ether. The output of 0.66 g, so pl, 9294 ° C
1 Example 88, 1- (n, N-Diethylsuccinamoyl) -2-cytosis iridine,
5 To a suspension of 3.46 g of K, s-diethyl monoamide of succinic acid, 4.3 g of dicyclohexylcarbodiimide in 35 ml of tetrahydrofuran were added 1.36 g of 2-cyanoaziridine. After 2 hours of stirring in an ice bath and keeping the mixture overnight at x The dicyclohexyl urea is filtered off at ambient temperature and the filtrate is evaporated. 2.9 g of compound are obtained in the form of an oil.
5 Example 89. 1-CK- (Furan-2carbonyl) -hydride D-2-cyrinosis iridine. To a mixture of 1.69 g of N- (2-furoyl) glycine and 0.68 g of 2-cyanoaziridine in 18 ml of tetrahydrofuran 2 slowly
0 - 2.25 dicyclohexylcarbodiimide is added at O - 5 ° C, stirred for 1 hour at 0 ° C and 3 hours at room teperate e, the precipitated dicyclohexylurea is sucked off on the filter
5 (2.2 g; t, pl,), the filtrate is evaporated in an vacuum, the oily residue is triturated twice with ether and there are obtained 1.3 g of the desired (substance, t, pl, 93-100s.
The preparation of the starting compound, L- (27Furoyl) -glycine, used is carried out as follows: to 2.5 g of aminoacetic acid, 0.8 g of solid NaOH, 2 g
anhydrous salt in 20 ml of water is added dropwise at lO-lS from 2.6 g of furan-2-carboxylic acid chloride, stirred for 2.5 hours at 15 s, 8 ml are added with cooling cm.
conc, HC1, is left for 30 minutes in an ice bath, the precipitated substance is sucked off on a filter, washed with water, and 2.5 g of H- (o (, - furoyl)) aminoacetic acid with
t, pl, 165-168 s,
Example 90. 1-and-Vutylsulfinylacetyl-2-cyanoaziridine.
To a solution of 2.8, g prepared according to example 7 of 1-H-butylmercaptoacetyl-2-cyanoaziridine in 60 ml of chloroform was added dropwise, at room temperature, a solution of 2.93 g of m-chlorobenzoic acid in 20 ml of chloroform, swept over 2 hours at room temperature, evaporated in vacuo To a volume of approximately 40 ml, shaken three times with 8 ml of an aqueous solution of sodium bicarbonate, dry the organic phase, evaporate chloroform and obtain 2.64 g of the desired substance as an oil. After chromatographic purification on a column with 180 tons of silica gel (elution with ethyl acetate), 1.07 g of an individual by this thin-layer chromatography of the substance in the form of a viscous yellow oil are obtained. The analytical data of the elemental analysis, cnos and mass spectra of its structure are determined.
Example 91. 1-Cyclopropylcarbonyl-2-cyanoaziridine.
1.34 g of this compound is obtained in the form of an oil as in Example 87I. 1.36 g of 2-cyanoaziridine and 2.2 g of triethylamine in 30 ml of ether are reacted with 2.09 g of cyclopropanecarboxylic acid nlrganhydride, then the ether filtrate after separating the triethylamine salt from HC1 extracted three times with 4 ml of water, the ether phase is dried and evaporated. After purification of 1 g of this compound by column chromatography on co-100 g of silica gel with elution with chloroform, O is obtained, 5 g of the desired compound are in the form of an oil. Analytical data of elemental analysis, PMR and mass spectra correspond to its structure.
Example 92. 1-Cyclopropylcarbonyl-aminoacetyl-2-cyano-epirpine. .
This substance is obtained by reacting 0.71 g of cyclopropylcarbonylglycine (mp. 128-130s) with 0.34 g of 2-cycloaziridine in 9 ml of tetrahydrofuran in the presence of 1.08 g of dicyclohexylcarbodiimide analr to example 89 with a yield of 0.75 g Lt. square 116-118 c)
Cyclopropylcarbonylglycine used as the starting material was prepared analogously to example 89 from cyclopropanecarboxylic acid chloride and aminoacetic acid.
PRI me R 93. 1- (2-Methylthiazole-5-carbonyl) -2-cyanoaziridine,
To 1.6 g of 2-methylthiazole-5-carboxylic acid (m.p. 209С) and 0.76 y: 2-cyanoaziridine in 20 ml, tetrabiolofuran is added at 2.4 g of dicyclohexylcarbodiimide, stirred for i h at and 3 at room temperature, the precipitated dicyclohexyl urea is filtered off on the filter, 5 is washed with tetrahydrofuran and ether, the filtrate is evaporated in vacuo, the residue is dissolved in ethyl acetate, extracted with saturated aqueous sodium bicarbonate solution, the organic phase is dried and evaporated in. vacuum, get 2.33 g of substance in the form of oil. The oily residue after evaporation is dissolved in 90 ml of ether, incubated overnight.
5 at ksmnatnoy temperature, the precipitated dicyclohexyl urea is filtered off on the filter, the ether solution is evaporated and the residue is triturated with a small amount of ether, 1.4 g are obtained
Q required substance with so pl. 90-92 s.
Example 94 1- (1- (6-Pyridazonyl) -acetyl) -2-cyanoaziridine.
Suspend 3.5 g of 1 -. (6-pyridazonyl) -acetic acid in 35 ml
5 of tetrahydrofuran, 1.59 g of 2-cyanoaziridine is added and, under ice-cooling, 4.91 g of dicyclohexylcarbodimide. After stirring for 2 hours in an ice bath, the mixture was left at room temperature, the dicyclohexyl urea was separated and the filtrate was evaporated. The crystalline residue is triturated with ether and sucked on the filter. Obtain 3.85 g of white crystals with so pl, 87-91 C, Example 95. 1- (3,4,5-Three
{methoxybenzoyl) -2-cyacoaziridine,
In the same way as described in Example 94, 1- (3,4,50 trimethoxybenzoyl) -2-cyanoaziridine is obtained from 3,4,5-trimethoxybenzoic acid: mp. 86-89 ° C.I
Example 96. 1-Acryloylaminoate IL-2-cyanoazir Idin.
To a suspension of 1.29 g of N-acryloylgly 5. Cin (m.p., 128-131 ° C) and 0.68 g of 2 cyanoaziridine in 25 ml of ether are added a cc with a solution of 2.06 g of dicyclohexylcarbodiimide in 5 ml of ether, the mixture is stirred at 0 ° C for 2 hours, clotted overnight at room temperature, filtered with suction. the crystals formed (3.25 g), mixed with 30 ml of ethyl acetate, the incompletely dissolved dicyclohexylurea is filtered off, the ethyl acetate filtrate is evaporated in vacuo and grind the oil, the remaining residue is absorbed by evaporation with
ether, O., 63g of the required Q / compound with t, pl. 125-126 ° C.
 Example 97. N, N-Terephthaloylbis -1- (2-cyanoaziridine).
To a mixture of 1.36 g of 2-cyanoaziridine and 2.4 g of triethylamine in 60 ml of abs. 5 ether is added dropwise with a solution of 2.03 g of dichlorohydrin
terephthalic acid in 20 ml abs. ether, stirred for 1 hour at 0 ° C and 2 hours at room temperature, the solid product (5.3 g) is rtsactivated on the filter, the finely divided solid product is shaken with 100 ml of dioxane at 60 ° C, the insoluble part is filtered, the dioxane filtrate is evaporated in vacuo , the residue after evaporation is triturated with ether to obtain 2.1 g of crystals. The resulting crystals were triturated with a saturated aqueous solution of sodium bicarbonate solution, the resulting crystals were filtered, washed with water, and thus 1.8 g of the desired compound were obtained, mp. 168170 C.
Example 98. 1-Propionyl-2 cyanoaziridine.
To a mixture of 0.68 g of 2-cyanoaziridine in 5 ml of abs. 1.95 g of propionic anhydride is added dropwise at room temperature, stirred for 4 hours at this temperature, then this solution is added dropwise to a vigorously stirred solution of sodium bicarbonate in 50 ml of water, extracted twice with ethyl acetate, the combined extract evaporated in vacuo to obtain 1.6 g of substance. This substance is treated with a suspension of 5 g of sodium bicarbonate in 30 ml of water, vigorously stirred for 30 minutes, the insoluble bicarbonate is filtered off with Hai, the filtrate is extracted twice with ethyl acetate, the organic phase is evaporated in vacuo to give 0.85 g of the desired substance, which is identical to the substance described in the example 73 (according to thin layer chromatography, mass and PMR spectra). Example 99. 1- (c (Pyridone (2) acetyl) -2-cyanoaziridine.
While stirring and cooling with ice, 3.06 g of N-pyridone (2) -acetic acid, 1.36 g of 2-cyano-pyridine and 4.3 g of dicyclohexylcarbodiimide and 31 MP of tetrahydrofuran are combined. After 2 h, the temperature of the reaction mixture is raised to room temperature and dicyclohexyl urea is filtered off. The evaporation drum is dissolved in butyl acetate, filtered, ligroin is added to the filtrate and the precipitated oil is crystallized with ether. Obtain 2.9 g of substance with so pl. 97-102 C, (foaming) ...
Example 100. 1- (1-Methyl-Znitropyrazole-4-carbonylglycyl) -2 cyanoaziridine.
1.14 g of H- (1-methyl-3-nitropyrazole-4-carbonyl) -glycine (m.p. 159161 C) is dissolved in 70 ml of hot tetrahydrofuran, 0.34 g is added
2-cyanoaziridine and then 1.5 g of dicyc-I-lehexylcarbodiimide are added in portions at 25-30 ° C, stirred for 5 hours at room temperature, left overnight, sucked off on
5 filter the precipitated substance (dicyclohexylureas), the mother liquor is evaporated in vacuo, the residue after evaporation (2.65 g of oil), after 30 minutes in
0 10 ml of tetrahydrofluoride are triturated therefrom, thus obtaining 0.45 g of the desired compound as a crystalline substance with m.p. 158160 ° C, from the mother liquor after
5 re-evaporation and grinding more O, 3 g of tubular substance, which as an impurity contains a small copy of B9 dicyclohexyl urea, therefore
0 it is dissolved in warm ethyl acetate, incubated overnight at room temperature, the precipitated dicyclohexylurea, ethyl acetate mother liquor is sucked on the filter
5 the solution is evaporated and the residue is triturated again.
The (1-methyl-3-nitropyrazole-4-carbonyl) -glycine used as the starting compound is obtained from 3.8 g of 1-methyl-3-nitropyrazole-4carbonyl chloride and 2.5 g of aminoacetic acid in the same way as. : described in example 89, with the release of 3.8 g
5 PRI me R 101. l- (A-Tiphilomethylbenzoyl) -2-cyanoaziridine.
To a mixture of 1.9 g of m-trifluoromethylbenzoic acid and 0.68. g 2-cyanoaziridine in 18 ml of tetrahydrofuran
0 is added in portions at 2.15 g of dicyclohexylcarbodiimide, stirred for 1 hour at and 3 hours at room temperature, the precipitated dicyclohexylurea is filtered off with suction,
5 The mother liquor is evaporated in vacuo, the residue is dissolved in 50 ml of abs. ether, hold for 3 days at room temperature, the residue is filtered dicyclohexylurea, the filtrate
Q is washed twice with 15 ml of water, the dried ether phase is evaporated, 2.7 g of substance are obtained. This substance is triturated with a small amount of ether, filtered off from an insignificant amount of crystalline by-product, evaporated from the mother liquor and obtain 2.2 g of the desired substance in the form of an oil. After chromatographic purification on a column of silica gel (approximately 120 times the amount of silica gel; elution with chloroform), a substance is obtained individually according to thin-layer chromatography (0.65 g). The same substance can
5 was also obtained from m-trifluoromethylbenzoyl fluoride and 2-cyanoaziri dine (analogously to example 43), Example 102. 1-Phenylsulfenyl-2-cyanoaziridine. To a mixture of 0.68 g of 2-cyanoaziridine and 1.2 g of triethylamine in 40 ml of abs, ether is added dropwise with a solution of 1.44 g of benzenesulfonyl chloride (mp. 38–40 ° C / O, 2) in 40 m abs. ether (for about 15 min), stirred for 1 h at and 2 h at room temperature, the precipitated salt with HCl is sucked off on the filter, the mother solution is evaporated in vacuo, the residue after evaporation is dissolved in ethyl acetate,. Shaking water with a solution of sodium bicarbonate and water, the organic phase is evaporated (the oily residue after evaporation is 1.4 g), the oily residue is shaken intensively four times with petroleum ether (20 ml each), resulting in 0 , 9 g of the required substance in the form of an Oil. It contains a little diphenyl sulfide. Elemental analysis data. PMR and mass spectra, as well as IR spectra confirm its structure. Example 103. 1- (2-Methylsulfinylbenzoyl) -2- cyanoaziridine .. This substance (m.p.143-145s) is given an antispeak py 90 out of 0.44 g of 1- (2-methylmercaptobenzoyl) -2 cyanoaziridine with a yield of 0.15 g, also known as column chromatography of Example 104. 1-H-Butylmercaptoacetylglycyl-2-cyano-vasiridine To a suspension of 1.025 N -butylmerca to acetylglycine (t.p., 80-82 s) and 1.3 p of dicyclohexylcarbodiimide in 25 ml of ether are added dropwise at 0 ° C a solution of 0.34 g of 2-cyanoazyr dine in 5 ml of ether, stirred for 1 at 1 hour at room temperature on the filter, resulting dicyclohexyl urea (1.1 Ff so pl. 226-230c), the ether solution is evaporated to a volume of about 10 ml, shaken twice with 2 ml of water, the ether phase is evaporated after drying, and thus 0.93 g of the desired substance is obtained as a yellow oil. The data of elemental analysis, mass and PMR spectra are consistent with its structure. The substance contains a small amount of i-butylmercaptoacetylglycine. The n-butylmercapto-acetylglycine used as the starting compound is obtained from 3.4 g of N butylmercapto-acetyl chloride and 2.5 g of aminoacetic acid with a yield of 2.4 g by a method similar to that described in Example 89. Example 105. 1- (i-Phenylbl-soyl) -2 -cyanoaziridine. To a mixture of 0.34 g of 2-cyanoaziridine and 0.6 g of triethylamine in 20 ml-abs. ether is added dropwise with a solution of 1.08 g of p-phenylbenzolyl chloride in 30 ml of abs. ether (for about 15 minutes), stirred for 1 hour at and 2 hours at room temperature, the precipitated compound was filtered off, washed with ether on a filter, combined washing with filtrate, the clear ethereal solution was evaporated, the residue was triturated with a small amount of ether and get totaling 0.7 g of the desired substance with so pl. 104-106 C. Example 106. 1- (2-Methylsulfonylbenzoyl) -2-cyanoaziridine. To a solution of 1.2 g of triethylamine and 0.68 g of 2-cyanoaziridine in 20 ml of dioxane a solution of 2.18 g of crude 2-methylsulfonylbenzoyl chloride (prepared from 6 g of 2-methylsulfonylbenzoic acid and 12 ml of thionyl; chloride under reflux for 3 hours and then evaporating the excess thionyl chloride) in 20 ml of dioxane, stirred for 1 hour at this temperature and 1 hour at room temperature, the resulting triethylamine hydrochloride 1.29 ml of mother liquor is evaporated in vacuum, residue after evaporation washed with izrpropanolom, 1.1 g, m.p. 126-130s, from which, after dissolving in ethyl acetate, washing this solution with an aqueous solution of sodium bicarbonate and evaporation of ethyl acetate in vacuo, 0.4 g of the desired substance is obtained; 135-137 ° C. Example 107. 1- (Phenylmercaptoacetyl) -2-cyanoaziridine, To a solution of 0.68 g of 2-cyanoaziridine and 2.1 g of dicyclohexylcarbodimide in 10 ml of ether is added dropwise. When a solution of 1.68 g of phenylmercaptoacetic acid in 20 ml of ether, stirred for 1 hour at 0 ° C and 2 hours at room temperature, the precipitated dicyclohexylurea (2.1 g) is filtered off with suction, the ether mother liquor is evaporated to a volume of approximately 10 ml, extracted twice with aqueous solution, bicarbonate and then the ether phase is evaporated , get 0.8 g of the desired substance in the form of yellowish Asla elemental analysis, PMR and which massspektrov confirm its structure. Example 108. 1- (c-Lethylmethionyl) -cyanoaziridine. To a suspension of 0.38 g of I-acetyl-Bmethionine and 0.136 g of 2-cyanoaziridine in 10 ml of ether are added dropwise with stirring with a solution of 0.412 g of dicyclohexylcarbodiim and 5 ml of ether, stirred for 1 hour at and 2 hours at room temperature and left overnight at room temperature. The dicyclohexyl urea formed is filtered off, the mother liquor is evaporated, the residue after evaporation is triturated with about 3 ml of ether, and thus 0.35 g of the desired substance is obtained with mp. 86-88 C. Example 109. 1-p-Ethoxycarbonylaminobenzoyl-2-cyanoaziridine. To a solution of 0.68 g of 2-cyanoaziridine and 1.2 g of triethylamine in 50 ml of ether, is added dropwise at 0 ° C. A consumption of 2.27 g of n-ethoxycarbonylaminobenzoyl chloride in 50 ml of ether, stirred for 1 hour at and 2 hours at room temperature, the crystals formed are filtered off with suction on a filter (2.9 g) and the mother liquor evaporated. The resulting crystals (2.9 g) are triturated with 20 ml of ethyl acetate, while 1.27 g of triethylamine hydrochloride remain undissolved, ethyl acetate the mother liquor is diluted with 30 ml of ethyl acetate, shaken twice with 5 ml of an aqueous solution of sodium bicarbonate, The cc phase is evaporated in vacuo to give 0.6 g of the desired material; mp. 137-139 From the residue (1.1 g) obtained after evaporation of the ether stock solution, another 0.49 g of the desired substance is obtained, having the same melting point, a solution of this residue in approximately 20 ml of ethyl acetate, extracting three times the extract with 5 MP aqueous solution of sodium bicarbonate and stripping the organic phase in vacuo. PRI me R 110. .1- (3-Cyclohexenecarbonyl) -2-ciaNoaziridine. Analogously to example 107, from 1.36 g of 2-cyanoaziridine and 4.2 g of dicyclohexylcarbodiimide in 40 ml of ether and 2.52 g of 3-cyclohexene of 1carboxylic acid in 20 ml of ether, 2.07 g of the desired substance is obtained as a yellow oil, from which dissolving in 5 ml of ether and keeping at room temperature for 12 hours, a further dicyclohexylurea is collected. After evaporation of the ethereal mother liquor, 1.8 g of yellow oil remain, which still contain some dicyclohexylurea. The data of elemental analysis, PMR- and mass spectra confirm the structure of the desired compound. Example 111. 1- (4-Cyanobenzoyl) -2-cyanoaziridine To a solution of 0.68 g of 2-cyanoaziridine and 1.2 g of triethylamine in 65 ml of ether, a solution of 1.65 g of 4-cyanobenzoyl chloride is added dropwise at 0 ° C 25 ml of ether, stirred for 1 hour at O®S and 2 hours at room temperature, precipitated triethylamine hydrochloride is filtered off on the filter, the ethereal mother liquor is evaporated, the residue is triturated with ether after evaporation and after chromatographic purification on a column of silica gel with elution of chloroform is separated 0., 6 g of the desired substance in the form of a white powder with m.pl, 107-110 C, Example 112. 1- (Phenylmercapto-acetylamidoacetyl) -2-cyanoaziridine. . To a mixture of 2.25 g of N-phenylmercaptoacetylglycine (m.p. 118-120s) and 0.68 g of 2-cyanoaziridine in 18 ml of tetrahydrofuran are added in portions at 0-5 ° C with 2.2 g of dicyclohexylcarbodiimide, stirred for 1 hour. at OC and 3 hours at room temperature, the precipitated dicyclohexyl urea (2.18 g, mp 226-228 ° C) is sucked on the filter, washed on the filter with tetrahydrofuran and then ether, / combined washing the filtrate with the filtrate, the combined filtrate is evaporated in vacuo, the oil inverse is triturated with ether; the ether insoluble oil solution in 30 ml of ethyl acetate , The resulting solution was allowed to stand overnight at room temperature, filtered, a small amount of the separated crystals, and the filtrate was evaporated in vacuo to give 1.6 g of the desired compound as a yellow oil which contained a small amount of ethyl acetate. The data of elemental analysis, NMR and mass spectra confirm the structure of the synthesized compound. The N-phenylmercapto-acetylglycine used as the starting compound was prepared as follows. To a solution of 2.5 g of glycine, 0.8 g of sodium hydroxide and 2 g of anhydrous soda in 20 ml of water, foT was added dropwise at 10-15 ° C. 3.73 g phenylmercaptoacetyl chloride, stirred for 2.5 hours at this temperature, add 8 ml of conc. in the cold. hydrochloric acid, after 30 minutes, the precipitated substance is filtered off, washed with water and thus obtained 4.3 g of substance with so pl. 118-120 ° C. Example 113. 1- (2-Phenylcyclopropane-1-carbonyl) -2-cyanoazkridin. To a solution of 1.2 g of triethylagline and 0.68 g of 2-cyanoaziridine in 20 ml
ether, added dropwise with a solution of 1.8 g of 2-phenylcyclopropane-1-carboxylic acid chloride in 10 ml of ether, stirred for 1 hour / at and 2 hours at a pitched temperature, precipitated triethylamine hydrochloride (1.36 g) the ether filtrate is evaporated to a volume of about 20 ml, extracted twice with portions of water of approximately 3 ml, the ether phase is evaporated, 1.43 g of substance is obtained as a yellow oil. This substance is subjected to chromatographic purification on a column containing 300 g of silica gel (elution with chloroform), resulting in a gain of 0.83 g of the desired substance in the form of a yellow oil. The data of elemental analysis, PMR and mass spectra confirm its structure.
Example 114. l -. (5-Hop6opHeH2-carbonyl) -2-cyanoaziridine.
Analogously to Example 113, from 0.68 g of 2-cyanoaziridine and 1.2 g of triethylamine in 30 ml of ether and 1.56 g of 5-norbornene-2-carbonyl chloride in 10 ml of ether after filtration of triethylamine hydrochloride (1.25 g), Shaking the ethereal filtrate of hrylodes with 5 MP portions of an aqueous solution of sodium bicarbonate and evaporation of the ethereal solution yields 1.82 g of the desired substance as a yellow oil. The data of elemental analysis, mass spectra of IR spectra confirm the structure of this compound.
Example 115. (2-Acetoxybenzoyl) -2-cyanoaziridine.
Analogously to example 113 and 1.36 g of 2-cya-1Noaziridine and 2.4 g of triethylamine in 60 ml of ether and 3.96 g of 2-acetoxybenzoyl chloride in 20 ml of ether after filtering the precipitated triethylamine hydrochloride (2.62 g), shake the ether filtrate three times with portions of an aqueous solution of sodium bicarbonate 10 ml each time, evaporation of the ether phase and purification of the PSU of the oil thus obtained by chromatography on a column of silica gel (elution with chloroform) gives 1.27 g of the desired compound as a clear, viscous oil containing a small amount of water. Data of elemental analysis of IR, PMR and mass spectra confirm the structure of this compound.
Example 116, 1- (H-Acetylpropi / 1) -2-cyanoaziridine,
To a suspension of 1.57 g of L-Y-Acetylproline (mp. 116-118c) and 0.68 g of 2c-11oaziridine in 40 ml of ether are added dropwise with a solution of 2.06 dicyclohexylcarbodiimide in 10 ml of ether, stirred for 1 hour at 0 ° C and 2 hours at room temperature, the precipitated dicyclohexyl urea (1.96 g) is aspirated on the filter, the filtrate is shaken three times with 5 ml portions of water, the combined aqueous extract is extracted three times with 10 ml portions of ethyl acetate and thus receive 1.2 g of the desired substance as a yellowish viscous oil. The data of elemental analysis, PMR and mass spectra confirm the structure of this compound.
Example 117. 1-Benzylmercaptoacetyl-2-cyanoaziridine „
Analogously to Example 116, from 1.82 g of benzylmercaptoacetic acid and 0.68 g of 2-cyanoaziridine in 40 ml of ether and 2 g of dicyclohexylcarbodiimide in 30 ml of ether after 3 hours of stirring at room temperature, filtering didloglohexylurea, washing the ether stock solution with an aqueous solution of the solution. and water, evaporation of the ether phase to a volume of about 4Q ml, keeping the resulting solution overnight at room temperature, filtering off the dicyclohexylurea residue and evaporating the filtrate to obtain (2.12 g of tubes compound as a viscous, colorless oil that contains a small amount of dicyclohexyl urea. Elemental analysis, IR-PMR and mass spectra confirm the structure of this compound,
Example 118. 1- (3-Ethoxy propionyl) -2-cyanoaziridine.
Analogously to Example 113, from 0.68 g of 2-cyanoaziridine and 1.2 g of triethylamine in 40 ml ether and 1.36 g of 3-ethoxypropanoic acid chloride in 40 MP ether after filtering 1.36 g of HC1 salt, evaporation of the filtrate to half the volume and Spent an aqueous solution of sodium bicarbonate and water to obtain 1 g of the desired substance as a yellowish oil. Data elementalTo analysis, IR, PMR and mass. The spectra confirm the structure of this compound.
Example 119, 1- (H, Hn-Dimethylamino-isoisoyl) -2-cyanoaziridine.
Analogously to Example 113, out of 0.34 g of 2-cyanoaziridine and 0.6 g of triethylamine in 20 ml of ether and the dissolved portion of 0.92 g of crude ft-dimethylaminobenzoyl chloride in 20 ml of ether, but after 3 hours of stirring at room temperature, make 0.3% g of the required substances st.pl, 104106 C. . P p i. meper 120, 1- (6-Methylpirndin-2-carbonyl) -2-cyanoaziridine,
To a solution of 0.68 g of 2-cyanoaziridi65 and 2.4 g of triethylamine in 20 ml of ether, is added dropwise at 0 ° C with 30 m of an ethereal solution of 6-methylpyridine-2-carbronic acid chloride obtained by adding 1.37 g of 6 -methylpyridine-2-carboxylic acid to 27 ml of thionyl chloride, heated
up to 80 ° C until a clear solution is formed (approximately 1 hour), followed by distilling off the excess thionyl chloride in vacuum at a bath temperature of 30-40 s and dissolving the residue after evaporation in 30 mp ether, stirred for 1 hour at 0 ° C and 2 hours at room temperature, the HC1 salt precipitated on the filter with suction, the ether filtrate was evaporated, the residue (0.9 g) was triturated with 4 ml of ether, 0.4 g of the desired compound was obtained, mp. 120-122 ° C
Example 121. 1- (2- (4-Chlorobenzoyl) -benzoi) -2-cyanoaziridine.
(2.6 g of 2- (p-chlorobenzoyl) -benzoic acid is dissolved in 30 ml of ether, 0.68 g of 2-cyanoaziridine is added, added dropwise with a solution of 2 g of dicyclohexylcarbodium in 20 mp of ether (approximately for 10 min), mix
1 hour at 0 ° C and 4 hours at room temperature, the precipitated dicyclbhexylurea is filtered off with suction on the filter (2.2 g), the ether filtrate is agitated with a sodium bicarbonate aqueous solution and twice with water, the ether phase is evaporated, 3 g of the desired substance is obtained in as a colorless, viscous oil containing a small amount of dicyclohexylurea. The data of elemental analysis, IR, PMR and mass spectra confirm the structure of this compound.
Example 122. 1- (4-Sulfs-IMO-Benzoyl) -2-cyanoaziridine.
To a suspension of 2.01 g of 4-sulfamoylbenoic acid and 0.68 g of 2-cyanoaziridine in 30 ml of tetrahydrofuran are added portionwise at room temperature 2 g of dicyclohexylcarbodiimide, distorted for 3 hours at room temperature, the precipitated dicyclohexyl urea is sucked off on a filter (1.4 g ), the filtrate is evaporated in vacuo, the residue after evaporation is dissolved in 70 ml of ethyl acetate, 0.3 g of the precipitated substance is filtered off, the ethyl acetate filtrate is shaken with an aqueous solution of sodium bicarbonate and then twice with water, the organic phase is dried and evaporated ayut in a vacuum. Pounded with ether residue after evaporation (2.1 g) melts at 1–2-165 s. 1.7 of this residue is boiled in 170 ml of chloroform, and 0.55 g of substance with m.p. 148-150 ° C remain undissolved. After cooling the chloroform solution, another 0.2 g of this substance is obtained. Thus obtained 0.75 g of crystals with so pl. 148-150 ° C are boiled again in 70 ml of chloroform, and after cooling5 to room temperature, 0.65 g of the desired substance is obtained, with a m.p. 145-146 "p.
Example 123. 1-Sorboyl-2 cyanoaziridine.
0 to a solution of 1.38 g of 2-cyanoaziridine and 2.4 g of triethylamine in 30 ml of ether is added dropwise with a solution of 2.6 g of sorbic acid chloride (mp. 73s / 12, obtained from sorbic acid
and thionyl chloride) in 10 mp ether, ne / stir for 1 h at and 2 h at room temperature, the precipitated HC1 salt is sucked off on the filter
Q (2.68 g), shake the ethereal filtrate twice with an aqueous solution of sodium bicarbonate, evaporate the ether phase, obtain 2.72 g of substance Gx of this substance are chromatographed on a graphical column.
silica gel (200 g silica gel, edited with a mixture of toluene-hexane 9: 1) and thus 0.75 g of the desired substance is obtained with mp. 56-58 c.
Example 124. 1- (Rodanine-Nmethylcarbonyl) -2-cyanoaziridine.
To a solution of 0.34 g of 2-cyanoaziridine and 1.06 g of dicyclohexylcarbodiimide in 20 ml of ether is added dropwise at room temperature a solution of 0.95 g of rodanine-M-acetic acid in 30 MP of ether, stirred for 3 hours at room temperature , precipitated crystals (1.8 g) are sucked on the filter, mixed with
0 10 ml of ethyl acetate and after evaporation of the latter in vacuo, 0.6 g of the desired compound is obtained in the form of a viscous orange oil containing a small amount of ethyl acetate. The substance is unstable at room temperature. The data of elemental analysis, IR, PMR and mass spectra confirm the structure of this compound.
0 Example 125. 1- (5-Fechylhydantoyl) -2-cyanoaziridine. ,
To suspensions of 1.94 g of K-phenyl-ncarboxycutylurea (m.p. 195197 C) and 0.68 g of 2-cyanoaziridine in 40 4n ether, are added dropwise with stirring a solution of 2 g of dicyclohexylcarbodiimide in 20 mp of ether, stirred for 4 hours at room temperature, then extract the mixture overnight at the same temperature. The mixture is filtered, prokstvot solid product. (3.6 g) with ether, triturate it with 100 MP of ethyl acetate, insoluble dicyclo / hexylurea so as 5 filter. 225-227 c), the filtrate is washed with a saturated aqueous solution of sodium bicarbonate and then several times with water, dried. Shake the organic phase, evaporate the ethyl acetate solution in vacuo. The solid residue after evaporation is triturated with ether and thus 1.1 g of the desired substance is obtained (mp 114-11b), which contains a small amount of 3-phenylhydantoin and dicyclohexylurea.
Example 126, 1- (4-g Acetamidomethyl-1-cyclohexylcarbranyl) -2 cyanoaziridine.
To 3.94 g of trans-4-aceto1Midomethylcyclohexane-1-carboxylic acid {m.p. 148-152 ° C) and 1.36 g of 2-cyanoaziridine in 80 ml of tetrahydrofuran are added dropwise at room temperature a solution of 4 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran, stirred for 4 hours at room temperature and left the mixture overnight. The resulting solid phase (5.6 g) is filtered off with suction, the tetrahydrofuranium and ether are poured, the liquids are combined with the filtrate, the filtrate is evaporated in vacuo to give 4.18 g of an oil. The oil is dissolved in ethyl acetate, shaken with a saturated aqueous solution of sodium bicarbonate and then several times with water, the organic phase is evaporated, the oily residue after evaporation of Cs, 3 g) is triturated twice with ether, 1.8 g of substance are obtained with m. square 97-100 seconds, from which, after trituration with ethyl acetate (approximately 50 ml), 0.5 g of an insoluble product was isolated with a mp. 190-193 s, while from one of the evaporated filtrate, after trituration with etheSF, 1 g of the desired substance is obtained, with a mp. 92-94 S.
Example 127. 1- (1-H-Chlorophenylcyclopentane-1-carbonyl) -2cy anoaz iridium n.
To a mixture of 0.68 g of 2-cyanoaziridine and 1.2 g of triethylamine in 40 ml of ether, a solution of 2.43 g of acid chloride - {/ chlorophenyl) -1-cyclopentanecarbonate acid (so boiling point) is added dropwise at 0-5 C. 176-178 C / 12) in 40 MP ether, stirred for 1 hour at 2 hours and at room temperature the precipitated HC1 salt (1.35 g) is filtered off with suction, the filtrate is extracted with aqueous sodium bicarbonate solution and twice with water, the ether phase is dried and evaporated , 2.5 g of substance is obtained in the form of an oil, which is crystallized when standing. Thus 2.5-g of the desired substance is obtained. 80-82 C.
Example 128. Cyclohexane 1, 2-dicarbonyl bis-1- (2-cyanoaziridine).
To a suspension of 1.72 g of ciscyclohexane1, 2-dicarboxylic acid and 1.88 g of 5 2-cyanoaziridine in 30 ml of ethanol, a solution of 4.1 g of dicyclohexylcarbodnimide in 20 ml of ether is added dropwise, stirred for 2 hours at room temperature, left for the night
0 dicyclohexylurea formed (mp. 227-230 ° C) is sucked off on
filter, ethereal filtrate twice
extracted with water, the ether phase
evaporated, get 3,02 g of substance
5 as a yellow oil. The oil is purified by chromatography on a column of silica gel (600 g of silica gel, elution with a mixture of toluene-dioxane 8: 2). Thus, 1.02 g of the desired substance is obtained in the form of a viscous clear oil, which contains a small amount of water and dioxane. The data of elemental analysis, IR, PMR and mass spectra confirm
5 structure of the desired compound.
Example 129. 1- (3-Camphorocarbonyl) -2-cyanoaziridine.
To a solution of 1.96 g of DL-3-camphoric acid and 0.68 g of 2-cyanoaziridine-. in 60 ml of ether, a solution of 2 g of dicyclohexylcarbodiimide in 20 ml of ether is added dropwise at room temperature, stirred for 3 hours and left overnight. The resulting didiclohexyl urea (2.18 g) is sucked off on the filter, the filtrate is concentrated to a volume of about 50 ml and left overnight in a refrigerator, after which another 0.03 g of dicyclohexyl urea drops out. Vacuum
0 and the filtrate is evaporated under vacuum (finally under high vacuum), to obtain 2.44 g of the desired substance as a colorless viscous oil, which contains an insignificant amount of 3-to-1-molar acid. Data of elemental analysis, IR, PMR and mass spectra undergo the structure of the desired compound.
Example 130. 1- (3-Acetyl0 propionyl) -2-cyanoaziridine.
To a solution of 3.48 g of levulinic acid and 2.04 g of 2-cyanoazyridine in 90 ml of ether are added dropwise at room temperature a solution of 5 to 6 g of dicyclohexylcarbodiimide in 45 ml of ether, stirred for 5 hours at room temperature, and left overnight then sucked on the filter to form dicyclohexyl urine wine (5.7 g, mp. 226/228 s),
the filtrate is evaporated to about 1/3 of a volume, washed with an aqueous solution of sodium bicarbonate and twice with water, the ether phase is evaporated, after which 5 5,3 g of oil remain. Water phase
re-extracting with ethyl acetate; the purified ethyl acetate extract is dried in vacuo, then 1.2 g of an oil remains, which consists essentially of the desired substance and 2-cyano-aziridine. The residue oil after evaporation of the ether (4.3 g) is left in the refrigerator for several days, after which the crystallization is formed, which is again triturated with about 10 ml of water. Thus, 1.05 g of crystals are formed, c. 93-94c (N-3-acetylpropionyldicyclohexylurea). The purified aqueous filtrate is then re-extracted with ethyl acetate, the purified ethyl acetate extract is dried and evaporated in vacuo. This gives 2.8 .g of the desired substance as a colorless oil. The elemental analysis data, IR, PMR and mass spectra, backlight the structure of the desired compound.
Example 131. Thiodiglycolyl-1- (2-cyanoaziridine). A solution of 3 g of thiodiglycolic acid and 8.6 g of dicyclohexylcarbodiimide is mixed with 2.7 g of 2-cyanoaziridine in 60 ml of tetrahydrofuran for 2 hours in an ice bath. After separation, the precipitated dicyclohexyl urea is purified by ethyl acetate on a column of silica gel and 2.5 g of a colorless oil are obtained. Example 132o Diglycolyl-bio1- (2-cyanoaziridine}.
The product obtained from 1.34 g of diglycolic acid as described above is recrystallized from ethyl acetate-ether. 0.75 g of product is obtained which melts at.
Example 133. 1- (11-Acetylaminoundecanoyl) -2-cyanoaziridine.
As described above, from 2.43 g of 11-acetaminoundecanoic acid, 0.85 g of oil is obtained, which crystallizes from ether and melts at 62-65 ° C.
Example 134. Benzene-phosphorus-1- (2-dianoziridin).
3 g of 2-cyanoaziridine and 6.1 ml of triethylamine are dissolved in 120 ml of ioxane. Then, 3.9 g of benzenediphosphonic acid dichloride is added dropwise, left overnight at room temperature and then the precipitated salt is separated. The residue after evaporation is purified with dioxane on a column of silica gel. After treatment with ligroin, 0.85 g of crystals are obtained with a mp. 11b-121 ° C.
Example 135. 1- (Phenoxy-oxioxy-fluoryl) -2-cyanoaziridine.
1.74 g of monophenyl phosphate and 1.39 ml of triethylamine are suspended in 17.4 ml of tetrahydrofuran. After adding 0.68 g of | 2-cyanoaziridine, a clear solution is formed which is mixed in an ice bath with 2.16 g of dicyclohexylcarbodiimide. After 2 hours, the precipitated dicyclohexyl urea is separated and obtained after purification, 2.4 g of the tri-i-ethyl ammonium salt as a yellowish oil.
Jl. Example 136. Dithio diacetyl U buc-l- (2-cyanoaziridine).
3.6 g of dithiodiacetic acid are dissolved in 72 ml of ether, cooled and 2.7 g of 2-cyanoaziridine and 8.6 g of dicyclohexyl arbo-5 dihydroyl are added. After 2 h, the precipitated dicyclohexyl urea is separated and the residue after evaporation is purified with xylene -. methyl ethyl ketone on a column of silica gel. 2.2 g of yellow oil is obtained.
Example 137. E - (-) - (| 1y, -Metoxy: phenylacetyl) -2-cyanoaziridine.
1 g of B (-) - 2-methoxy-2-phenylacetic acid is dissolved in 10 ml of 5 ether. Under ice cooling, 1.3 g of dicyclohexylcarbodiimide was added. After 15 minutes, 0.4 g of 2-cyanoaziridine in 2 ml of ether was added. The mixture is cooled for 2 hours in an ice bath, then the Q precipitated dicyclohexylurea is separated, the filtrate is collected, and 1.2 g are obtained as an oil. M -99, C 0.5; ethanol).
3 (+) -1- (o-methoxyphenylacetyl) -2c cyanoaziridine.
The optical antipode is obtained ana, logically from 5 (+) - 2-methoxy-2-phenylacetic acid, also in the form of oil,, 9. (C 0.5; ethanol),
Example 138. 1-K-Methylglycyl0 2-cyanoaziridine.
A suspension of 3 g of N-mesylglycine, 1.36 g of 2-cyanoaziridine and 4.32 g of dicyclohexylcarbodiimide in 30 ml of ether is stirred for 2 hours in an ice-cold 5 bath. The formed dicyclohexyl urea is then filtered off and the filtrate is evaporated. The residue is recrystallized from ethyl acetate-ligroin, and 1.17 g of 0 white crystals are obtained with mp. 83-88 0.
Example 139. Benzene tyophosAfono-ois-1- (2-cyanoaziridine),
1.36 g of 2-cyanoaziridine and 2.78 ml of triethylamine are dissolved in 27 ml of 5 (c. Ether. A solution of 2.11 g of benzenethiophosphonyl dichloride in 21 ml of abs. Ether is added dropwise. After 2 hours, the precipitated salt is separated , the filtrate is evaporated, the residue is purified by chromatography on a column of silica gel, eluting with ethyl acetate. Thus, 1.75 g of substance is obtained in the form of a yellowish oil.
Example 140. Phenoxyphosphorus 5 11Л-5ис-1- (2-cyanoaziridine).
5.4 g of 2-cyanoaziridine and 11.1 ml of triethylamine are dissolved in 198 ml (abs. Ether. At 5-10s, 8.4 g of phenoxyphosphoryl dichloride in 84 ml of abs. Ether are added dropwise. After 2 hours, the precipitated salt is filtered off , the residue after evaporation of the filtrate was purified on a column of silica gel, eluting with ethyl acetate to obtain 0.7 g of substance with mp 81-88 C.
Example 141. 1- (Diphenylaminophosphoryl) -2-cyanoaziridine.
A solution of 2.67 g of phosphoric acid dianilide chloride in 10 times the amount of abs.; Tetrahydrofuran is added dropwise with ice cooling to a solution of 0.68 g of 2 cyanoaziridine and 1.38 ml of triethylamine in 13.6 ml of tetrahydrrfuran. After 2 hours, the salt is filtered off and the filtrate is evaporated. When the residue is triturated with ethyl acetate, 1.26 g of BetaecTBa are obtained with the like. 1b9-172®C.
Example 142. 1- (Benzenemethoxyphosphonyl) -2-cyanoaziridine.
Similarly, 1.9 g of the substance is obtained in the form of a light yellow oil from 5 g of benzenemethoxyphosphonic acid chloride.
Example 143. 1-Dimethoxyphosphoryl-2-cyanoaziridine.
The desired compound as an oil is obtained from phosphoric acid dimethyl chloride in the same way. Spectral data confirm its structure.
Example 144. 1- (3-Methyl mercaptopyridazine-6-carbonyl) -2 cyanoaziridine.
2.2 g of 3-carboxy-6-methylmercaptopyridazine is suspended in 2 ml of ether, 0.88 f of 2-cyanoaziridine and 2 are added, and in g of dicyclohexylcarbodiimide and stirred for 2 hours in an ice bath. After overnight, the suspension is filtered, the filtrate is evaporated, the residue is purified by chromatography on a column of silica gel, eluting with ethyl acetate. Obtain 0.4 g of substance with so pl. 97100 ° C.
Example 145. - (Pyridine-2-carbonyl) -glycyl -2-cyanoaziridine 3.6 g of H- (pyridine-2-carbonyl) -glycine is suspended in 36 ml of tetrag1 | {{crofuran, 1.36 is added g of 2-cyanoaziridine and 4.3 g of dicyclorexylcarbrdiimide, stirred for 2 hours in an ice bath, after separation of dicyclohexenylurea, 2.85 g of substance are obtained as a yellowish oil.
Example 146. 1- (Ethanmethoxyphosphonyl) -2-cyanoaziridine.
1.29 g of 2-cyanoaziridine is dissolved in 13 ml of abs. ether, 2.63 ml of triethylamine was added, then 2.7 g of ethanomethoxyphosphonic acid chloride was added dropwise with ice-cooling. After 3 days 0, the precipitated triethylamine hydrochloride is filtered off and 2.95 g of a water-soluble substance is obtained in the form of an oil.
Example 147. 1- {K-og, rb-Fene. - 5 tilsuctionimoyl) -2-cyanoaziridine.
2.21 g of polyamide Hb-β-phenethyl succinic acid, 0.68 g of 2-dianoaziridine, and 2.16 g of dicyclohexylcarbodiimide are stirred for 2 hours.
ice bath in 22 ml of tetrahydrofuran. After standing overnight at room temperature, the precipitated dicyclohexyl urea is separated and the substance is obtained in the form of a yellow oil 1B -94,2® (C 0.5; ethanol) o
Example 148. 1- (N-; oC-D-Phenylethylcycloimoyl) -2-cyanoaziridine.
This is obtained in an analgesic manner from Q D-acids in the substance has the appearance of a yellowish oil. EJ-l +92, (C 0.5} ethanol).
Example 149. 1- (N-Acetylglycyl) -2-cyanoaziridine. with K 11.7 g of N-acetylglycine in 400 ml abs. 11.5 ml of N-methylmorpholine is added to methylene chloride. While cooling in an ice bath, a solution of 13.8 ml of isobutyl chloroformate in 100 ml of abs is added dropwise. methylene chloride and after 15 min the solution
6.8 g of 2-cyanoaziridine in 100 ml of abs. methylene chloride. Stir for 2 hours in the cold. After being kept overnight at a temperature of cmt, evaporation is carried out in vacuo, the residue is dissolved in acetone, and N-methylmorpholine hydrochloride does not dissolve. The residue after evaporation of acetone is recrystallized from
0 mixture ether - methanol 1: 1. 8.4 g of white water-soluble crystals, which are identical to the product indicated in Example 30, and the product of the interaction of 2-cy5 anoaziridine with N-aethylglycyl chloride in ethyl acetate are obtained in the presence of three ethyl amine 4i.

权利要求:
Claims (1)
[1]
The method of obtaining derivatives
1-acyl-2-cyanoaziridines of the general formula.
Xia about *.
where R is the —CR _t residue, wherein R is hydrogen, nitrile, carbamoyl, a lower alkoxycarbonyl or acyl residue, a saturated or unsaturated cycloalkyl group, optionally one or multiple substituted with a halogen, nitrile, aryl, aryloxycarbonyl group, a lower alkoxy , an acyloxy group, a lower alkoxycarbonyl group, optionally substituted with a lower Ν, Ν-dialkylamino group, a lower alkyl group, if appropriate, substituted with a ureido, lower acylamino or acyloxy group, an amino group substituted with a bamoyl, alkoxycarbonyl or acyl group, or a residue or, where appropriate, condensed with phenyl, or may contain hydrocarbon bridges containing 1-3 carbon atoms, or an oxygen bridge, the residue is a straight or branched saturated or non-insignificant alkyl residue containing 2-18 carbon atoms , straight or branched branched or unsaturated hydrocarbon chain, one- or multiple-substituted by nitrile, halogen, nitro, aryl, aryloxy, aryl mercapto, in accordance In general, a substituted heteroaryl mercapto group, a saturated or unsaturated cycloalkyl group, which may optionally be attached via 1 to 3 carbon atoms, as appropriate, an N-alkyl carbamoyl group, a lower alkoxycarbonyl group, in some cases substituted by an N, N-dialkylamino group, as appropriate substituted N-alkylated sulfamoyl group, respectively; cited cases of an N-alkylated urethane group; lower acyl, acyloxy, alkylsulfonyl or alkylsulfinyl group, or lower alkyl mercapto or alkoxy groups which may be substituted with phenyl or a residue, as appropriate
SU <„, 1077565 or, as appropriate, a substituted aromatic or non-aromatic heterocyclic residue or a group l _ and or or a lower dialkoxyphosphoryloxyalkoxyphosphonyl residue, the residue - or R (- an aryl residue, one- or multiple substituted with halogen, nitrile, trifluoromethyl-, sulfamo ,, if appropriate substituted with 'halogen, alkyl, alkoxy or a residue or a group “1 ^A ” ^R f2 ¹ G in which the residues AR ^ are the same or different; A is the sign of valency, carbonyl, thiocarbonyl, or -CO-CH ₂ group; R _e - in a hydrogen, nitrile, aryl, lower straight or branched saturated or unsaturated alkyl group, which, as appropriate, may be substituted once or repeatedly by halogen, aryl, a residue, or
I i, as appropriate, substituted by an aryl lower alkoxy group, lower alkyl mercapto-, alkylsulfinyl or alkylsulfonyl group, optionally one- or multiple-substituted by phenyl, heteroaryl, lower alkyl, alkylsulfonyl acylamino-substituted carbamidoyl or acyl-amino group of the corresponding methyl group aromatic heterocycle, aryl or lower alkyl group, aryl mer ap up-, arylsulfinyl - '/ or arylsulfonyl group, aryloxy or cycloalkyl group, or, respectively In certain cases, a substituted aromatic or non-aromatic heterocycle, wherein aryl in all of the above groups, as appropriate, can be substituted once or repeatedly by halogen, nitrile, nitro, sulfamoyl, and, if appropriate, N-alkyl carbamoyl, trifluoromethyl, phenyl, phenoxy; methylenedioxy, lower alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, alkyl mercapto, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl groups, single or multiple substituted by alkyl, phenyl, acyl amino group or the residue.
-FROM-"
O phenyl, phenoxy or phenyl sulfone 1 & -. a group, methylenedioxy group, / lower alkyl group, as appropriate substituted by carbamoyl, lower alkoxycarbonyl-, alkoxy-, acyloxy-, N-alkylaminocarbonyloxy-, N-alkoxycarbonylamino- or N-acylamino-group, lower alkoxy-, acyl-, acyloxy- -, alkoxycarbonyl, alkylsulfinyl or alkylsulfonyl group, an amino group substituted by an alkyl, aryl, acyl, alkoxycarbonyl group or, if appropriate, substituted by an alkyl or aryl carbamoyl group, or, as appropriate, by an N-alkyl carbamoy flax group or residue
—N = N ′ or R — the residue is S (C *) _n —R ^, wherein n is 0 or 1;
R <3 is a straight or branched, saturated or unsaturated <alkyl group, which, if appropriate, can be one- or multiple-substituted by halogen, cycloalkyl or, if appropriate, substituted by phenyl, halogen, nitro, lower alkyl -, alkoxy, alkyl mercaptoyl or alkylsulfonyl group, an aryl residue or, if appropriate, a substituted heteroaromatic residue, or R is a residue so ₂ -r |, wherein Rj is, where appropriate, an N-alkylated amino group, straight or branched, saturated I or an unsaturated alkyl group, which, if appropriate, can be substituted once or repeatedly by a halogen or liacyl group, cycloalkyl or substituted by an alkoxy, phenoxy or phenyl group: naphthyl or ₎ substituted by a CURRENT OR R aromatic or non-aromatic, if appropriate, a substituted tical heterocyclic residue is a phenyl group, where appropriate a heteroaromatic residue is' i
-R-in. ₊ * 5 where Z is oxygen or sulfur;
R ^ and Rj are the same or different. and represent oxy-, piperi * di-, anilino-, N-alkoxycarbonylamino, phenyl-, phenoxy, lower alkyl- or alkoxy-group, or a residue or R and Rjj is also alkylenedioxy, or R is a 3-camphoric, bietin residue or 6-acetamidopenicillanic acid, wherein all of the indicated aromatic and non-aromatic heterocyclic radicals are, where appropriate, substituted once or repeatedly with halogen, nitro, phenyl, lower acyl, acyloxy, alkyl, alkoxy, alkyl mercapto, alkylsulfinyl, an alkylsulfonyl or amino group which is one or more 'Multiply substituted at the alkyl, aryl or acyl, and N-containing heterocycles can be oxidized, or their salts, characterized i in that the 2-tsianoaziridin reacted with compounds of the general formula
R is X, where R has the indicated meanings;
X is an oxy group, halogen, azide, lower alkoxy, alkoxycarbonyloxy, phenoxycarbonyloxy group or the remainder is OR, and R residues may be the same or different in an inert solvent, if appropriate, in the presence of a water or acid binding agent, followed by isolation of the target product in free form or in the form of salt.

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1077565A3|1984-02-29|Process for preparing derivatives of 1-acyl-2-cyanoaziridines or their salts

---

EP1472215A2|2004-11-03|carbamoyl fatty acid amide hydrolase inhibitors

---

DD201782A5|1983-08-10|PROCESS FOR PREPARING OCTAHYDRO-1- | -1H-INDOL 2-CARBOXYLIC ACID COMPOUNDS

---

DE2228012A1|1972-12-28|Process for the production of new penicillanic acid esters

---

PT97846B|1999-11-30|PROCESS FOR PREPARING AROMATIC AMIDES OF PYRROLIDINE AND THIAZOLIDINE

---

EP0490820A2|1992-06-17|Biphenylyl compounds

---

SU795462A3|1981-01-07|Method of preparing thiocarbamide derivatives

---

CS241039B2|1986-03-13|Method of new n-|pyrrolidinyle|((-benzamides production,substituted in positions 2,3,4,5,6

---

US2748125A|1956-05-29|1-substituted-4-sulfamylpiperazine and method of preparing the same

---

Hashem et al.2014|Synthesis and reactions of some 2 |-and 2 |-furanone derivatives: a comparative study

---

WO2000027808A1|2000-05-18|N-arylsulfonyl amino acid omega amides

---

CH628902A5|1982-03-31|METHOD FOR PRODUCING 7-BETA- | -CEPHALOSPORINES.

---

DE2934592C2|1989-10-05|

---

DE2828578C2|1983-12-15|Thiazolidines, their manufacture and use

---

DE2239511A1|1973-04-19|PROCESS FOR THE Esterification of ORGANIC CARBONIC ACIDS

---

FR2496666A1|1982-06-25|NOVEL CEPHALOSPORINE DERIVATIVES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME

---

DE2709634A1|1978-09-07|BENZYLPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THE SAME

---

CH619468A5|1980-09-30|

---

IE45782B1|1982-12-01|1-|-2-cyanoziridines

---

EP0088252B1|1986-04-09|Process for the preparation of 1-|-5-methoxy-2-methyl-3-indolacetoxy-acetic acid

---

SU415876A3|1974-02-15|METHOD FOR PRODUCING DERIVATIVES OF BENZIMIDAZOLE

---

DE2737195A1|1979-03-01|BENZOLSULPHONAMIDE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF

---

CH633290A5|1982-11-30|Process for preparing derivatives of 7-oxo-1,3-diazabicyclo[3.2.0]heptane-2-carboxylic acid

---

SU503517A3|1976-02-15|The method of obtaining derivatives of indole acetic acid or their salts

---

DE2649545A1|1977-05-12|CEPHALOSPORIN DERIVATIVES, THEIR SALT, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS

同族专利:

---

公开号 | 公开日

---

AT356663B|1980-05-12|

---

PT68263A|1978-08-01|

---

AU519219B2|1981-11-19|

---

BE868796A|1979-01-08|

---

JPS5436254A|1979-03-16|

---

CS208656B2|1981-09-15|

---

IT7825474D0|1978-07-07|

---

NL7807276A|1979-01-15|

---

US4267174A|1981-05-12|

---

NZ187794A|1980-05-08|

---

NO782399L|1979-01-12|

---

HU179428B|1982-10-28|

---

FI782157A|1979-01-12|

---

PL208195A1|1980-03-24|

---

DE2731264A1|1979-02-01|

---

AU3782578A|1980-01-10|

---

ZA783829B|1980-03-26|

---

PL126639B1|1983-08-31|

---

DD137710A5|1979-09-19|

---

AU3782678A|1980-01-10|

---

DK306978A|1979-01-12|

---

IL55109A|1982-07-30|

---

IT1096910B|1985-08-26|

---

GB1594079A|1981-07-30|

---

CA1086309A|1980-09-23|

---

LU79937A1|1980-02-14|

---

IL55109D0|1978-09-29|

---

SE7807642L|1979-03-14|

---

ATA496478A|1979-10-15|

---

ES471512A1|1979-10-01|

---

FR2397403A1|1979-02-09|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

DD110492A1|1974-03-21|1974-12-20|

---

JPS5932772B2|1974-09-21|1984-08-10|Asahi Optical Co Ltd|

---

DE2528460A1|1975-06-26|1977-01-13|Boehringer Mannheim Gmbh|1-Carbamoyl 2-cyano aziridine as immunostimulant - for therapy of bacterial and viral infections|DE2906603A1|1979-02-21|1980-09-04|Boehringer Mannheim Gmbh|N-SUBSTITUTED AZIRIDINE-2-CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE SUBSTANCES|

---

US4393000A|1979-12-12|1983-07-12|Mitsui Toatsu Chemicals, Inc.|Cyclization process for producing aziridine-2-carboxylic acid or its salts|

---

US4925835A|1986-05-01|1990-05-15|Sloan-Kettering Institute For Cancer Research|Aziridinyl putrescine containing compositions and their uses in treating prostate cancer|

---

US6982263B2|2001-06-08|2006-01-03|Boehringer Ingelheim Pharmaceuticals, Inc.|Nitriles useful as reversible inhibitors of cysteine proteases|

---

MXPA05007485A|2003-01-14|2006-01-30|Arena Pharm Inc|1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia.|

---

WO2004076413A2|2003-02-24|2004-09-10|Arena Pharmaceuticals, Inc.|Phenyl- and pyridylpiperidine-derivatives as modulators of glucose metabolism|

---

AR045047A1|2003-07-11|2005-10-12|Arena Pharm Inc|ARILO AND HETEROARILO DERIVATIVES TRISUSTITUIDOS AS MODULATORS OF METABOLISM AND PROFILAXIS AND TREATMENT OF DISORDERS RELATED TO THEMSELVES|

---

AU2005252211A1|2004-06-04|2005-12-22|Arena Pharmaceuticals, Inc.|Substituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto|

---

DOP2006000010A|2005-01-10|2006-07-31|Arena Pharm Inc|PROCEDURE TO PREPARE AROMATIC ETERES|

---

MY148521A|2005-01-10|2013-04-30|Arena Pharm Inc|Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto|

---

DK1931654T3|2005-09-16|2009-07-27|Arena Pharm Inc|Metabolic modulators and treatment of disorders related thereto|

---

TW200811140A|2006-07-06|2008-03-01|Arena Pharm Inc|Modulators of metabolism and the treatment of disorders related thereto|

---

TW200811147A|2006-07-06|2008-03-01|Arena Pharm Inc|Modulators of metabolism and the treatment of disorders related thereto|

---

CN103539791B|2010-09-22|2017-01-11|艾尼纳制药公司|Modulators of the GPR119 receptor and the treatment of disorders related thereto|

---

CN107405332A|2015-01-06|2017-11-28|艾尼纳制药公司|Treatment and S1P1The method of receptor related illness|

---

LV15518A|2019-02-18|2020-08-20|Latvijas Organiskās Sintēzes Institūts|Derivatives of aziridine-2-carboxamide as inhibitors of thioredoxin reductase, their synthesis, anti-cancer and anti-metastatic effect|

---

WO2021141507A1|2020-01-10|2021-07-15|Uniwersytet Jagielloński|Aromatic sulphonamides derivatives that inhibits pdi a3, their synthesis and use|

---

WO2021141506A1|2020-01-10|2021-07-15|Uniwersytet Jagielloński|Aromatic sulphonamides derivatives that inhibits pdi a1, their synthesis and use|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

DE19772731264|DE2731264A1|1977-07-11|1977-07-11|NEW 1-ACYL-2-CYANAZIRIDINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS|

---