SU378011A1 - - Google Patents

Description

Method of producing 4-morpholinothieno (3,2-a) -PYRIMIDINE DERIVATIVES

one

The invention relates to a process for the preparation of new compounds - derivatives of 4-morpholinothieno (3,2-a) -pyrimidine or their salts, which can be used in medicine, and have a more effective action compared to their closest analogues. In the chemistry of heterocyclic compounds, the reactions of piperazine as secondary amine are known,

The proposed method is based on the known organic chemistry of the reaction of piperazine, in particular, a halogen atom.

A method for the preparation of compounds-derivatives of 4-morpholinothieno (3,2-Sc) -pyrimidine of the formula I is described.

(CH)

HN -f

 V-s

BS

OR their physiologically acceptable salts with inorganic or organic acids.

In formula I, the radicals from Ri to Rg may be the same or different and represent hydrogen atoms or methyl groups, the radical Rs may mean, in addition to the above values, also the phenyl radical, or 2.

The method is a compound of formula I

N

AT

Rg

N rfi

15

N

R

Rt

ABOUT

where RADICAL A denotes an halogen ETHOM, an alkylsulfonyl group, for example a methylsulfonyl group, or a mercapto group free or substituted by a lower alkyl radical;

the radicals from Rs-Re have the above-mentioned values, are reacted with a compound of the formula P1 1SC,) RNT B2, where the R is a hydrogen atom or is substituted, for example, carbethoxy or formyl group, which can then be cleaved by treatment with acids or alkalis; n, RI and R2 are as defined above, followed by isolation of the target product by known methods in free form or in the form of its salt. The reaction is usually carried out at O-200 ° C. If radical A is a halogen atom, an agent that binds hydrogen halide is used. An inorganic or tertiary organic base, as well as at least a molar excess of the amine of formula III used in the reaction, can serve as such an agent. An additional excess of this amine can also be used as a solvent. If the reaction is carried out in the presence of a solvent, then alcohols, for example ethanol, or ether (dioxane), or high boiling ketones or dimethylformamide, are particularly suitable as solvents. The use of a solvent is optional; the reaction also proceeds in the absence of solvents. The reaction temperature depends on the reactivity of the reactants. Replacement of the halogen atom or alkylsulfonyl group is usually carried out faster and at lower temperatures than the replacement of the mercapto group. If, as a result of the reaction, a compound of formula I is obtained, which is still in position 4 of the piperazine or diazocycloheptane ring and contains the radical R of the starting compounds of general formula III, then this radical can be removed by boiling with strong inorganic acids, in particular with concentrated hydrochloric acid. From the salts of the compounds of the formula I thus obtained, the free base is then isolated using aqueous solutions. The radical R can also be cleaved off by boiling with alkalis. The compounds of general formula I can, if necessary, be converted in a known manner into their physiologically tolerable acid addition salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric, phosphoric, succinic, tartaric, citric, malecova, fumaric or sulfuric acid. The preparation of the starting materials of general formula II, in which A is a halogen atom, a free or alkyl substituted mercapto group, is carried out in a known manner. When this Z-aminothiophene-2-carboxylic acid or a reactive derivative of this acid is first subjected to interaction with urea or thiourea. Suitable reactive derivatives of 3-aminothiophene-2-carboxylic acids are especially their esters or amides. Compounds are obtained which initially have free hydroxyl groups in the field 4. The reaction with thiourea leads to the formation of compounds with the free mercapto group at position 2, and the reaction with urea leads to the formation of compounds with the free hydroxyl group at position 2. These reactions are usually carried out at elevated temperatures, preferably at 100-200 ° C under known conditions. in the presence of an inert, high boiling solvent (toluene, xylene, tetrahydronaphthalene). Compounds thus obtained, which have free hydroxyl groups in position 2 or 4, are then converted by known methods, for example by reacting with a phosphorus oxyhalide, into the corresponding halogen-substituted compounds. Thieno (3,2-a) -pyrimidine, which contain free or alkyl-substituted mercapto groups, can also be obtained by exchanging halogen atoms, respectively halogen-substituted compounds, by using hydrogen sulfide alkali metal compounds, alkali metal mercaptides or thiourea. They can also be obtained from the corresponding hydroxy compounds by reacting with phosphorus hemipentasulfide. Compounds with free mercapto groups can be converted by alkylation, for example by alkyl halides, to the corresponding alkyl mercapto compounds. The starting materials of formula II, in which A is a halogen atom, are more expediently prepared as follows: 2,4-dioxythieno {3,2-a) pyrimidines obtained as a result of the cyclization of urea with the corresponding 3-aminothiophene-2 carboxylic esters, are converted phosphoroxyl by 2,4-dihalo-phenyloxy (3,2-a) pyrimidines, and the latter are reacted with a calculated amount of morpholine of general formula IV R, K, Compound of formula II, in which A is an alkylsulfonyl group, can be obtained by oxidation soot etstvuyuschih compounds in which A - alkylmercapto group. Below are examples (1-6) of starting materials. Example 1. 2,4-dioxnieno (3,2-a) -pyrimidine.

1.6 g (0.01 mol of 3-aminotkofen-2-carboxylic acid methyl ester and 3 g (0.05 nil of urea are thoroughly mixed and heated for 2 hours to 200 ° C. A clear brown melt is obtained, which hardens at It is dissolved in warm 1N sodium soda: wood, decolorized with coal and acidified with 2N hydrochloric acid. The precipitated crystalline products are filtered on a putsch and recrystallized from water. The melting point of the crystals is 300 ° C, yield 1.2 g (72% of theoretically possible), mol. weight. 168.18.

Calculated,%: C 42.84; H 2.40; N 16.66.

CsH, iN2O., S.

Found,%: C 42J5; H 2.57; N 16.82.

In a similar manner, the following compounds were prepared:

2,4 - Dioxy - 6 - methylthieno (3.2-a) - pyrmidine - from methyl ester of 3-amino-5-methylthiophene-2-carboxylic acid and urea, t. Pl. 320 ° C.

2,4-Dioxp - 7 - methylthieno (3.2-a) - pyrimidine - from methyl ester of 3-amino-4-methylthiophene - 2 - carboxylic acid and urea, t. Pl. 300 ° C.

2,4-Diox1 - 6,7 - dimethylthieno (3,2-a) -pyrimidine - from methyl ester Z-amino-4,5 - dimethylthiophene - 2 - carboxylic acid and urea, so pl. 360 ° C.

2,4 - Diokoi - 6 - phenylthieno (3,2-a) - nnrimidine - from methyl ester 3-amine - 5 - phenylthiophene - 2 - carboxylic acid and urea, t. Pl. 300 ° C.

Example 2. 2.4 - Dichlorothieno (3,2-a) pyrimidine.

8.4 g (0.05 fAOAb 2,4-dpoxithieno (3,2-a) pyrimidine and 100 ml of phosphorus oxychloride) are heated for 10 hours under reflux, and a clear solution is obtained. Excess phosphorus oxychloride is removed in vacuo The remaining oil is allowed to decompose in ice water, and it is extracted with chloroform.

The organic phase is washed to neutrality with water and dissolved over sodium sulfate. The solid residue obtained after removal of the solvent is recrystallized from ethanol. T. pl. product 141 - 142 ° C, yield 7.6 g (74% of theoretically possible), mol. weight. 250.08.

Calculated,%: C 35.13; H 0.98; C1 34.58.

CeHoCbNsS.

Found,%: C 35.25; H 1.02; C1 34.68.

In a similar way, the following compounds are obtained;

2,4 - Dichloro - 6 - methylthieno (3,2-a) -pyrimidine - from 2,4 - DIOXY - 6-methylthieno (3,2-a) - pyrimidine and phosphorus oxychloride, the product obtained by recrystallization from ethanol, has t. pl. 150 ° C.

2,4 - Dichloro - 7 - methylthieno (3,2-a) - pyrimidine - from 2,4 - DIOXI - 7 - methylthieno (3,2-a) - pyrimidine and phosphorus oxychloride.

The product obtained by recrystallization from ethanol is m.p. 186 ° C.

2,4 - Dichloro - 6,7 - dimethylthieno (3,2-a) pyrimidine - from 2,4 - dioxy - 6, 7 - dimethylthin (3.2-a) - pyrimidine and phosphorus oxychloride. The product obtained by recrystallization from ethyl acetate has an mp. 169 ° C.

2,4 - Dichloro - 6 - phenylthieno (3,2-a) - Nirimidine - out of 2.4 - DIOXI - 6 - phenylthieno

(3,2-a) - pyrimidine and phosphorous phosphorus.

The product obtained by recrystallization from

acetone, has t. pl. 175-177 ° C.

Example 3. 2-Chloro-6,7-dimethyl-4-morpholchutyuleno (3,2-a) -pyrimidine.

7.8 g (0.034 mol of 2,4-dichloro-6,7-dimethylthieno (3,2-a) - pyrimidine) is shifted from 150 ml of absolute ethanol. To the suspension obtained in this way at room temperature, 8.7 are added dropwise with careful transfer. g (0.1 mol} of morpholine. The reaction mixture is moved for another 2 hours at room temperature, and then water is added. The precipitated reaction product is sucked off, washed with water and recrystallized from a mixture of petroleum ether and acetone. The resulting product has a melting point of 157 ° C, yield 8.4 g (87.2% of theoretically possible), mol. Weight. 283.79.

Calculated,%: C 50.80; H 4.97; C1 12.51; N 14.87; S 11.20. C, 2H1LS155.

Found,%: C 50.60; H 4.94; C1 12.50; N 14.60; S 11.07.

In a similar manner, the following compounds were prepared:

2-Chloro-6-methyl-4 - morpholinogne (3,2-a) pyrimidine - from 2,4-dichloro-6-methylthieno (3,2-o :) - P11rimidine and morpholine. The product obtained by recrystallization from acetone is m.p. 180-181 ° C.

2 - Chloro - 7 - methyl - 4 - morpholinothieno (3.2-a) - pyrimidine - from 2,4 - dichloro - 7 methylthieno (3,2-a) - pyrimidine and morpholine. The product obtained by recrystallization from ethanol is iltet t. Pl. 128 ° C.

2 - Chlorine - 4 - (2-methylmorpholino) - thieno (3,2-a) - pyrimidine - from 2,4 - dichlortieno (3,2-a) - pyrimidine and 2 - methyl - morpholine. The product obtained by recrystallization from ethanol is m.p. 169-171 ° C.

2 - Chloro - 4 - morpholino - 6 - phenylthieno (3,2-a) - pyrimidine - from 2,4 - dichlo p - 6 phenylthieno (3,2-a) - pyrimidine and morpholine. The product obtained by recrystallization from acetone is m.p. 183-185 ° C.

2 - Chlorine - 4 - (2,6 - dimethylmorpholino) thieno (3,2-a) - pyrimidine - from 2,4-dichlortieno (3,2-a) - pyrimidine and 2,6 - dimethylmorpholine. The product obtained by recrystallization from ethanol is m.p. 144-146 ° C.

Example 4. 2-Chloro-4-morpholinothieno (3,2-a) -pyrimidine.

To 5.1 g (0.025 mol) of 2,4-dichlorothieno (3,2-sat) - pyrimidine is mixed with 200 ml of absolute ethanol. To the suspension obtained with vigorous stirring and cooling to 20 ° C, 4.8 g (0.055 mol) of morpholine is added. A clear solution is obtained from which iBCKOpe crystalline matter is extracted. The reaction mixture is stirred eh, e for 2 hours at room temperature. Suction is carried out, the product is washed with water and ethanol and recrystallized from methyl ethyl ketone, so pl. product 196-198 ° C, yield 5.75 g (90% of theoretically possible), they say. weight 255.74.

Calculated,%: C 46,97; H 3.95; N 16.44.

CioHioClNsOS.

Found,%: C 47.10; H 4.03; N 16.30.

Example 5. 2-Methylmercapto - 4 - morpholinothieno (3,2-a) -pyrimidine.

Methyl mercaptan gas, freshly prepared from 6.0 g of S-methylisothiourea sulfate and 10 ml of 5N. The sodium soda cell is introduced into 15 W / g of a solution of sodium hydroxide in ethanol, which contains 1 mol / L of sodium hydroxide. This solution is added dropwise over 5 minutes to a boiling solution of 2.6 g (0.01 mol) of 2-chloro-4-mo-rfololinothieno (3,2-a) -pyrimidine in 25 ml of ethanol.

The reaction mixture is cooled through ZoLhyn by passing carbon dioxide to room temperature. The solvent is removed by suction. The final product that drops out is sucked off, washed with water, dried and recrystallized from methanol. The product has a t. Pl. 138-139 ° C, yield 2.4 g (90% of theoretically possible), mol. weight 267.38.

Calculated,%: C 49.41; H 4.90; S 23.99.

CiiHisNgOSa.

Found,%: C 49.50; H 4.99; S 23.85.

Example 6. 2 - Methylsulfonyl - 4 - morpholinothieno (3,2-a) -pyrimidine.

To a solution of 2.7 g (0.01 mol) of 2-methylmercapto-4-morpholi of thieno (3,2-a) -pyrimidine in 25 ml of glacial acetic acid at 25 ° C over a period of 15 min, 3.5 g of dropping is added (15 0.022 mol of potassium permanganate dissolved in 25 ml of water.The reaction mixture is then stirred for 3 hours at 25 ° C, decolorized with sodium bisulfite solution, mixed with caustic soda until alkaline, and extracted repeatedly with methylene chloride.

The combined extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from ethanol. The product has a t. Pl. 191 - 193 ° C, yield 1.84 g (62% of theoretically possible), they say. weight 299.38.

Calculated,%: C 44.12; H 4.38; N 14.03.

CuHisNgOsSs.

Found,%: C 44.19; H 4.44; N 13.90. Below are examples (7-11) of the final products.

Example 7. 4- Morpholino - 2 - piperazinothieno (3,2-a) -pyrimidine.

10.2 g (0.04 mol) 2-chloro-4-morpholinothieno (3,2-a) -pyrimidine, 15.6 g (0.08 mol) of piperazine hexahydrate and 100 ml of absolute ethanol are heated in an autoclave for 3 hours up to 120 ° C. After cooling, the ethanol is removed in vacuo and the residue is dissolved in water.

By adding 2 n. hydrochloric acid was adjusted to pH-6 and extracted three times with chloroform. Then, 30% sodium hydroxide is added to the aqueous phase until the pH value is 12 and extracted three times with methylene chloride.

The combined extracts were dried over sodium sulfate, evaporated and wiped; a non-crystalline residue was obtained by chromatography on a column (sorbent-silica gel for column chromatography, 0.2-0.5 mm fraction; the solvent was a mixture of benzene and acetone, 7: 3). The same fractions are combined and evaporated, and the remaining noncrystalline 2-piperazino-4-morpholinothieno (3,2-a) - pyrimidine is dissolved in absolute ethanol and the hydrochloride is precipitated by ethereal hydrochloric acid, filtered off under suction, washed with ether and recrystallized from absolute ethanol. The product decomposes, starting from 175 ° C, yield 2.9 g (from the theoretically possible), they say. weight 378.34.

Calculated,%: C, 44.44; H 5.60; N 18.51; From 18.75.

Ci4Hi9N5OS-2HCl.

Found,%: C 44.15; H 5.71; N 18.30; C1 18.51.

Example 8. 4-Morpholino-2-piperazinothieno (3,2-a) -pyrimidine.

2.6 g (0.01 mol) of 2 - chloro - 4 - morpholinothieno (3,2-a) -pyrimidine and 6.3 g (0.04 mol) of 1-carbethoxy piperidine are heated to 120 ° C for 3 hours. After cooling, the reaction solution is poured into ice-cold water, and 2- (4-carbethoxypiperazino) -4-morpholine-thieno (3,2-a) -pyrimidine precipitates in a greasy form. The resulting material is triturated to form crystals, filtered overnight and recrystallized from ethanol. T. pl. product 139-141 ° C, yield 3.2 g (86% of theoretically possible).

1.9 g (0.005 mol) of 2- (4-carbethoxypiperazino) -4-morpholinothieno (3,2-a) -pyrimidine and 20 ml of terminally saturated hydrochloric acid are heated for 10 hours in a reflux vessel. After cooling, the reaction solution is poured onto ice, using 30% sodium hydroxide solution, it is made strongly alkaline and extracted several times with methylene chloride.

The combined extracts are dried over sodium sulfate and evaporated, and the non-crystalline residue is dissolved in absolute ethanol and the hydrochloride is precipitated by addition of ethereal hydrochloric acid, which is filtered under suction, washed with ether, and

recrystallized from absolute methanol. The product decomposes, starting from 175 ° C, yield 1.2 g (63% of theoretically possible).

Example 9. 4-Morpholino-2-piperaz1; otieno (3,2-a) -pyrimidine.

2.7 g (0.01 mol 2 - Methyl mercapto-4-morph. Inothieno (3,2-a) - pyrimidine (mp. 138-139 ° C) and 11.4 g (0.1 mol 1- formylpiperazine heated for 10 hours to 150 ° C.

The cooled reaction solution is not converted into water, while 2-4-formylpiperazino4-morpholsyutyeno (3.2-; a) - pyrimidine is ointmenty in a greasy form. Rub the ointment with a glass rod, this compound can be maintained in a crystalline form. It is then recrystallized from ethanol. T. pl. product 139 ° C (decomposition), yield 1.8 g (54% theoretically possible).

Claims (4)

1.6 g (0.005 mol) of 3- (4-formylpiperazino) 4-morpholinothieno (3,2-a) -pyrimidine and 20 m, l of concentrated hydrochloric acid is heated for 9 hours in a reflux vessel. The cooled reaction solution is poured onto ice, alkalinized with 30% sodium hydroxide solution and extracted several times with methylene chloride. The offset extracts are dried over sodium sulfate, the solvent is distilled off in vacuo, the non-crystalline residue is dissolved in absolute ethanol and the dihydrochloride is precipitated by means of ethereal hydrochloric acid. The latter is filtered off with suction, washed with ether and recrystallized from ethanol. The product decomposes, starting at 175 ° C, yield 1.35 g (71% of theoretically possible). Example 10. 6,7-Dimethyl-4-morpholino-2piperazinothieno (3,2-a) -pyrim.idin. A mixture of "3 4.25 g (0.015 mol) of 2-chloro-b, 7-dimethyl-4-morpholinothieno (3,2-a) - pyrimidine and 30 g (0.35 mol) of anhydrous piperazine is heated for 1 hour to 130 ° C. Pomelem cooling to the reaction mixture, mix with water and extract, rutize two times with methylene chloride. The extracts are dried with sodium sulfate, evaporated and the residue is purified by column chromatography (sorbent-silica gel for column chromatography, 0.2-0.5 mm fraction, the solvent is a mixture of benzene, acetone, methanol, ammonia 60: 25: 15: 1). The same fractions are concentrated and the residue is recrystallized from ethyl acetate and petroleum ether (1: 1). T. pl. product 156 ° C, yield 3.8 g (76% of theoretically possible), mol. weight 333,47. Calculated,%: C 57.60; H 6.96; N 21.00; 59.61. CisHssNsOS. Found,%: C 57.80; H 6.89; N 20.70; S 9,53. The following compounds are prepared in a similar manner: 6,7-Dimethyl - 2 - (1,4 - diazacycloheptano) 4 - morpholinothieno (3,2-a) - pyrimidine - from 2 - chlorine - 6,7 - dimethyl - 4 - morpholinothieno (3,2-a) - pyrimidine and 1,4 - diazacycloheptane. T. pl. dihydrochloride, obtained by recrystallization from isopanol, 283 ° C (decomposition). 6 - Methyl - 4-morpholino-2-piperiazinothio (3,2-a) - pyrimidine - from 2-chloro-6-methyl 4-morpholinothieno (3,2-a) - pyrimidine and pinarazine, t. Pl. the dihydrochloride obtained by recrystallization from ethanol, 291 - 293 ° C (decomposition). 2 - (1,4 - diazacycloheptano) - 6 - methyl 4 - morpholinothieno (3,2-a) - pyrimidine - from 2-chloro-6-methyl-4-morpholinothieno (3,2-a) pyrimidine and 1,4 - diazacycloheptane. T. Il. dihydrochloride. obtained by recrystallizing it from ethanol at 185 ° С (decomposition). 7-Methyl-4-morpholino - 2 - piperazinothieno (3,2-a) -pyrimidine - from 2 - chloro - 7-methyl-4 morpholinotheno (3,2-a) -pyrimidine and piperazine, t. Pl. 92-93 ° C (a mixture of petroleum ether and ethyl acetate 1: 1). 2- (1,4-1Diazacycloheptano) - 7 - methyl - 4 morpholinothieno (3,2-a) - pyrimidine - from 2 - chloro - 7 - methyl - 4 - morpholinothieno (3,2-a) - pyrimidine and 1, 4 - diazacycloheptan, m. Pl. dihydrochloride, obtained by non-recrystallization from ethanol 273-275 ° С (decomposition). 4 - Morpholino - 2 - piperazino - 6 - phenylthieno (3,2-a) - pyrimidine - from 2 - chloro-4 morpholino - 6 - phenylthieno (3,2-a) - pyrimidine and piperazine. T. pl. dihydrochloride, obtained by recrystallization from 90% ethanol, 298-300 ° C. 2 - (2,5 - Dimethyl piperazino) - 4 - morpholinothieno (3,2-a) - pyrimidine - from 2-chloro-4-morpholinothieno (3,2-a) - pyrimidine and 2,5 dimethyl piperazia, m.p. dihydrochloride, obtained by recrystallization from isopropanol, 250-255 ° C (decomposition). 4 - (2 - Methylmorpholino) - 2 - piperazinothieno (3,2-a) - pyrimidine - from 2-chloro-4 (2-meth: ylmorpholino) - thieno (3,2-a) - pyrimidine and piperazine, t. square dihydrochloride, obtained by recrystallization from ethanol, 220 ° C (decomposition). 4 - (2,6 - Dimethylmorpholino) - 2 - piperazinothieno (3,2-a) - pyrimidine - from 2-chloro-4 (2,6 - dimethylmorpholio) - thieno (3,2-a) pyrimidine and piperazine, t pl. the dihydrochloride obtained by recrystallization from ethanol, 264 ° C (decomposition). 2 - (1,4 - Diazacycloheptano) - 4 - morpholinothieno (3,2-a) - pyrimidine - from 2-chloro-4 - morpholinothieno (3,2-a) - pyrimidine and 1,4 - diazacycloheptane, so pl. dihydrochloride, obtained by recrystallization from ethanol, 290 ° C (decomposition). Example 11. 4 - Morpholino - 2 - piperazinothieno (3,2-a) - pyrimidine. 3.0 g (0.01 mol) of 2-methylsulfonyl-4 morpholinothieno (3,2-a) -pyrimidine and 6.3 g (0.04 mol) of 1-carbethoxypiperazine are heated to 80 ° C for 2 hours. The warm reaction mixture is poured onto ice-cold water, and 2 - (4 - carbethoxypiperazino) - 4 - morpholinothieno (3.2-a) - pyrimidine falls in a greasy form. The latter crystallizes within a few hours. It is filtered and recrystallized from ethanol, so pl. product 139-141 ° C, yield 3.4 g (90% of theoretically possible). 1.9 g (0.005 mol) of 2- (4-carbethoxypiperazino) -4-morpholinothieno (3,2-a) -pyrimidine and 20 ml of concentrated hydrochloric acid are heated for 10 hours in a refluxed vessel. After cooling, the reaction solution is poured onto ice, strongly alkalinized with 30% sodium hydroxide solution, and extracted several times with methylene chlord. The offset extracts are dissolved over sodium sulfate and evaporated, and the non-crystalline residue is dissolved in absolute ethanol and the dihydrochloride is precipitated by the addition of ethereal hydrochloric acid. The dihydrochloride is filtered on suction, washed with ether and recrystallized from absolute methanol. The product decomposes, starting from 175 ° C, yield 1.2 g (63% theoretically possible). The subject of the invention is 1. A method for producing 4-morpholinothieno (3,2-a) -pyrimidine derivatives of general formula I. lN,) „j HN N-f - i k / Rs K-iIS radicals from Ri to Re may be the same or different and mean hydrogen atoms or methyl groups; Rs - can mean, in addition to the above values, also phenyl group; n is NUMBER 1 or 2; or salts thereof, characterized in that the compound of the general formula II where the radical A denotes a halogen atom, an alkylsulfonyl group, a mercapto group free or substituted by a lower alkyl radical; the Cs-Re radicals have the values indicated above and are reacted with a compound of the general formula III (CH) RN NH target product by known methods in free form or in the form of its salt. 2. A method according to claim 1, characterized in that the reaction, if A is a halogen atom, is carried out in the presence of a hydrogen bonding agent. 3. Method according to paragraphs. 1 and 2, characterized in that the reaction is carried out in a solvent or an excess of the title amine. 4. The method according to paragraphs. 1-3, characterized in that. . uu; uu iiu 1111. 1-o, and that it is carried out at O, -200 ° C.