SU504482A3 - Method for preparing 1-phthalazone derivatives - Google Patents

Description

(54, METHOD FOR OBTAINING DERIVATIVES OF 1-PHTHALAZONE

T1E is an example of a method for the production of new compounds derived from il-phtapazone of the formula CH iOCNI iRj, where RI is a hydrogen atom or an alkyl type containing 1-6 carbon atoms, in particular (apkip containing 1-3 undama atoms; P , is a hydrogen atom, un branched or branched, with 1, in accordance with the preferred option, this alkyp contains 1-6 carbon atoms; cycloalkyl, alkenyl; moreover, according to the alternative, this kelyl contains 2-5 carbon atoms, in particular, anpenyl, containing 2-4 permeable atoms, reel, 1predp6chtiteyyu fenip or drowning, Arapka, and in accordance with a preferred embodiment - benzyl or phenethyl, dialkilamshyualkip preferably dialkyl containing 15 carbon atoms, aminoalkyl latter alkyl radical which contains 1 or 2 carbon atoms, furfurilna (Group picolyl or piridipna group; R, is a hydrogen atom, an alkyl, preferably 1 alkyl, containing 1 to 6 carbon laTOMOB, especially alkyl with 1 to 3 carbon {hydrogen atoms, aryl, preferably phenyl or tolyl, a carbamoyl group, N is alkylcarboyl Na group, preferably N-alkyl (PI-Cjj) carbamoyl group, N, N-dialkylcarbamoyl group, preferably N, L / -dial; kil (Ct-j) carbamoyl group, alkylsulfonyl group, preferably alkyl (CI -Y) a sulfonyl group, in particular an alkyl (Cj,) sulfonyl group, or an arylsulfonyl group, ap respectfully folnll or tolylsupfnol group: a hydrogen atom, a halogen atom, for example, chlorine, bromine, iodine or fluorine, preferably chlorine or bromine, alkyl, preferably alkyl with J.-6 carbon atoms, especially and alkip with 1-3 carbon atoms, or alkoxyl is preferred but apkokssh containing 1-4 carbon atoms j 13-atom hydrogen, halogen, eg. chlorine, bromine, iodine or fluorine, preferably chlorine or bromine, alkyl, preferably al 1 S, especially alkyl Cf.j, alkoxy, Preferably alkoxy C 1-4, amino group of the adylamino group, preferably acylamino group Cj.j., alkoxycarbonyl group, preferably alkoxy Cj, a carbonyl group or a .carbamoyl group; R and Rj may together mean a divalent alkyd radical containing or. not containing a heteroatom, preferably an oxygen or nitrogen atom (besides the nitrogen atom of the group that corresponds to the general formula WRi j) These compounds have physiological activity and can be used as drugs. The method of obtaining the derivatives of formula 11 is based on the known reaction of carbamyl halides with ammonia or amines and consists in the fact that the compounds of the formula where, Rj. R have the meanings, are reacted with compounds of the formula AA-C-Cg where A-aixiM is chlorine or alkoxy, arylok forces, and; 1kylthio or artiltiogroup, followed by performing an action of the composition of the formula CHgOC-A where 1, 1 and Py and L have the indicated amounts, with an ammonia or an amine of the formula Y where. and j have the indicated meanings. . If necessary, the intermediate compound of formula IV can be isolated and purified. Since the intermediate formula formula, W. . Where A is a chlorine atom, is unstable and difficult to identify, then the process is preferably carried out in one stage without isolating the purification of intermediate W. However, in the case when, in the formula, 1M A means a radical different from the chlorine atom, intermediate is stable and easy to clean. According to the proposed method, the interaction between the compound of formula 11 dissolved or suspended in an inert solvent 7 and an equimolar amount or excess that can vary, in particular, from 1.0 to 3 moles, of the compound of formula 111 in the presence or in the absence of a dehydrochlorinating agent. As examples of such solvents or diluents, benzene, toluene, xylene, ethyl ether, dioxane, chloroform, dichloroethane and pyridine or mixtures thereof can be given. In a preferred embodiment, as a dehydrochlorinating agent or catalyst, the reaction mixture is added AminT; such as dimethylnip; ethylaniline, triethylamine, N-allogostlith rtdine or pyridine. In preferably the first stage, the B temperature range is from -1O to + 50 ° C and usually lasts for 1-25 until the reaction is complete. As examples of compounds of formula 111 may be mentioned phosgene, alkyl chloroformates such as methyl ,, or et1shhlor4yurmiat, an aryl chloroformate such as fe11ilhlor (1hermiat, alkilhlortioformi- Ata such as methyl etilhlortiofor- MIAT and arilhlortioformiaty ,. such as fenilhlortio (yurmiat}. A preferred an aryl chloroformate is a phenyl chloroformate because it is cheap and easy to reach. 1. Phenyl can be fixed or unsubstituted, for example, p-chlorophenyl, p.promphenyl and gy-1 is a nitrophenyl group, and also a - and p - aphyl group, AT As examples of compounds of the formula W, it is difficult to give 4-methoxycarbonyloxymethyl-1-pchitaoon; 4-4 noxncarboni / poximethyHH-phthalazoH; 4 (n "to kporpenok sicarbonyloxymetip) i canaaoH; Phthalazone 4..iMei ffii thiocarbonipoximetip-1 Phthalazone and 4C) 8 nylthiocarbonypoxymethyl phthalaone "4 ™ phenoxycarbonyloxymethyl" A "4 bands are considered to be suitable. completion in a few hours. Ammonia or amine formulas V can be used in excess, and an excess of from 1 to 10 moles of the length per 1 mole of the compounds of form “I mules W. As examples of amines of formut.1 M, one can cite such primary "" (amine amines, such as metyl ethyl nropyl, -, isopropyl-j, butyl, aplil "" cshsho "" "Teyugyl-, benzyl-f p. -Dimetypaminoethyl, -diethylaminopropyl , pygalil and furfurilamine, and secondary amines such as di "methylamine, diethylamine, pyrrolide, piperidine, N -" methylpiperazine to yn. Cros. It is aromatic, moglypolspolob:;:,,), example of the primary and secondary ei opuidin and 3 amshüpir1i: al.): idin. . When A is a chlorine atom, the mountain of the same i & ro is the same ;; it proceeds warmly in cpsAt, “. When doing the best, as riepi VSKH of the second stage in quality is. p | E a glueing agent can be used. /; an excess of the reacting formula U „) However, in the th-th one you drop, when A ke; a la It is carried out in the presence or absence of a solvent and in the presence of a dehydrochloride / agent. 1 Preferred agents for carrying out the second stage are methane, h-andop and lropanol. The co-eternal product can be selected and cleaned according to conventional methods. Example 1. 4 Phenoxycarbonigoxoximethyl-1 4 talazone, To a solution of 5 g of 4.ximethyp-1-phthalon aona ml of pyridine, 6 g of phenyl chloroformate is added with cooling. Leave overnight at room temperature. The reaction mixture is evaporated under reduced pressure and diluted with water. The precipitate is filtered and crystallized from zfir, .6) enoxycarbonyloxymethyl-1-phthalazone with the like. 113-114c. 4 -Karbamoksimetim-1 |} tala; 5oi. To a solution of bg 4) onoc.carbonyloxy-methcp-1-alaoea, described in the above example, B 1OO mn of methyl alcohol, add 2 g of ammonia at room temperature. It is left overnight and then evaporated, the residue is crystallized from methyl alcohol, to obtain 3.1 g of 4 - ': arbamoxymethyl .1-phthalazone with m.p. C .. - Calculated,%; € -54.79; H-4D4; -19.17, Found,%: C-55.03; H-4.20; N-19.30 Example 2. 4-N chietylcarbamo1 & simets1 | -7- etoxy 2-child 1-1 phalazone. , To a stirred mixture of 4 ml of a ZO% aqueous solution of monomethylamine and 5 O ml of methyl alcohol 1, 2 g of 4-phenoc was added. Sicarbonyloxymethyl-7-chetoxy-2-flew and. -falazone obtained in example 1. 05 ,; After this, the reaction mixture is left overnight. subsequent evaporation of solvents. The residue is extracted., Hporoformoll; and the chlorofor extract is washed successively with 59% sodium hydroxide solution and water. Next, chloroform is distilled off and; A crystal current is drawn from a mixture of methyl alcohol with ethyladetate to obtain 0.7 g, 4 "(N-methylcarbamoxymethyl) -7-methoxy-2 methyl-1-4 methyl with t, pl. 171-173 C. Calculated. %: C-59.76; H-5.79; / (| -1b108: C, li | 04: NjI Hatfi Ko,%: C-S9.65; H-5.47; -15.32 Example 3. 4 g of 4-letthiocarbonyloxymethyl- 1-phthalazone obtained by using 4-hydroxymethyl-1-gt-vlasone and methyl chloro-4-thioformate as a starting material, measure 1, dissolved in 20 ml of methyl alcohol. After that, 1 g of dimethylamine is added to the solution with transfer. The reaction mixture was then left nptf at room temperature for 3 hours, evaporated under reduced pressure, the residue was red; became free from ethyl acetate mixture with petropeum 21 m ether to give 0.6 g of 4 .- (K) 5 N-d; methylcarbamoxymethyl }""one- phthalaon with t, gg 174-176 C. Calculated,%: 28.H-5.30; M-17.00; Found,%: C-58.21; H-5, -17.22 P p and Example 4-21. In Example 1, derivatives of 4-4 | enoxoxcarbon Shoxymethyl-1-phthalazone of the formula are obtained on the basis of the reaction of 4-hydroxymethyl-1-phthalazone P derivatives with fezischloroformate. pronounced 4 phenoc- .sicarbonyloxymethyl-1-phthalazone IV with methylamine as in Example 2, and the products of formula I are obtained with an yield of 80-90%, as shown in Table 2. 1. According to Example 2, 4 $ of snoxycarbonyloxymethyl-1-phthalazole prepared in Example 1 is reacted with amines Y. The result is products that are flawed in Table D. 2, with the release of 8O-9O%. Example s 31-5O. By examples

(1 "-4" Compounds of the formula I are reacted with compounds of the formula 1) 1, for example, phenyl chloromate, phenyl porphyry formate or methyLchlorothioformate, then the reaction is formed between the intermediate compounds of the formula (Y amines of the formula V, resulting in a floor HajoT products of formula 1 with a yield of 80-90%, as illustrated in Table 3.

Table 1

table 2

Example 51 To () a solution of 3.4 g of 4-ox11met1sh-1-phthalazone and 3.2 g of dnmethylniline in 100 ml of dry topuba, a solution of 2.2 g of phosgene in 20 mp of toluene is added dropwise at 0-5 C, 6

After the addition is complete, the reaction mixture is stirred for 3 hours at 0–5 Siv for 3 hours at a temperature of approximately 10 ° C. Next, keeping the mixture temperature below 10 ° C and adding 10 l kgt of excess ammonia. After the mixture, the mixture is kept at a temperature below 10 ° C and left to stand at room temperature for 3 hours. After Toro, the mixture is washed with water, the toluene 15 "evil is separated and the aqueous phase is extracted with ethyl acetate. Next, the joint toluene and ethyl acetate solution is dried and evaporated under reduced pressure. The resulting residue is crystallized from methyl 20 pter, to give 4-carboxymethyl-1-a-lazone with m.p. 23 ° -232 ° C.

Example 52. A solution of 9.2 g of 7-chloro-4. Oxymethyl-2 gmethyl-1-phthalazone and 7 g of dimethylaniline in ZOO ml of dry toluene. 25 Cool to -5 to O. C. 5.5 g of phosgene are added at stirring at a temperature of -5 to O C. The mixture is stirred at 0-5 ° C for 5 hours, and then at-5 ° C and rem;

PRI m about J) (L., K solution 3 g 4-OK-.4 enoxycarbonyloxymethyl -2-methyl-1-phta-

simetil-2-motype-1- 1Chs). in 15 ml of pi-lazona with t. pl. 97-09 C, Ridina at ohzhzhd. MU11 and poromeshivapiya to-K solution 4 g of 4-4 alkoxycarbonyloxy add 3.5 g of pho lppo to the | | The reaction is 1mt-2-methyl-1fsch1-ooic and 50 mp of the methane mixture is left to stand at room temperature, while stirring, is added to G (X -

temperature; in TeHoitsio 3 concentrate-Dimethylaminopyropi / iaMiina.Roakshyunsmsmsz

was evaporated, and then}) 1 Yashyshut water. stirred at the same time as

The solution was filtered off and crystallized. For 5 hours, after which it was distilled off but this -o-ether, giving 4 g of 4- (Yuiol. The residue was dissolved in li ethioxy ajjiipo.

5 ml of an aqueous solution of methylamine are added. The reaction mixture is stirred for an hour and left to stand at room temperature for 3 hours. Next, the mixture is washed with water and the toluene solution is dried and evaporated.

The residue was crystallized from ethyl acetate, to give 6.5 g of 7-ooiop-4- (N-methylcarbamoxymethyl) -2-methyl-1-phthalazone with mp. 148-149 ° C.

Calculated,%: C-51.15; H-4.26; -14.92

qi% O W, W

Found,% .- C-50.89; H-4.35; N-14.79

Examples 53-60. Similarly to Examples 51-52, the products of formula 1 are obtained using as starting materials, compounds of general formula II and general amines of the formula Y,

Example 60. A mixture of 4 g of 7-hr-4-hydroxymethyl-2-methyl-1-phthalazone, 3 g of d-methylaniline, 2 g of methylcarbamyl chloride and 40 ml of absolute diethyl ether are heated under reflux condensate in solution 5 hour. The reaction mixture is washed successively with water, 3% hydrochloric acid solution and water, dried and evaporated. The resulting residue was crystallized from ethyl acetate to give 2.2 g of a 7-chloro- (N- -; -methylcarbammoxy-type) -2-methyl-1-anflii zone with m.p. 148-149 C.

Tb

4 and the ether solution is washed thoroughly with 10% sodium hydroxide solution and water. After drying, the ether is distilled off, and 1 g of oxalic acid is added to the oily residue, and the mixture is crystallized with ethyl alcohol to obtain 3 g of 4 4 1 - (((C dimethylaminopropyl) -f1cap6amoxymethyl) -1-phthalazone oxton with m. square 168-169 Calculated,%: C 52.93; H 5.92; Nl3.2; 9RLRL (soon) a; Found,%: C 52.78; H 5.86; Example 62: 2g of 4-phenoxycarbo, nipbxmethyl-1-4-talalaone, extracted in i. RoTjB lO Mn methanol: iK 4r N methyl piperazite is added to the stirred jfacTBopy. The reaction mixture is methyl piperazite. The reaction is stirred at room temperature for 3 hours, and then methanol is distilled off. The residue is crystallized from methanol, yielding 1.3 g of 4-. , N - (ethylmethylDY; mino-ethylene) -carbamoxymethyl3 -1-phtapazoiHa ,, Calculated,%: C 59.59; H 6.00N18.33 qjHfgOjN H 5.89; Found,%: C 59.71; N: 18.60 Example 63. According to Example 61 through 4, 4-phenoxycarboxyxytype-2-mv4- is obtained. til-1-4) talazone based on 4-oxymetip-24-metip-1-phtapazone, and then 4-phenoxycarbonyloxymethyl-2-me-, tyl-L-phthalazone is promoted with a p-dimethylaminoethypg min. The result is 4- W -; - (p-dimethylaminoethyl) -carbamoxymethyl -2-methyl-1-phthalazone with m. PP. 193-193 G (recrystallization from ethanol). M yr 64-74, In examples: From 61 to 62 n, the product 4 is reacted. Α-oxymethyl-1-phtapazone of the general formula T1 with phenyl chloroformate to give the derivatives 4-4 | enoxycarbonyl oxymethyl- The 1-phthal zone of the general formula IV, Then the compounds of the general formula 1U are reacted with amines of the formula Y with a total yield of 70-90% of the product, as indicated in the table. five.

in to

3

s

t D 0

H 1 7 Formula of iaobrete and 1. Method of obtaining ionoprotective 1-phga lazon formula 1 CH., N where R is a hydrogen atom or agasil; K is a hydrogen atom, an unbranched or branched alkyl, cycloalkyl, alkoyl, aryl, aralkyl, dialkylaminoalkyl, fur furyl, picolyl, or pyridyl; i R; b is a hydrogen atom, alkyl, aryl, carbamoyl; - alkylcarbamoyl; j is dialkylcarbamoyl, alkylsulfonyl or arylsulfonyl; - a hydrogen or halogen atom, an alknl or alkoxy; - a hydrogen or halogen atom, an alkyl, alkoxy, amino or acylamino group of an alkoxycarbonyl or carbamoyl; 1 and F can mean together a two valence alkylene residue, containing or not containing a heteroatom, characterized in that the compounds of the formula I | Where 1 $, t, bff have the above values, are reacted with compounds of the formula iHl, where A is an atom chlorine or aloxy, Garyl oxyl, alkylthio or arylthiogrugsha, and the compounds of the general formyl IV CHROC-A where R ,,, R ,, R are given, are reacted with am 2 miak or amine of formula V, WHR, T: where f ( j and R have the indicated meanings. Priority on the basis of: 27.02.71 with R, is a hydrogen atom or an alkyl; E is a hydrogen atom, a linear or branched alkyl, cycloalkyl or alkenyl, aryl, aralkyl, furfuryl, nicolyl or pyridyl group; a hydrogen atom; R (j and Rj can mean a divalent alkylene residue containing or not containing a heteroatom ; A alkoxy, aryloxy, alkylthio or aryl group; 27.O2.71 with R is a hydrogen atom or alkyl; Rj is a hydrogen atom, a straight or branched alkyl, cycloalkyl or alkenyl group, aryl, aralkyl, furfuryl, picolyl or pyridyl group; hydrogen atom, alkyl or aryl; R and Rt are hydrogen atoms; Rij and Rj can mean a bivalent alkylene residue containing or not containing a heteroatom, they can react the compounds of formula (JT), where R and R are defined as above, with phosgene, and then the reaction is formed to form a compound of formula (SlV), where Rj, R4 and Ru are determined according to the compound and A is a chlorine atom with ammonia or an amine of formula (V), where R and Rg are determined according to with the above; 08.08.71 when RI is a hydrogen atom or I alkyl; R is a hydrogen atom, unbranched or branched alkyl; cycloalkyl, alkenyl, aryl, aralkyl, furfuryl, picolyl or pyridyl group; ij is a hydrogen atom, alkyl, aryl; R, is a hydrogen atom ILE halogen atom, alkyl i or alkoxy; - a halogen atom, an alkyl, alkoxy, amino, acylamino, alkoxycarbonyl or carbamoyl group; 1 RI and R may mean a divalent alkylene residue containing or not containing a heteroatom; A is an alkoxy, aryl, oxy, alkylthio or arylthio group; 10.0 to 8.71 with RJ, a hydrogen atom or an alkyl; R is a hydrogen atom, a branch that is not branched or branched alkyl or cycloalkyl, alkenyl, aryl, aralkyl, furfuryl, picolyl or pyridyl group; Rj is hydrogen, alkyl or aryl; Rj is a hydrogen or halogen atom, alkyl or alkoxy; Ry is a halogen atom, an alkyl, alkoxy, amino, acylamino, alkoxycarbonyl or carbamoyl group; R and 1 can mean a divalent alkylene residue, | containing or not containing a heteroatom, from d to N, 19.50448220 characterized by the fact that it is higher; A is a chlorine atom with ammonia or an amireaction of a compound of formula (P), with the formula (Y}, where R; and R have ENEN and Ru. Have the meanings defined above.