SU584779A3 - Method of preparing tricyclic compounds or salts thereof - Google Patents

Description

Wb IB H / JJ-No.2), - # G) where, in, L1, X, Rj and R are indicated above, preferably in an inert organic solvent in the presence of an acid binding agent at 30-2OO C, and the target product is isolated in the form of a base or salt. The reaction between the starting compounds of formulas II and III can be carried out without a solvent. Tsepesoobrazno employed not ny organic solvent such as aromatic hydrocarbon: chainsaws nly toluene, a lower alkanol, for example methanol or ethanol, chlorinated hydrocarbon, e.g. methylene chloride, trichlorethylene, chloroform, carbon tetrachloride or chlorobenzene, an aliphatic or cyclic ether, e.g. dnetilovy ether, tetrahydrofuran or dnoxane, dimethylformamide or dimethyl sulfoxide. The temperature is reasonably beneficial for SOs - 2OOPs, and the aprons are operated at 6O - 1SO ° C. The reaction is preferably carried out in the presence of an acid binding agent, for example in the presence of an alkali metal carbonate, for example potassium carbonate, or in the presence of an excess of the starting compound of formula III. The resulting bases of formula i form salts with inorganic, organic acids, for example, hydrochloric acid, hydrobromic or hydroiodic acid, other mineral acids, such as sulfuric, phosphoric or nitric, or organic acids, such as tartaric, citric, camphoros lfonovoy, methane- or ethanesulphonic, toluotyuulfonovoy salicylic, ascorbic or mandelic acids. Preferred compounds are hydrohalides, in particular hydrochlorides, maleates and methanesulfonates. Salts are preferably prepared in a suitable solvent, for example, ethanope, acetone or acetonitrile, by treating the free base with an appropriate non-aqueous acid, and depending on the molar ratio between the free base and the acid, get (because of two nitrogen atoms on the piperazine radical) salts with one or two moles of acid per mole of base (mono- or di-salt). When processing d-salts, depending on the solubility of the mono- or d-salt in the solvent used, the corresponding diyl or mono-satin is obtained. The bases of the formula I are partly crystalline solids, which are relatively soluble in dimethylsulfoxane, dimethylformamide or chlorinated hydrocarbons, such as chloroform, methylene chloride, or alkanols, vaprnmer, methanol or ethanol, and in water, are not creative. Cope compounds of the formula I are crystalline solids. Oig are well soluble in cimethylsulfox de, dimethylsmurmide, lower alkanols, methanol or ethanol, worse in chloroform, methylene chloride and in water. They are practically insoluble in benzene, ether and petroleum ether. It is necessary to note the compounds of formula I, in which RJ and R are hydrogen, R (is methyl and R is chlorine, fluorine or methylthio, and also salts, then the compounds of formula I, where Rg and RJ are hydrogen, Ri is chlorine and R is fluorine, as well as their salts. Preferred 9 compounds are {compounds ({Yurmules T., where P is 2, nt is O, X is oxygen or methylene, and n Rg - as well as their salts. Preferred compounds are are 1- {2- 4- (6-chloro-10,11-dngidro-2-methyldibenzo {&, f) tiepin-1O-ip) -1-piperazinip-ethyl} -2-pyrrolidinone, 3- {2 - 4- (8-fluoro-10,11-dihydro-2-metidibenzo (& f) tiepin-1O- and ) -1-piperazinilZ etip -2oksazalidinon} 3 - 2- {4- {2-chloro 8-fluoro-10, 11-digvdrodibeizo ({, f) -gnepin-1CX-yl) - 1-piperazinyl;.. | -8til) -2-ssgaz opidin he and 3- {2- 4- (1О, ll-digio-2-metip-in-l methyl) -aibenzo (i, {) tiepin-1O-yl) -1-piperazinyl -ethyl} -2-oxazolidinone, as well as salts of these compounds. The starting compounds of general formula I are usually obtained from the corresponding 1O-hydroxy derivatives by reaction with a suitable halide, for example thionyl chloride, thionyl bromide or hydrohalide in the presence of a water-binding agent, for example hydrogen chloride and calcium chloride. The starting compounds of the formula U can be obtained by reacting N.-protected piperazine, for example, Jf-benzyl or K.-lowering alkoxycarbonylpiperazine, with the corresponding W-haloalkyl lactam mainly in the presence of an acid-binding agent, for example potassium carbonate or triethylamine, followed by removal of the protective group by hydrolysis or hydrogenolysis. Example 1. 29 g of 1O-chloro-8-fluoro-10, 11-dihydro-2-methyldibenzo (B, f) -thiepine in 13O ml of chloroform are heated with 45 g of 1-piperaznnp) etnl -2-oxopidnnon for 20 h with reverse flow. Chloroform is evaporated, the residue is stirred in ether in caustic soda solution, the precipitate is washed off with water, the precipitate is dried with ethanol. Pungent 3 - (((& -fluoro-10,11-dihydro-2methylaibouvzo (L, f) tn-nO-1O-1 (n) -1-pnp zinip5-etip} -2-oxazopndinone pavatc pr 174-175 ° C. The base is reacted with methanesul by the background acid to produce dimethanesupho, which, after recrystallization, from this pa / ether melts at 2 ° C ° C. Nickel% C: 65.26; H 6.37; H 9.57 S 7.33, C24 28 2 3 Calculated,%: C, 65.28; H, 6.39; K, 9.51: 7.26. Mass spectrum: The auto-peak peak 441 f 341 corresponds to 243, 99 corresponds to -g and rlg "DI Source 10-chloro 8-fluoro-10,11-digitsro-2-metibenzo {, f) tiepin is prepared as follows: To a solution of 474.5 g of hydroxide to Ali in 3.6 l of water is added under nitrogen at 50 ° C with 217 ml of 4-fluorothiophenop and stirred for 15 minutes at room temperature. After adding a few grams of copper powder and 536 g of 2-iodo-5-methylbenzoic acid, the mixture is heated The reaction mixture is filtered in a hot state, acidified with concentrated hydrochloric acid more than once (} zhltruyut. The residue is washed with water until neutral, dried with reduced color. 3-methyl-6- (4-fluorophenyl-thio} bea-bic acid is obtained with gp 166167 C. ZOO g 3-metip-6- {4-fluorophenyl) -tH3-bezoic acid in 2 p of absolute tetrahydrofluoride dropwise under nitrogen at reflux to 780 ml of a 7O% solution of sodium dihydro-bis- (2-methoxy-ethoxy) -aluminate in bevzole and heated for another 1 hour with a 1-m condenser. The reaction mixture is shed to 4 ° C dropwise acidified with 13OO ml of Sv. hydrochloric acid and then concentrated hydrochloric acid is added and extracted with benzoop. The organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. 3-methyl-6- (4-fluorophenip) -thio} -benzyl alcohol is obtained as a yellow oil. 337 g of 3-metal-6- {4-fluorophenyl) -two-benzyl alcohol is dissolved in 1 liter of absolute benzene and brought to a boil. To the solution is added dropwise 19 O ml of thionyl chloride and additionally boiled for 45 min The reaction mixture was evaporated under reduced pressure. The residue is extracted several times with benzene, the benzene extract is evaporated. Get 3-metip-6- {4-fluorophene l) -thio-benzyl chloride in the form of a brown oil. 115 g of potassium cyanide in 150 ml of water are heated with 344 g of 3-methyl-6- (4-fluorophenyl) -thio-benzyl chloride in 450 ml of ethanol for 1 oh under reflux. Ethanol is stripped off in vacuo. Water was added to the residue and extracted with benzene. The benzene solution is washed with water, dried over sodium sulfate and evaporated. 3-metnp-6- (4-fluorophenl) -tno-phenylacetonitrile is obtained in the form of a dark brown oil. 106 g of 3-methyl-6- (4-fluorophenl) -THoJ-fenipetsezonitripa, ZOO ml of ethanol, 100 g of potassium hydroxide and 300 ml of water are heated for 5 hours under reflux. Then the ethanop is evaporated under reduced pressure. The residue is dissolved in water and the neutral components are extracted with benzene. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried with sodium sulfate, filtered and evaporated under reduced pressure. 3-methyl-6-t (4-fluorophenyl) -thio-phenylacetic acid is obtained in a dark brown oil, which, after crystallization from benzene / hexane, melts at 117 C. 1810 g of popiphosphoric acid are heated under nitrogen to 128 C quickly prn-

Bavly 173.6 g of 3-metip-6 .- {4-fluorophenyl) -thio3-phenipucetic acid and stirred for 10 minutes at 12 ° -130 ° C. The mixture is drunk on ice and extracted with benzene, the organic phase is washed with water and saturated sodium carbonate aqueous solution, dried over sodium sulfate and evaporated. 8-fluoro-2-methi71-dibenzo (b, f) tiepin-1O (11H) -one is obtained, which melts at 1OZ-1O4 ° C. 10

SW of 8-fluoro-2-metidibenzo (b, f) tiepin -1O (11H) -one is suspended in 550 mp of ethanol, 24.3 g of sodium borohydrnd is added, the reaction mixture is heated under reflux for 10 minutes and after addition of water is extracted with chloroform. The organic phase is washed with water, dried over sodium sulfate and evaporated. 8-fluoro-10,11-dihydro-2-methyldibenzo (b, f} tiepin-1O-ol is obtained in the form of a 20 oil.

103 g of 8-Fgor-10,11-dihydro-2-metidibenzo (& f) tiepi-10-ol, 500 ml of benzene and 38.4 g of finely ground calcium chloride are saturated with hydrogen at 15 ° C with 25 and stirred for nights The precipitate is washed off, washed with benzene and evaporated in -vacuum. Obtain 1O-chloro-8-fluoro-10,11-dihydro-2-methyldibenzo (b, f) tiepin, which is plateau-30 at 63-64 ° C,

Example 2 Analogously to example 1 is obtained from 1O-chloro-10, I-dihydro-3-met-oxy-8- {methylthio) -dnbenzo (& f) tiepina in 3-G2- (1-piperazinyl) -ethyl - 2-psazolidi-35onon 3- {2-C4- {10, I-dihydro-3-methoxy-8- {metipto) -dibenzo (b, f) tiepin-1O-un) -1-piperazinyl-ethyl} -2-oxazolidinone, which, after recrystallization from ethyl acetate / petroleum ether, melts at 98-1OO ° C), the hydrochloride melts after a pen crystallization from ethanol at 217-219 ° C. The original 10-chloro-10,11-d1 hydro-3-methoxn-8- (methyltno) -dibenzo (L, f) tiepin prepared as follows: 15O g 4-methoxyanthranilic acid is suspended at 0 ° C in 2 l of water and BO ml of concentrated hydrochloric acid. To the suspension is added dropwise while stirring at O-5 ° C for 30 minutes, a solution of 62 g of sodium nitrite with 130 ml of water is added. The resulting solution of the diazonium salt is stirred for 15 minutes at 0–5 ° C. A solution of 1–4 g of iodine potassium in 700 mp of sulfuric acid is added dropwise at 3 ° C for 45 minutes. The mixture is stirred for 30 minutes at room temperature, then it is slowly heated to boiling; the mixture is cooled to room temperature for 2 hours. Precipitated brown

the crystals are filtered and washed with water of the neutral medium. The precipitate is dried under vacuum. 2-Iodo-4-methoxybenzoic acid is obtained in the form of brown crystals which melt at 174 ° C.

411 g of 2-iodine-4-mexibenzoic acid, 4 l of methanol and 400 ml of concentrated sulfuric acid are heated for 4 hours under reflux. The solution is evaporated under reduced pressure, water is added and the mixture is extracted with ether. The organic phase is washed with an aqueous solution of sodium thiosulfate and sodium bicarbonate and dried over sodium sulfate. The solution is filtered, evaporated under reduced pressure and distilled. The methyl ester of 2-iodo-4-methoxybenzoic acid is obtained, which is prepared at 95–98 ° C (O, O4 mm Hg).

2O5 g of methyl ester of 2-iodo-4-methoKg of sibenzoic acid, 4OO ml of methanol, 39O ml of water and 95 g of potassium hydroxide are stirred for 30 minutes at 48 ° C. 3 & the solution is concentrated. Under reduced pressure and acidified with hydrochloric acid. The resulting yellow crystalline 2-iodine-4-to etoxybenzoic acid is filtered off, washed with water until neutral and dried. The compound melts at 185 ° C.

102 g of 4- (methylthio) -thiophenol are added to a solution of 170 g of potassium hydroxide in 1.6 l of water under nitrogen at 5 ° C. The mixture is further stirred for 15 minutes, 2.4 g of copper powder and 180 g are added is iodine-4-methoxybenzoic acid and heated under reflux for 7 hours. The reaction mixture was filtered while hot, acidified with concentrated hydrochloric acid, cooled and ({ilt). The residue was washed with water and evaporated under reduced pressure.

Get 4-methoxy-6- 4 - {methylthio) -thiophenyl-benzoic acid with so pl. 2 O 2 203 ° C.

190 g of 4-methoxy-6- 4- (methyltno) -thiophenne-benzoic acid in 1.8 l of absolute tetrahydrofuran is added dropwise under nitrogen to 85 O ml of a 7O% solution of d-hydro bis- (2- methoxyethoxy) sodium asominate in benzene. The mixture was further refluxed for 30 minutes. After cooling to 5 ° C, the reaction .ivieub is acidified with 5OO ml of 3N hydrochloric acid and then with concentrated acid. Extracted with ether. The organic phase is washed with iiH. an aqueous solution of sodium hydroxide, water and dried with sodium sulfate, filtered and evaporated. Get 4-methoxan-6-T4 - (mtiltio) -thiophenyl} -6enzyl alcohol in the form of a brown oil,

165 g of 4-metchexn-6-4- (methylgio) -thiophenip-benzyl alcohol is dissolved in 550 ml of absolute benzene and heated under reflux. The solution is added dropwise within 45 minutes by 62 m of tononyl chloride and boiled for 30 minutes The reaction mixture is evaporated. The residue is extracted with benzene three times. After the benzene solution, 4-methoxy-b-g- (methylthio) -thiophenyl benzyl chloride is obtained as a dark brown oil.

51 g of cyanide drip in an HO ml of water is boiled for 9 hours with 186 g of 4-methoxy-6- | 4- {methylthio) -thiofesh-n-benzyl chloride in 27 O ml of ethanol. The ethanol is distilled off, water is added to the residue and the mixture is extracted. O (| oil extracts are washed with water, dried with sodium sulfate and evaporated. 4-methoxy-6-14- (methylthio) -thiophenyl-phenacetonitrile is obtained as a dark brown oil,

160 g of 4-methoxy-6- 4- (methylthio) -thiophenyl-phenylacetonitrile, ZZO ml of ethanol, 162 g of potassium hydroxide and 330 ml of water are boiled for 8 h. Under reflux, the ethanol is evaporated under reduced pressure. The residue is dissolved in 2 l of water. The solution is extracted with ether and the ether extract is discarded. The aqueous solution is cooled and acidified with concentrated hydrochloric acid, extracted, with benzene and the benzene phase is washed with water, dried with sodium sulfate, filtered and evaporated. A crude 4-methoxy-6-C4 - (methylthio) -thiophenyl-phenylacetic acid is obtained, which, after recrystallization from benzene / hexane, melts at 125 ° C.

29.3 g of 4-methoxy-5- 4- (methylthio) -thiophenip -fe1-acetic acid are stirred for 17 hours with 15O g of polyphosphoric ACID and 6OO ml of tottuol. Reaction: the mixture is cooled to 60 ° C and the toluene solution is decanted. Ice and water were added to the residue and extracted with toluene. The combined toluene solutions were washed with water and an aqueous solution of sodium hydroxide, dried over sodium sulfate, and concentrated under reduced pressure. Get 3-methoxy-8- (methylthio) -dibenzo (b, i) tiepin-10 {11H) -one in the form of blood oil. After recrystallization from acetone / hexane, a product with m, pl. 127 C.

17.8 g of 3- "etoxy-8- (methylthio) -dibenzo {b, i) thiepin-1O (11H) -one is suspended in 150 ml of ethanol and added to 3.8 g of sodium borohydride. The reaction mixture is stirred for 9O minutes, then water is added and the mixture is extracted with ether. The organic phase is washed with water, dried with magnesium sulfate and evaporated. Get 10,11-dihydro-3-methoxy-8- (methylthio) -dibenzo (b, f) tiepin-10-ol with t, pl. 122124 ° C.

157.7 g 10, ll-dvhydro-3-methoxy-8- (methylthio) -dibenzo (b,}) tiepin-1O-ol, 250 ml of benzene and 6 g of finely sprayed calcium chloride are saturated for 2.5 hours at - 15 ° C with hydrogen chloride and stirred further for 3 hours. After adding O, 8 g of active carbon precipitate from ({ptert and washed with benzene. The benzene phase is evaporated under reduced pressure. 1O-chloro-10,11-dihydro-3- is obtained methoxy-8- (methylgio) -dibenzo (B, f) tiepin with t, pl 12O-123 C,

Example 3. Analogously to example 1, from 8,10-dyslor-1O, ll-digadro-3-methoxy-dibenz D (6, f) tiepina and (1-piperazinyl) -ethyl) -2-oxydidium (8-HLOR- 10,11-dihydrr-3-methoxydibenzo C b, f) tiepin-1O-i) 1-piperazinyl-ethyl} -2-oxazolidinone, which after cross-crystallization of the back of ethyl acetate / petroleum ether melts poi 182-185 ° C, Dimethanesulfonate melts after the recrystal ethanol / ethyl ether at 148-15 ° C,

The starting 8,1O-dichloro-10,11-dihydro o-3-methoxybenzo {b, f) -thyepine is obtained on 2-iodo-4-methoxybenzoic acid and 4- -chlorothiophenol analogously to example 2. As intermediate products receive: 4 -methoxy-2- (4-chlorophenyl) -fib} -benzoic acid, so pl. 195-198 ° C; 4-megoxy-2- (4-chlorophenyl) -thio-benzyl chloride, m.p. 61-64 ° C;

4-methoxy-2-1 (4-chlorophenyl l) thio-phenylacetonitrile, brown oil; 4-methoxy-2- (4-chlorophenyl) -thio-phenylacetic acid, so pl. 117-118 C; 8-chloro-3-methoxydibenzo (b, f) of tyepium-10 (IIH) -OH, so pl. 132-134 ° C; 8-chloro-10,11-dihydro-3-methoxydinbenzo, (i, f) tiepin-1O-ol, so pl. 10-5-10 ° C. ,

1 Crushed 8,10-dichloro-10,11-digcdro-3-methoxydibenzo (b, f) tiepin melts at 10 0 -1 0 2 ° C.

Example 4. The exchange reaction of 2,1O-dichloro-8-fluoro-11, 11-dihydrobenzo (kf) tiepina with (1-piperazinyl) -ethyl -2-oxazolidinone is obtained similarly with MBDY 1 (2-chloro-8-fluoro-1O .11-dihydrodibenzoSb, () t epnn-1o-yl) -1-piperazinyl-ethyl} -2-oxazolide non, which by reaction with maleic acid translate paragraphs. 164 in the corresponding maleate with t, 166 ° C. The starting 2,1O-dihpor-8-fluoro-10,11-di hydrodibeneo (6,) -tnepin was prepared as follows / To a solution of 214 g of hydroxide drip in 2 l of water was added under nitrogen at 50 ° C 122 g of fluoro - {thiophenol) and stirred for 15 minutes. After adding 3, O g of copper powder to 2.69 g of 5-chloro-2-iodobenzoic acid, the reaction mixture is heated for an additional 7 hours with a refrigerator. The filter / sweat mixture was hot and the filtrate was acidified with concentrated hydrochloric acid. The obtained precipitate is filtered off, washed with water until neutral and evaporated under reduced pressure. Get Cr-hpor-6- (4-fluorophenip) -thioz-benzoic acid, so pl. 176-177 s. To 264 g of 3-hpor-6-1 (4-4 | Torfenyl) -thio-benzoic acid in 2 l of absolutely tetrahydrofuran is added dropwise in a nitrogen atmosphere 450 ml of a 70% aqueous solution of sodium dihydro-6c- (2- methoxyethoxy) aluminate in benzene and then boiling for another 30 minutes under reflux. After cooling to 1 ° C, the reaction mixture is acidified with 1 L of 3N. hydrochloric acid was added concentrated hydrochloric acid and extracted with ether. The organic phase is washed with water, 2 n. aqueous solution of sodium hydroxide and again with water until neutral, dried with sodium sulfate, filtered and evaporated. 3-chloro-6- (4-ftschaphenyl) -thio-benzyl alcohol is obtained as a brown oil. 224 g of 3-chl (-6-4-fluorophenl) -thio-benzyl alcohol is dissolved in 800 ml of absolute benzene and brought to a boil. 97.5 ml of tin chloride was added dropwise to the solution over 4 minutes. Then boiled for another 30 minutes. The reaction mixture is evaporated under reduced pressure. The residue was added three times. Benzene and evaporated. 3-chloro-6- (4-fluorophenyl) -thio} -benzyl chloride is obtained in the form of a brown oil, 81 g of potassium cyanide in 16 O ml of water are added to a solution of 255 g of 3-chloro-6-P4-s-fluorophenyl) -two -benzyl chloride in 400 ml of ethanol and heated for 9 hours under reflux. Ethanol was evaporated under reduced pressure, the residue was diluted with water and extracted with ether. The ether extract is washed with water, dried over sodium sulfate in a mixture. 3-chloro-b (4-fluorophenyl) -thioZ-phenylacetonitrile is obtained as a dark brown oil, 234 g of 3-chloro-6- (4-fluorophenyl) 6 -1 {) enylaceto1 ntrnla, DOO ml of ethanol, 254 g of hydroxy Potassium and 500 ml of water are heated for 18 h with a reverse crush. Ethanol was evaporated under reduced pressure, the residue was dissolved in water and extracted with ether. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with benzene. The benzene phase is washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude 3-chloro-6- (4-fluorophenyl) -thio) -phenylene acetic acid is obtained in the form of a dark brown oil. After recrystallization from benzene / hexane, the product is obtained in the form of crystals, which melt at 93 ° C. 990 g of polyphosphoric acid are heated to atmoS ({nitrogen to 12 ° C, 99 g of 3-chloro-6- {4 - fluorophenyl) -thio | -fesh1-acetic acid and Tfi 12 O C is stirred for 5 minutes. After adding ice, the mixture is extracted with chloroform. The organic phase is washed with water, aqueous sodium hydroxide and water, dried with sodium sulfate and evaporated. 2-chloro-8-fluorodnbenzo (b,) -thiepin-10 {IN) -one is obtained, which melts at 132 ° C, 60 g of 2-chloro-8-fluoridibenzo {b, {) tiepin-10 {11H} - it is suspended in ZO3ml ethanol and 13.9 g of sodium borohydride is added. The mixture is stirred at room temperature for 1 hour, then water is added and the mixture is extracted with ether. The organic phase is washed with water, dried over sodium sulfate and evaporated. 2-chloro-8-fluoro-1O, 11-dihydrodnobenzo (5,) tiepin-10-ol (ZOOml) is obtained from which it melts at. 58.3 g of 2-chloro-8-fluoro-1b, I-dihydr6di-. benzo (i,) tiepin-1O-ol, 300 ml of benzene and 21 g of micronized calcium chloride are saturated at 15 ° C for 2 hours with hydrogen chloride. The resulting precipitate is filtered off, washed with benzene and upar {shed under reduced pressure. 2,10-Dichloro-8-fluoro-16,11-dihydrodibeneo (6 if) tiepin is obtained in the form of white crystals, which melt at 84-85 ° C. Example 5. 10.6 g of Yu-chloro-B-fluoro -iO, 11-digndro-3-metildibenzo (b, f) hyepin is heated together with 200 ml of chloroform and 22.8 g of (1-piperazinyl -) - ethyl} -oxazolidinone for 30 hours under reflux. The reaction mixture is evaporated under low pressure. The residue is treated in the same manner as in Example 1. Insoluble base is recrystallized from ethanol. 3- (2- 4- (8-fluoro-10,11-dihydro-3-metnidibenzo (B,) tiepin-1O-yl) -1-piperazinig-ethyl} -2-oxazolysyun, which melts at 173- 175 ° C. Maleat

crystallized from acetone / ether and get the product with so pl. 147-149 C.

The original 10-chloro-8-fluoro-10,11-dngidro-3-miptidibenzo {b, | ) -vipers get 2-IODE-4-methylbenzoic acid and 4-fluoro- (thiophenol) as in example 4. As intermediate products receive:

4-methyl-2 - {(4-fluorophenyl) -thio-benzoic acid, so pl. 185-186 ° C;

4-methyl-2- (4-fluorophenyl) -thio-benzyl alcohol, orange oil; 4-methyl-2- (4-fluorophenip) -tno-benzyl chloride, red-brown oil;

4-methyl-2- (4-fluorophenyl) -thio-phenyl-petonitrile, brown oil; 4-methyl-2-1 (4-fluorophenyl) -thio) -phenipucetic acid, so pl. 135-137 ° C from acetone / petroleum ether (low boiling); 8-fluoro-3-methyldibenzo (t, f) tiepin-1O

(IIH) -OH, m.p. 96-99 ° C (from ethanol); 8-fluoro-3-methyl-1O, 11-dihydrodifenzo (($, 1) tiepin-1O-o, brown oil.

The resulting 10-chloro-8-fluoro-10, 11-dngndro-3-metidibenzo (b, f) tiepin is a brown maspo that crystallizes on STANDING.

Example 6. Analogously to Example 5, was prepared from 2,10-dysloro-1O, 11-dihydrr-8 (methylthno) -dnbenzo (b, |) tiepina and 3- 2- (1-piperazinyl) ethyl -2-oxazolidinone 3- {2- 4- (2-chloro-1O, 11-cyhydro-8- (methylthio) -dibenzo (L, 1) tiepin-1O-yl) -1-piperazinyl} -ethyl -2-rxazolidinone, which after recrystallization from ethyl acetate / pv5folic ether (low boiling) melts at 90-92 ° C. The salt melts from 1.8 mol of the salt acid at 203-205 C.

The original 2,10-dichloro-10,11-dihydro-8- (methylthio) -dibenzo (b, f) tiepina obtained from 2-iodine 5-xporbenzoic acid and 4- - (metipto) -thiophenol analogously to example 4

As intermediate products receive:

5-chloro-2- (methylthio) -phenyl-thio} benzoic acid, so pl. 17О-18О С;

5-chloro-2- {4 - (metipto) -phenyl-thio} -benzyl chloride, red-brown oil; 5-ENT-2 (methylthio) -fenyl) -thio} -phenipucetic acid, mp. 112-113 ° C from ethyl acetate / low boiling point petroleum ether;

2-hpor-8- (metipto) -dibenzo (a, t) tiepin-1O (11H) -one, t. Pl. 173-175 C from xylene 2-hpor-1O, 11-dihydro-8- (methylthio) -dibene (b, f) tiepin-1O-ol, yellow crystals.

The resulting 2,1O-dichloro-10,11-dngydro-8- (methyl) -dibenzo (B, |) tiepnn is an oil that can be used without further purification.

Example 7. Analogously to Example 5, was prepared from 1O-chloro-10,11-dihydro-3-methl-8- (metiptio) dibenzo (cb, I) tiepina and (l-piperisinyl) -ethylj-2-oxazolidinone 4- ( 10,11-dihydro-3-methyl-8- (methylthio) -dibenzo (6, f) tiepi -1O-yl-2- piperazinyl-etip} -2-oxaolidinone melts at 14O-143 after recrystallization from ethanol C. Maleate is crystallized from acetone / em ira, mp 151-153 ° C

The starting 10-chloro-10,11-dihydro-3-metip-8- (methylthio) -dibenzo () tiepine is obtained from 2-iodo-4-methylbenzoic acid and 4- (metipto) -thiophenol analogously to example 4.

As proyezhuchn1 products receive:

4-methyl-2- {4 - (methyltno) -pheny -ToJ-benzoic acid, so pl. 250-255 ° C; 4-methyl-2- - (methylthio) -phenyl-3-thio-benzyl alcohol, a yellow oil, which crystallizes on standing; 4-metip-2- {4 (methylthio).-Phenyl-thio} -benyl chloride, brown maso; 4-metip-2- {4- (metipthio) -phenip -thio -phenylacetonentryl, brown oil; 4-methyl-2 -. (4- (methylthio) -phenyl} -thio} -phenylacetic acid, mp. 14O-142 C from acetone / nitrous boiling petroleum ether 3-methyl-8- (metsttio) -dibenzo ( in, |) tiepin-1O (11H) -one, melting point 1 O8-114 ° С for ethanol;

10,11-dihydro-3-metip-8- (methyl lithio) -dibenzo (b, f) tiepin-1O-ol, red-brown oil.

The resulting 1O-chloro-10,11-dihydro-3-methyl-8- (methylthio) -dibenzo (4,) tiepine is a crystalline mass that can be used without further purification.

Example 8. Analogously to example 5, prepared from 1O-chloro-1O, 11-dihydro-2-methyl-8- (metipto) -dibenzo (b, J) tiepina and 3-G2- (1-piperazinip) -ethip5 -2- oxazolidinone 3-7 (2- G4- (10,11-dihydr6-2-me THJT-8- (methylthio) -dibenzo (b, f) tiepin-1O-yl) -1-piperazinyl-ethyl} -2-oxazolidinone which, after recrystallization from ethyl acetate / low-boiling petroleum ether, melts at 122-123 ° C. The maleate is crystallized from adheon-ether, mp 1S6158 C. Two-methyl sulfonate is crystallized from methanol / ether, mp 211-213 ° C ( compound contains 1.54% water).

The starting 10-chloro-10,11-dihydro-2-methyl-8- (methylthio) -aibenzo (b, t) tiepin is prepared from 2-iodo-5-methylbenzoic acid and 4- (methylthio) -thiophenop, in a manner similar to 4. As intermediate products, ga-ray is: 5-megyl-2- {4-methylgio) -phenip1-tno-ben-o-zoic acid, t. Pl. 153-157 ° C; 5-mWTP-2- - (met ltno) -phenyl - tao-bicewood alcohol, yellow oil, which at one hundred nn crystallizes} 5-methyl-2- {f4 - (methnlthio) -phenyl / j -thio} -bfcporpid, brown oil 5-methyl-2 - {{4- {methyl-0o) -phenyl-J-tho-phenylacetone, edge oil; 5-methyl-2- {4- (methylthio) phenyl-thio} -phenylacetic acid, so pl. 89-92 ° C. Of ethnyl acetate / low concentration petroleum ether; 2-methyl-8- (methylthio) -dibenzo (b,}) of the dip-10 (11H) -one, t. Pl. 109-111 C from etavol; 10,11-digadro-2-methyl-8- (methyl tno) -dnbenzo (, f) tiepin-1O-op, red oil. The resulting 10-chloro-10,11-dngydro-2-methyl-8- (methylthio) -diben.zo (L, |) tiepine represents with its bulk a red crystalline mass, which can be used without additional purification. . Example 9. 25 g of 1- (3-chloro-8-fluoro-10, 11-dihydrodibenzo (b, f) tiepin-1 -yl) piperazine is mixed with 25.6 g of Jt-G2-chloroethyl) -oxazolidnnon, 2O g of potassium carbonate, 0.4 g of sodium iodide and 200 m of toluene for 5 hours at boiling point. The reaction mixture is cooled, water is added and extracted with benzene. The benzene solution is washed with sodium bicarbonate and water, dried with sodium sulfate and evaporated under reduced pressure. 3-1 2-G4- (3-chloro-8-fluoro-10,11-dihydrodibenzo (6, f) gnepin-1O-yl) -1-pipa razinip-ethyl-oxazolidinone is obtained in the form of a brown oil, which is dissolved in ethanol and in which the south solution ethanol solution of maleic acid. After cooling and addition of acetoia and ether, 3- (- (3-chloro-8-fluoro-10, 11-dihydrodibenero (6, f) tiepin-1O-yl) -1-piperazinyl -) melting at 143-146 ° C is obtained. ethyl} -ox & 30 l idinone al at. Starting 1- (3-chloro-8-fluoro-10,11-dngidrodibenzoC b,) tiepin-10-yl) piperazine was prepared in a manner similar to Example 4 from 4-xpor-2- iodobenzoic acid and 4-fluorothiophenol. The following intermediate products are obtained: 4-hpor-2- (4-fluorophenol) -thio-benzoic acid, etc., para. 212-214 C; 4-chloro-2- (4 fluorophenyl) -thio-benzip alcohol, m.p., 86-87 C; 4-chloro-2- (4-fluorofesh1l) -thio-benzylchloride; cinnamon; h-hpor-2-14 -fluorofenc) thio-phenyl acetonitrile, black oil; 4 ENT-2- (4-phth) rfen l) -thio-phenyl xusic acid, so pl. 97-100 C: 3-chloro-3-fluoridibenzo (fe, f), tiepin-1O {11H) it, t. Pl. 160-161 ° C; H-chloro-8-fluoro-10,11-dihydrodibenzo {b, f) tiepin-10-ol, m.p. 113-115 ° C; -3,10-dichloro-8-fluoro-10,11-dihydrodibeyzo {S, f) tiepin, t. Pl. 133-134, 1-k arbethoxy-4 -3-lor-8-fluoro-10,11-dihydrodibenzo (b, f) tiepin-10-yl-piperaziv, yellow oil. The resulting 1- (3-chloro-8-fluoro-10,11-dngidrodibenzo (b, f) hyepin-10-yl) piperazine is a brown oil that can be further used without further purification. Example 1O. In 15.4 g of U-chloro-8-fluoro-10,11-dngndro-3-methoxy-di-6-ene ((5, $) carton), 41 g of (1-B1-vvrasinyl) -ethyl -2-oxazolidinone is added and stirred for 10 min. at 12 ° C-130 ° C (internal temperature). A 2N sodium hydroxide solution is added to the cooled mixture and extracted with chloroform. The chloroform solution is washed with water until neutral and shaken with diluted MataSulfonic acid. The acidic solution is brought up with sodium hydroxide solution to an alkali reaction and the base is extracted with chloroform. The solution is organically washed with water, dried with sulphate rot and concentrate. The residue is recrystallized from acetone. 3 - ((8-fluoro-10,11-dihydro-3-methoxydibenzo (b, f) tiepin-1O-yl) -1-piperazinyl-ethyl -2-oxazolidinone, t .177-179 C. The corresponding maleate melts at 212-214 C. The original 10-lor-8-fluoro-10,11-dihydro-3-methoxy-benzo (b, f) tiepin is prepared analogously to example 4. As intermediate products are obtained; 4-methoxy-2-P 4-fluorophenyl) thio-1-benzoic acid; mp. 2OO-202 ° C; 4-methoxy-2- (4-fluorophenpl) -thio-benzyl alcohol, yellow oil; 4-methoxy-2- (4-fluorophenyl) -thio-benzyl chloride, brown oil; 4-methoxy-2- (4-fluorophenyl) -thioZ-phenylacetonitrile, brown oil; 4-methoxy-2- {4-fluorophenyl) thio-phenylacetic acid, m.p. 78-81 C; 8-fluoro-3-meth exhibibenzo (b, f) tiepin-10, (IIH) -OH, m.p. 112-114 ° C; 8-FGOR-10,11-dihydro-3-methoxydibenzo (, f) TNES-1O-ol, yellow oil, Obtained 10-LOR-B-FGOR-10,11-dihydro-3-methoxydibenzo (b, f) Tiepin melts prn 74-76 ° C.

Example 11. In 17 g of 3,10-dichloro 7-fluor-1O, 11-digdrodnbekzo {; b, | )

45.5 g of 3- {2- (1-pipvraznnnp) -ethnl -2-oxazol1vd {pus and stirring for 8 mnn at 12 ° -13 ° C (internal temperature). 2N is added to the mixture, sodium hydroxide solution v is extracted. The equilibrium extract is washed until neutral with shaking with dilute methanesupipic acid. The solution is adjusted to caustic with sodium hydroxide solution and extracted with methylene chloride. The organic solution is washed with water and dried over magnesium sulfate. The residue is recrystallized on acetone. 3 - ((3-chloro-7-fluoro-1O, 11-dngidro-dibenzo (6, f) hyepin-10-yl) -nperazinnl-ethyl} -2-oxazolindinone, t, pl. 16 & 17O C, which is converted with methanesulfonic acid to dimethanesulfonate with mp 191-193 ° C.

The starting 3,1O-dichloro-7-fluoro-10,11-d gdrodibenzoCo, f) tkepin is prepared analogously to example 4 on 4-chloro-2-iodobenzLoic acid and 3-fluorothiophenol. The following intermediates are obtained: 4-chloro-2 - (3-fluorophenl) -thio-benzoic acid, so pl. 183-185 ° C; 4-chloro-2- (3-fluorophenyl) thio-benenl sprint oil;

4-chloro-2- (3-fluorophenyl) -thio} -6% ester oil;

4-chloro-2-C 3 -fofershyl) -tn-J-Fennluxus button, etc. 117-119 ° C; 3-chloro-7-fluoridibenzo (b, f) tiepi-10 (11H-one, i.e. 145-148 ° C;

3-chloro-7-fluoro-10,11-dihydrodibenzo (b, f} tiepvn-1O-ol, so pl. 1ОЗ-105 С.

The resulting 3,10-digndro-7-fluoro-1O, l: -dihydrobenzo (fc,) hyepin melts at 117-118 ° C.

Example 12. To 11.6 g of lO-chloro-8-fluoro-10, 11-digdro-3-trifluoromethyldibenzo (b, 1) tiepina was added 27.8 g of (1-piperineinyl) ethyl-2-oxaolidinone and stirred for 1O min at 115120 ° C. The reaction mixture was cooled and 2N sodium hydroxide solution was added. The product precipitated as an oil is extracted with ether, the organic solution is washed with water until the medium is neutral and shaken with a dilute aqueous solution of methanesulphonic acid. The aqueous solution is brought to a basic solution with sodium hydroxide solution and extracted with ether. The 4m solution is washed with water, dried over magnesium sulfate and concentrated. Get 3- (8-fluoro-10, l-dihydro-3-triftopermethyldibenzo (jb, f) type-lp-nl) -l-piperazinip | -ethylU-2-oxazolndone in the form of a yellow oil, which is converted into dimethane- . sulfonag with megansulfonic acid, mp 149-151 ° C.

The starting 1 (-chloro-8-fluoro-10,11-dihydro-3 trifluoromethyldibenzo {b, f) tiepin is prepared from 2-iodo-4-trifluoromethylbenzoic acid and 4-fluorothenophenol in analogy with Example 4.

Intermediate products are obtained:

2- (4 -faxphenyl) -tis3-4-trifluorometnylsoic acid, so pl. 161-163 C; 2-f (4-fluorophenyl) -thio-4-trifluoromethyl benzyl alcohol, m.p. 108-125 ° С (О, 1mm of mercury.) T. Pl. 53.5-55 ° C; 2 - {(4-fluorophenyl) -thio -2-trifluoromethylbenzyl chloride, oil;

2- (4-fluorophenl) -thio-4-trifluoromethylphenylpetonitrile, t. Bale. 114-12 ° C (0.3 mmHg);

2- (4-fluorophenl) -thio-4-trifluoromethylphenylacetic acid, so pl. 117-119 ° Ci 8-fluoro-3-triftsfmetildibvnzo (b, f) tn-10-11 (11H) -one, t. Pl. 88-89 ° C; 8-fluoro-Yu, 11-digndro-3-trifluoromethyldibenzo (b, f) tiepnn-1O-ol, yellow oil.

The 10-chloro-8-fluoro-10,11-dvgndro-3-trifluoromethyldibenzo (b, i) obtained is recovered by melting of 1FI 73-75 C.

Example 13. 2O g of 2,1O-dichloro-10, 11-dngndro-7-methyldibenzo (L, /) tivpvia is mixed with 41 g of (1-pchlerazinch) -8til -2-oxazolidinone and 4OO ml of chloroform for 2Oh at boiling point. The solution is cooled and washed with 2n. Solution {sodium hydroxide and water. The organic phase is decanted and extracted with dilute methanesulfonic acid. The acidic solution is adjusted with caustic soda to an alkaline medium and the separated oil is shaken with ether. The ether solution is washed with water, dried over magnesium sulfate and evaporated under reduced pressure. (2-Chlo {-1O, 11tDyhydro-7-methyldibenzo (, t) typin-1O-yl) -1-piperazinyl-ethyl} -2-oxazolidinone is obtained, m.p. 161-163 ° C, which is converted to the corresponding dimethanesulfonate, m.p. 18189 ° C.

The starting 2,1O-chloro-10,11-dihydro-7-methyldcbenzo C b, f) tiepin is obtained from 5-chloro-2-iodobenzoic acid and 3-methylthiophenol analogously to example 4. As intermediate products receive: 3-chloro-6 - (3-tolyl) -thio-benzoic acid, m.p. 163-166 ° C; 3-chloro-6- (3-tolip) -thio-benzyl chloride, brown oil;

H-chloro-6- (3-thall) -thio1-phenyl acetone, brown oil;