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    • 专利摘要:
    The method of obtaining 3-
    公开号:SU1155157A3
    申请号:SU823417550
    申请日:1982-04-02
    公开日:1985-05-07
    发明作者:Дэвид Джонз Чарльз；Элизабет Гоэттел Мэри
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    I The invention relates to a process for the preparation of 3- (4-aminoethoxybenzoyl) benzo CI) thiophenes of the general formula OCHjCHjN.  where R, and R2 - each C -C-alkyl yl together form polymethylene with 4-6 carbon atoms, the group is - (CH hOCNH- or -CR2CH (CHj) CH2CH2 or their salts, which have biological activity and can be used in medicine.  There is one known method for the preparation of compounds of formula (1), which encapsulates the compound in the acylation.  ly, OCHNH2 R / J where R is chlorine, bromine or iodine; R4 - X or - NR, Rj-rpynna, where X is chlorine or bromine; R and R- have the indicated meanings.  Compounds of the formula wherein Ry is an alkyl group, phenacyl and p-halo phenenacyl group, under the conditions of the Friedel-Crafts reaction in an inert organic solvent such as 1,2-dichloroethane or dichloromethane, at a temperature of from -20 ° C to the boiling point of the reaction mixture followed by if necessary, transfer the resulting compound, where the corresponding amino compound, and hydrolyze, for example, by treatment with zinc in acetic acid, if R is a phenacyl-or-halo-phenoacyl group, and pyridine chlorohydrate, ethyl mercaptide sodium and trichloro boron, whether R5 is an alkyl group f The disadvantage of the known method is the low yield of the intermediate product obtained at the acetion stage, which does not exceed 39%, 7, 2.  which accordingly affects the overall yield of the target product (up to 14%).  The purpose of the invention is to increase the yield of the target product.  The goal is achieved by the fact that according to the method for producing 3- (4-amino-ethoxy-benzoyl) benzo (b) thiophenes of the general formula (I), the compound of the general formula (III), where Ry is the group - COR, where R, is unbranched or a branched C -Calkyl or phenyl, or a -SOjR group, where R is an unbranched C -C-alkyl or phenyl, is acylated with a compound of the general formula P under the conditions of the Friedel Crafts reaction in an inert organic solvent, such as 1,2-dichloroethane or dichloromethane, at a temperature from room temperature to followed by if necessary, treating the obtained compound, where RX, with an amine of the formula NHY, Yag where R, and R2 have the indicated values, and the hydrolysis is carried out with a base, such as sodium hydroxide, at a temperature from room temperature to the boiling point of the reaction medium in a solvent, such as lower alcohol and / or tetrahydrofuran if Rj is, or an aqueous lower alcohol, in the presence of methanesulfonic acid as an acid catalyst, if R is CORg.  . The yield at the stage of ac lyration is 7193%, the total yield is 27–87%.  PRI me R 1.  6-acetoxy-2- (4-acetoxyphenyl) -3-G4- (2-pyrrolidinoeth6xn) benzoyl benz (b) thiophene hydrochloride.  25 g (0.092 mol) of 4- (2-pyrrolidinoethoxy benzoic acid in the form of its hydrochloride is converted into the acid chloride by dissolving in 200 ml of 1,2-dichloroethane and adding one drop of dimethylformamide and 36.5 g of thionyl chloride.  The mixture was stirred under nitrogen for 2 hours and then evaporated in vacuo to give an acid chloride of an off white color.  To the acid chloride is added 1 l of 1,2-dichloroethane, 20 g (O, 0613 mol). 6-acetoxy-2- (4-acetoxyphenyl) benz (19) thiophene and 73.4 g of aluminum chloride; during the addition, the mixture is stirred vigorously for 3 minutes.  The mixture is then stirred for 1 hour and poured into 1 liter of ice water.  The layers are separated and the aqueous layer is extracted three times with 200 ml portions of warm chloroform.  The organic layers were combined, dried over magnesium sulphate, filtered and evaporated in vacuo to give a yellow oil, which was not further separated.  Pr km e p 2.  6-Benzoyloxy-2- (4-benzoyloxyphenyl) -3 | D- {2-pyrrolidinoethoxy) benzoyl 1-benz (b) thiophene hydrochloride.  The acid chloride is prepared from 18.1 (0.066 mol) 4- (2-pyrrolidinoethoxy) benzoic acid hydrochloride, as described in Example 1.  The acid chloride is then used to acylate 20 g (0.044 mol) of 6-benzoyloxy-2- (D-benzoyloxyphenyl) benz (1)) thiophene, as described in step 1, using 53.2 g (0.40 mol) aluminum chloride.  A sample of the crude product as a brown foam is recrystallized from denatured ethanol to obtain an analytical sample, t. square  218-222 C.  PRI me R 3.  Hydrochloride 6-methanesulfonyloxy-2- (4-methanesulfonyl oxyphenyl) (2-pyrrolidinostoxy) benzoyl benzo (15) thiophene.  The acid chloride 20.4 g (0.075 mol) of 4 - (- pyrrolidinoethoxy) benzoic acid hydrochloride is prepared as described in 1Ho in example 1, and acylation of 20 g (0.05 mol) of 6-methanesulfonyloxy-2 (4-methanesulfony hydroxyphenyl ) Benzo (1) thiophene, as described in Example 1, except that the total amount of alumina chloride weighing 60 g (0.46 mol) is added in portions, first 30 g and then 10 g each with an interval of 15 minutes.  The reaction mixture is stirred for 16 hours and treated as described in Example 1 to obtain an oil, which is crystallized from denatured alcohol to obtain 27.5 g (0.042 mol) of the purified product, t. square  196-199 S.  The yield of the acylation stage is 84%.  Sample 4 g is further purified by chromatography to obtain an analytical sample, t. pl, 207-207 ,.  PRI me R 4.  6-methanesulfonyloxy-2- (4-methanesulfon-7-nyloxyphenyl) (2-dimethylamino-to-noxy) benzoyl-benzo (b) thiophene hydrochloride.  Out of 8.8 g (0.036 mol) of 4- (2-dimethylaminoethoxy) benzoic acid hydrochloride, the acid chloride is prepared as described in Example 1, 4 g (0.01 mol) of 6-methanesulfonyloxy-2 (4) is added to this acid chloride. -methanesulphonyloxyphenyl) benzo (b) thiophene, 150 ml of 1,2-dsorsorztan and 14.4 g (0.108 mol) of alkyi1ini chloride, of which 4,, 8 g are added first, and the residue is added in 3.2 g portions 15 minutes after the start of the addition.  45 minutes after the end of the addition of aluminum chloride, the reaction mixture is poured onto ice.  The precipitate formed in the aqueous organo-halo mixture is collected by filtration and air-dried to give 6.2 g of crude product, which is recrystallized from 90 ml of methanol to give 5.4 g (0.086 mol) of purified product, t. square  204-208 ° C.  Exit on. this stage is 86%.  PRI me R 5.  6-methanesulfonyloxy-2- (4-methanesulfonyloxyphenyl) (2-hexamethyleneiminoetoc) benzoyl benzo (()) thiophene hydrochloride.  From 4- (2-hexamethyleneiminoxy) benzoic acid in the form of its hydrochloride, 5.6 g (0.019 mol) of acid chloride is obtained, as described in example t, except that 50 ml of toluene is used as the solvent.  To the acid chloride, 150 ml of 1,2-dichloroethane, t3.4 g of aluminum chloride and 5.0 g (0.013 mol) of 6-methanesulfonyloxy-1- (4-methanesulfonyloxyphenyl) benzo (1)) thiophene are added.  The mixture was stirred for 30 minutes and 1.7 g of alcmini chloride was further added.  After 15 minutes of additional stirring, the reaction mixture was poured onto ice.  The layers are separated and the aqueous layer is washed twice with 50 ml of chloroform each time.  The organic layers are combined, washing with 25 ml of an aqueous solution of common salt and dried with magnesium sulfate, filtered and evaporated to dryness to form 9.5 g of oil, which is not further purified.  PRI me R 6.  (2-Diethylaminostoxy) benzoyl-6-methanesulfonyloxy-2- (4-methanesulfonic-11-oxyphenyl) benzo (b) thiophene hydrochloride.  A portion of 5.2 g (0.019 mol) of 4- (2-diethyl-amino-ethoxy) -benzoic acid hydrochloride is converted into an acid chloride and used for acylation of 5 (0.013 mol) of 6-methanesulfo-iyloxy-2 (4-methanesulphonyloxyphenyl) benzo (-thiofiorethiophenoxy) benzoate (4-methanesulphonyloxyphenyl) benzoic (6-methanesulphonyloxy-2 (4-methanesulphonyloxyphenyl) benzo) (6-methanesulphonyloxy-2 (4-methanesulphonyloxyphenyl) benzo) (6-methanesulphonyloxy-2 (4-methanesulphonyloxyphenyl) benzo) (denote)) The amount of aluminum chloride is 15.1 g, and the reaction mixture is stirred t, 5 hours after the addition of aluminum chloride.  The mixture is worked up as described in Example 5j and a yellow foam is obtained, which begins to crystallize with several days standing.  It is triturated with denatured alcohol and recrystallized from denatured alcohol to obtain 6.5 (0.010 mol) of purified crystalline product, t. square  172-174 C.  Example 7.  Hydrochloride (2-diisopropylaminoethoxy) benzoyl 6-methanesulfonyloxy-2- (4-methanesulfonyloxyphenyl) benzo (b) thiophene, A portion of 7.6 g (0.025 mol) of 4- (2-diisopropylaminoethoxy) benzoic acid hydrochloride is converted into an acid Example 1, and used for the acylation of 5 g (0.025 mol) 6 methanesulfonyloxy 2 (4-methanesulfonyloxyphenyl) benzo (1) thiophene in the presence of 20 g. .  (0.151 mol): aluminum chloride.  The mixture is worked up as described in measure 4, and 7.4 g of crystalline product is obtained after trituration with denatured alcohol.  The product is recrystallized from denatured alcohol to obtain 6.5 g of purified product, and a portion of 1.5.  g is further purified by chromatography on silica gel using a mixture of 1: 3 methane / chloroform as eluent to form 1.15 g of an analytical sample, t. square  198201 ° C.  Froze  The acid chloride 6-methanesulfonyloxy-2- (4-methanesulfonyl oxyphenyl. ) -3-4- (2-ororfolinoethoxy).  beioyl benzo (b) thiophene.  The indicated product is obtained according to Example 7 from 7.2 g,. (0.025 mol) of 4- (2-morpholinoethox) benzoic acid hydrochloride and 5 g (0.025 mol) of 6-methanesulfonyl si-2- (4-methanesulfonyloxyphenyl) benzo (b) thiophene.  4.25 g (0.064 mol) of a recrystallized product are obtained, from which 1.25 g are purified by chromatography, as described in Example 7, to give: 0.9 g of product, t. square  197-200 S.  Example9.  6-acetoxy-2- (4-acetoxyphenyl) (2-piperidinotoxy) benzoyl: enzo (b) thiophene hydrochloride.  An acylating agent in the form of an acid chloride is prepared by reacting 26.3 g (0.920 mol) of 4- (2-piperidinoethoxy) benzoic acid hydrochloride, 3655 g (0.306 mol) of thionyl clonal and one drop of dimethylformamide in 200 ml of 1,2-dichloroethane with stirring mixture under nitrogen at boiling.  Then the reaction mixture is evaporated to dryness in vacuo to obtain the desired 4- (2-piperidinoethoxy) benzoyl chloride hydrochloride, which is dissolved in 1 l of 1,2-dichloroethene.  To this solution, 20 g (0.613 mol) of 6-acetoxy-2 - {4-acetoxyphenyl) benzo (b) thiophene are added and the mixture is vigorously stirred.  After this mixture, 73.4-g of atomium chloride is added over 3 minutes.  During the addition, the reaction mixture turns dark brown and hydrogen chloride is released.  The mixture was then stirred for 1 hour and poured into 1 liter of ice water.  The layers are separated and the aqueous layer is extracted three times with 200 ml of warm chloroform.  The organic layers are combined, dried over magnesium sulphate, filtered off and evaporated in vacuo to give a brown-yellow oil that is not purified.  The presence of the desired product was confirmed by thin layer chromatography (TLC) on silica gel using 9 / t of chloroform / methanol as eluent, which confirms that the basic substance has the same R. as 6-acetoxy-2 (4-acetoxyphenyl) (2-piperidinoethoxy) benzoyl benzo (b) thiophene, Example 10.  Hydrochloride 6-benzoyloxy-2- (4-bnzosh1oksifensh1) (2 piperidinoztoksi) beksoyl benzo (b) thiophene.  The example is carried out in the same manner as Example 9, starting from 18.9 g (0.066 mol) of 4 (2-pyrpchdinoethoxy) benzoic acid hydrochloride 4 and 20 g (0.044 mol) of 6-benzoyloxy-2 (4-benzoyl syphenyl) benzo Co a) thiophene. The reaction mixture is stirred for 1.5 hours and worked up as described in Example 9 to obtain the desired product in the low oil.  A small portion of the desired product is crystallized from denatured ethanol to obtain an analytical sample of m, mp, 230-233 ° C, the identity of which is confirmed by an NMR spectrum, 8: 1.30-2. , 50 (bN, t.  NH (CH / JH2) 2CHj); 2.50-3.75 (6H, t. , NH (CH2CH2) jCH2 and OCH2CH2N); 4.56 (2I, t. Osilen (N); 6.77 (2I, d, Hz, aromatic protons in the ortho-position to CCA); 7.10-7.90 - (17H, t. aromatic); 8.00-8.27 (6H, t. aromatic in the ortho-position to 12.30 12.80 (1H, broad singlet; NH).  Example 11  Hydrochloride 6 - benzosulphonyloxy-2- {4-beneolsulphonsh1oxyphenyl) (2-Piperidinoethox-0 benzoyl benzo COO) gkofena.  From 8.21.  g (0,029 mlzl) hydrochloride, yes 4- (2-1Shperidinoeto. . . si) benzonic acid get 1H chlorohydrin, as described in example 9, m combining it with 10 g (0.019 zero) 6 benzenesulfs ---. 5-1-1 hydroxy-2- (4-benzenesulfonyloxyphenyl benz (15) thiophene in 500 ml of 1, 2-dichloroethane and treated with 22.9 g of aluminum chloride.  The mixture is stirred overnight at room temperature and processed as described in Example 9. The product, weighing 15 g, as dirty, cannot be further crystallized.  The sample, 1 g of the crude product, is purified on a 4–20 cm chromatographic column with silica gel, eluted first with chloroform and then with a mixture of 25% methanol in chloroform t The fractions containing the product are combined and treated with hydrochloric acid to obtain the hydrochloric acid salt and then evaporated in vacuo to dryness to form a product in the form of an oil, which is identical with the maximum absorption at 1646 in the IR spectrum indicating an -CO-functional group of the product.  Its identity is also further confirmed by the conversion to 6 hydroxy-2- (4-hydroxyphenyl) (2-piper | adinoethoxy) benzoyl 2 benz (b) thiophene.  EXAMPLE t2.  Hydrochloride 6-methanesulfonuxyxn-2- {4-methanesulfonyloxyphenyl) 3-A-C3-yiper dinoethoxy) benzoyl | benzo (i) thiofea.  The acid chloride, prepared as described in Example 9, out of 2.0 g (0.07 mol) of 4- (2-piperidinoethoxy) "besoic acid hydrochloride, is combined with 2 g (0.005 mol) of 6-methanesul B Fonyloxy-2- (4-methanesulfonyl (:: and (}) e-nyl) ben o (b) thiophene in 50 ml of methylene chloride.  A portion of 2.4 g of trifluoromethanesulfonic acid is added and the mixture is stirred overnight at the boil.  The reaction mixture is then poured onto ice and into sodium bicarbonate solution.  The organic layer is dried over magnesium sulfate and filtered.  The filtrate is evaporated in vacuo to a yellow foam, which is treated with an excess of 3% hydrogen chloride in anhydrous methanol.  The mixture is then evaporated in vacuo to dryness to give a white foam, which is dissolved in 18 ml of boiling methanol.  The solution is cooled and. Punch out 3.1 g (0 mol) of product with m. square  128-130 C, which is identified by the NMR spectrum, 8: 1.60-2.00 (6H, m. N (CH2CH2) 2CH2); 2.57 -3.75 (6H, t. , (and OCi; jCH2N); 3.36 (3H, S, CH3); 3.46 (3N, S,); 5 (2H.  wide triplet, Hz, OCtiyCti tl)} 6.97 (2H, d. , Hz, aromatic in ortho-position to OCH2); 7.25 - (8H, M. j aromatic protons); 8.25 (1H, d , Hz, aromatic proton in ortho-position to O and S); 10.7011, 00 (W, broad singlet, NH).  IR absorption in a tablet with KBr for ketone CO is observed at 1640 cm.  Absorption of ethanol, nm: 273 (ext. 2. 6,000); 290 (extinction coefficient 29,5000).  The yield on the acylation stage is 93%.  PRI me R 13.  Hydrochloride 6-methanesulfonyloxy-2- (5-methanesulfonic 1oxyfencle) (2-piperidinoethoxy) beta and 3 n-zo (b) thiophene.  Out of 19.7 g (0.069 mol) of 4- (2-pyperidinotoxy) benzoic acid and hydrochloride in 200 ml of toluene with 44.9 g of thionyl chloride, acid chlorohydride is prepared, which is used for acylation of 20 g (0.050 mol) of 6-methanesulfonic and 1-x-2 - (4-methanesulfonipoxyphenyl) benzo (1)) thiophene in the presence of 59.6 g of alcmini chloride.  alkyminol is added in portions and for 30 minutes, after which the reaction mixture is stirred for 16 h.  The mixture is poured onto 2 liters of ice and the product is extracted from the aqueous layer in two portions of 200 ml of warm chloroform.  The organic fractions are combined, dried, and concentrated to give an oil, which is crystallized from 350 ml of methanol to give 28 g of a crude product with m. square  133-135 ° C.  In the next set of examples, the protecting groups are cleaved from the enriched compounds.  Example14.  b-hydroxide-2 (4-hydroxyphenyl) (2-pyrrolidinoethoxybenzoylJ benzo (b) thi6phen.    6-Acetoxy 2- (4-acetoxyphenyl) (2-pyrrolidinoethoxy) benzoyl benzo (b) tofen obtained by acylation of 10 g (0.031 mol) of 6-acetoxyphenyl benz () thiophene with an acid chloride prepared from 25 g (0.092 mol a) 4- (2-pyrrolidinoethoxy) benzoic acid hydrochloride, is added to 275 ml of methanol, after which 55 ml of 3N is added.  caustic soda solution.  The mixture was stirred at reflux for 45 minutes and the solvent was removed in vacuo.  The residue is taken up in 300 ml of methanol and extracted twice with diethyl ether.  The ether layers were combined and washed again with 1N.  sodium hydroxide solution.  The aqueous layers are combined, acidified to pH 2-3, then processed again with alkali to a pH of about S.  This alkaline solution is extracted several times with ethyl acetate, the organic layers are combined, dried over magnesium sulphate, filtered and evaporated to dryness in vacuo.  After many hours of drying under vacuum at room temperature, the weight of the residue is 10.4 kg. The NMR analysis shows that the product is 6-hydroxy-2 (4-hydroxyphenyl) -3-4- (2-pyrrolidinoethoxy) benzoyl benzo ( ) thiophene, however, it contains an approximately equimolar amount of ethyl acetate.  A sample of 1.02 g is chromatographed on 8.0 g of silica gel using ethyl acetate / methanol (9: 1) to elute.  Column size cm, collect 50 ml fractions.  Fractions 13–27 give a yellow oil which is spread in 30 ml of 1N.  sodium hydroxide solution and stirred for 15 minutes at room temperature.  After acidification, 32 ml of 1N.  hydrochloric acid and imparting basic properties with an excess of sodium biconide to collect the yellow solid, which is dried under vacuum overnight to a weight of 0.57 i.  This product is a pure substance, which is confirmed by NMR analysis, UV spectra, and elemental analysis.  A portion of 1 g of the obtained intermediate product is again chromatographed on a column of silica gel (grain size ZgZO cm) using methanol / chloroform (1/9) as eluent.  50 ml samples are collected and the 13-30 fractions are combined and evaporated to dryness to give a yellow oil, which is dissolved in 30 ml of 1N.  sodium hydroxide solution.  A solution is bubbled through the solution.  nitrogen for 15 minutes and ice and 32 ml of 1N are added.  hydrochloric acid.  Then, 8 ml of saturated sodium bicarbonate solution is added, the mixture is stirred for 1 h and taken off.  The solid is washed with water and dried under vacuum, after which the sample was analyzed at 100 MHz.  NMR spectrum (D-dimethyl sulfoxide), 8: 1.72 (4H, m , N (CH2CH2) 2); 2.68 (4H, m , N (CH ,, CH2) 2, - 2.94 (2H, t. ,, Hz, OCH2CH ,, N); 4.15 (2H, t. J 6 Hz, OCH2CH2K); 6.68 (2H, dn, Hz, aromatic in the ortho position to the OH group); 6.85 (1H, c. J. ft.   9 Hz, H 5 benzothiophene ring); 6.93 (2H, d , Hz, aromatic in ortho position to,); 7.18 (2H, d , Hz, aromatic in meta-position to OH-group ;; 7.25 (1H, d , Hz, 4 N benzothiophene ring); 7.67 (2H, d , Hz, aromatic in ortho position to CO-group); 9.75 (2H, broad singlet, OH).  .  PRI me R 15.  6-hydroxy-2- (4-hydroxyphenyl) -3 -: {4- (2-pyrrolidinoethoxy) benzoyl benzo (b) thiophene.  The yellow oil obtained in Example 1 was dissolved in 700 ml of methanol and 100 ml of 5 N was added.  sodium hydroxide solution.  The mixture was stirred at room temperature for 2 hours, after which the solvent was removed in vacuo.  The residue is dissolved in 500 ml of water and washed with two 500 ml portions of diethyl ether.  The aqueous layer is acidified to pH 2 with cold methanesulfonic acid and diluted to approximately 3 liters, then washed again with two portions of t 1 of diethyl ether.  The aqueous layer is separated, degassed-G in vacuo, and oxy-carbonated sodium bicarbonate is carefully ovified.  The precipitate formed is collected by filtration and washed with water.  The solids are dried at 70 ° C to give 13 g of crude product, which is dissolved in 500 ml of hot acetone, filtered and evaporated to a volume of approximately too ml.  The solution is cooled and scraped to give 11.3 g (0.025 mol) of the product, which is identified by an NMR spectrum, an IR spectrum and which is identical to the products of examples 14 and 18.  Total yield for acylation (Example 1) and cleavage 40%; with respect to i the amount of 6-acetoxy-2 (4-acetoxyphenyl) benzo (b) thiophene used, EXAMPLE 16.  6-hydroxy-2 - (- hydroxyphenyl) -3-4- (2-pyrrolidinoethoxy) benzoyl benzo (1) thiophene.  To a portion of the intermediate obtained in Example 2, 400 ml of ethanol, 400 ml of water and 55 ml of methanesulfonic acid are added.  The mixture is heated in a steam bath for 72 hours and the volatile compounds are removed in vacuo.  The residue was diluted with 4 L of water and the solution was washed with two portions of 1 L each, pure diethyl ether.  The remaining aqueous layer was degassed under vacuum and cooled to 20 ° C, by adding ice.  Then, the pI was adjusted to 8.4 with added ammonia water.  The precipitated solid is collected by filtration and washed with cold water.  The solid material is dried at a constant weight of 18.8 g, after which it is recrystallized from acetone to obtain 16.3 g (0.0355 mol) of the purified product, which is characterized by NMR and UV spectra as well.  and identical products of examples 14 and 18.  The total yield by acylation (Example 2) and 80% cleavage with respect to the amount of sulfur in this case 6-benzoyloxy-2- (4-benzoyloxyphenyl) benzo (b) thiophene, I p and me 17.  6-pxy-2- (4-hydroxy-phenyl) -3-4- (2-pyrrolidinoethoxy) tieH zoyl benzo (b) thiophene.  A portion of 5 g (mol) of 6-methanesulfonyl-2- (4-methanesulfonyloxyphenyl) (2-pyrrolidino-ethoxy) benzoyl 3-benzo (b) thiophene hydrochloride is dissolved in 125 ml of denatured alcohol and 15 ml. 5 N, caustic soda, after which the mixture is stirred for 1 h at 5712 refluxing.  Ethanol is evaporated in vacuo and the residue is dissolved in a node. The mixture is made acidic with 1N.  hydrochloric acid and then alkalinized with sodium bicarbonate.  The alkaline solution is extracted three times with 100 ml portions of ethyl acetate, dried over magnesium sulphate and evaporated to an oil in a vacuum, the weight of the oil is 3.6 g.  Using thin-layer chromatography, it is shown that the oil contains the desired substance when compared with a notorious sample.  The oil is further purified by chromatography on a column of silica gel (3.5-2.5 cm in size) and 20 ml of the fractions are collected.  Fractions 31 to 150 contain 2.4 g (0.0052 mol) of a partially purified product, which is identified by thin layer chromatography when compared with a known sample of the desired product.  one .  .  PRI me R 18.  6-hydroxy-2- (4-hydroxyphenyl) -3-4- (2-pyrrolidinoethoxy) bsnzoyl benzo (b) thiophene. .  Portion 23, In g (. and, 36 mol) of the product from 3 is added to 600 ml of tetrahydrofuran, 240 ml of methanol and 40 ml of 5N.  sodium hydroxide solution.  The mixture is stirred for 60 hours at room temperature and then evaporated in vacuo.  The residue is dissolved in 400 ml of water and the solution is continuously extracted with diethyl ether for 8 hours.  The aqueous phase is filtered, cooled to a temperature below 10 ° C and acidified with methanesulfonic acid to pH 2.  The phase is then diluted with water to approximately 7 liters and extracted with ethyl acetate.  The aqueous layer is degassed under vacuum and made basic. .  using sodium bicarbonate.  The precipitated precipitate is collected, dried under vacuum and purified by chromatography on a silica gel column (4.560 cm columns) using a mixture with varying composition as eluent: from 2 l of 1% methanol in chloroform to 2 l of 25% methanol in chloroform .  Collect fractions of 20 ml, fractions 33-150 give 13.5 g (0.029 mol) of the product with tons. square  146-147 C after crystallization from acetone.  The yield at the cleavage stage is 81%. The UV spectrum shows a foot band of 290 nm (32,500).  The IR spectrum has a maximum at 1607 cm, i which corresponds to the conjugated keto-enol system.  Example 19  3- (2-dimethylaminoethoxy) benzoyl-6-hydroxy-2- (A-hydroxyphenyl) benzo (b) thiophene.  2 g (0.032 mol) of the product from example 4 are dissolved in 100 ml of denature 1. .   ethanol and 5 ml of 5 n.  sodium hydroxide, after which the solution is stirred at boiling in a nitrogen atmosphere for 1.5 hours  The mixture is then evaporated in vacuo to remove most of the methanol, the residue is diluted with 200 ml of water and washed with 300 ml of diethyl ether.  The aqueous layer is degassed and nitrogen is bubbled through the solution to remove traces of ether.  The mixture is then acidified with 1N.  hydrochloric acid and made basic with an excess of sodium bicarbonate.  The yellow precipitate is collected, washed with cold water and dried to obtain 1.21 g of intermediate.  A silica gel column is then prepared in a size of 2-30 cm and the semi-solid product is purified by eluting with a mixture of methanol and chloroform 1/9.  A product eluted from impurities is collected by evaporation of the fractions containing the product in the yellow oil.  Crystallization from. acetone, recrystallization from acetone, gives 0.64 g (0, OU15 mol) T1 of the boiled product with m. square  141-144 C, which is identified by NMR-sinter RP (% Dimethylsulfoxide 100 MHz), S: 2.7 (6I, p. , Nch,); 2.57 (2H, t.   Hz, NCHj); 4.05 (2H, t ,, Hz, OCBj); 6.66 (2H, d , Hz, aromatic protons in the ortho-position to the OH group; 6.85 (1H, c. , G JKS-HT Hz, H5 benzo. thiophene ring); 6.90 (2H, d, Hz, aromatic protons in ortho-position to OC, -group); 7.18 2H, d , Hz, ardmatnye protons in meta-position to the OH-group); 7.26 (tH, d , J 9 Hz, I4 benzothiophene ring); 7.34 (1H, D. , J-2 Hz, H7 benzothiophene ring); 7.65 (2I, d. , Hz aromatic protons in the ortho-position. . . . . “.  n -tv oi. .  to CO-gruipe); 9.73 (2H, broad S. .  HE).  UV spectrum, d, (5) in ethanol nm: 290 (32500).  The infrared spectrum 8 kVg demonstrates half su 1608, corresponding to the keto-enol system.  Mass spectrum, t / e: 11 7; 14,433 (for C ,, H.  calculated 433). The yield at the cleavage stage is 46%.  PRI me R 20.  (2-Hexamethyleneimostoxy) benzoylJ-6-oxy-2- (4pxiphenyl) benzo (b) thiophene.  The method of example 19 is repeated to hydrolyze 9.0 g of the product of example 5.  A half weight product of 5.2 g is a yellow solid. which is purified by chromatography as described in Example 19, except that the eluent of variable composition is 1.5 liters of 5% methanol in chloroform and up to 1.5 liters of 10% methanol in chloroform.  Collect fractions of 20 ml each; fractions 78-100 yield 2.45 g (0.0050 mol) of yellow foam, which is identified by the NMR spectrum (D-dimethyl sulfoxide, 100 MHz), B: 1.53 (8H, p. , "(СНзСНгСНр-г 2,65 (4Н, m ,) ; 2.81 (2H, t. / Hz, N (CH2CHjO); 4.04 (2H, t. , Hz,); 6.68 (2H, d , Hz, aromatic protons in the ortho position to the OH group); 6.85 (1H, c. , "T n benzothiophene ring); 6.90 (2H, d , J 9 Hz, aromatic protons in the orthopodeia to the OCH2-group); 7.18 (2H, d , Hz, Aroma. tical protons in the meta-position to the OH group); 7.26 (W, d , Hz, H4 benzothiophene ring); 7.34 (1H, d , Hz, H7 benzothiophene ring); 7.66 (2H, d , Hz, aromatic protons in the ortho-position to the CO-group); 9.71 (2H, broad singlet, OH).  High resolution mass spectrum: calculated for G, H, 487.18172 ;; found 487.18070.  UV spectrum, () in ethanol shows a band of 290 nm (32,500).  The IR spectrum in KBG shows a band at 1608 cm related to the catvolatile system.  The total yield of the acylation stage together with the elimination of 41%.  Example 21.  (2-Dethylamine ethoxy) beizosh1-6-oxn-2- (4-ok. .    / Gl siphenyl) benzo (b) thiophene.  A portion of 4 g (0.006 mol) of product 6 is added to 100 ml of tetrahydrofuran, 40 ml of methanol and 5 to 5 ml of methanol.  sodium hydroxide, after which the mixture is stirred 24 h at room temperature.  The volatile compounds are stripped off in vacuo and the product is treated as described in Example 19.  The resulting yellow solid is dried and purified by chromatography, as described in step 20, Purification yields 2.0 g, (0.0043 mol) of a yellow foam, which is identical to the desired product.  NMR spectrum (D, -dimethyl sulfoxide at 100 MHz), 5: 0.93 (6B, t. , Hz ,, a); 2.50 (4H, q , Hz, 2.72 (2H, t. , Hz, NCH) f 4.01 (2H, t. , Hz, OCHjCH2N); 6.67 {2H, d ,  Hz, aromatic protons in the ortho-position to the OH-group); 6.85 (1H, c. , L „,. , Hz, Ln, -N7 2 Hz, I5 of the benzothiophene ring); 6.88 (2H, d , Hz, aromatic protons in ortho-position to OCH2) 7, t8 (2H, d. , Hz, aromatic protons in the meta-position to the OH-group); 7.27 (1H, d , Hz, 4H benzothiophene ring); 7.34 (1H, d , Hz, H7 benzothiophene ring); , 7.66 (2H, d , Hz, aromatic protons in the ortho-position to the CO-group); 9.72 (2H, broad. singlet, OH).   High resolution mass spectrum: calculated for 461.16607, found 361. 16551.  UV - spectrum Lid (. ,) in ethanol: 290 them (34000).  Infrared spectrum in KBr: band at 1608, which is related to the ketoenl system.  The output at the stage of splitting 72%.  The total yield of acylation (Example 6) and opschee enS is 54%.  PR 22  3- 4- 2-Diisopropylaminoethoxy) benzoc 11-6-oxy-2- (4-oxyfensh1) bismic (b) thiophene.  A portion of the product of example 7, about 5 g (0.0073 mol), was hydrolyzed as described in example 21, and the residue obtained after removing the volatile components of the mixture was dissolved in 300 ml of water.  The solution is washed with 150 ml of a mixture of DIETH 10 10 ether / ethyl acetate, 15: Ij and then acidified with methanesulfonic acid. The solution is then washed with 200 ml of diethyl ether and degassed under vacuum, and then made basic by adding sodium bicarbonate.  The precipitated solid is collected, pro. evaporated in vacuum to obtain 3.2 g of intermediate.  The sub-product is chromatographed on a column (2 cm) with silica gel using a variable composition for elution, starting from 2 l of 2% methanol B chloroform to 2 l of 20% methanol in chloroform, and the resulting product from several fractions Weigh in vacuo to a constant weight of 2.5 g (0.0051 mol) of the purified substance, which is characterized by an NMR spectrum (D, -dimethyl sulfoxide, 100 MHz), 8: 0.96 (12H, d. , Hz (CH (C. H) d) 2; 2.72 (2H, t. , Hz, NCH. ); 2.96 (2H, m  , J- Hz, (CH (CH3) 2) -); 3.88 (211, t ,, Hz, OCH); 6.65 (2H, d , Hz, aromatic protons in ortho-position to the OK-group); 6.83 (1H, c. , - woofer, Hz, H5 benzothiophene ring); 6.87 (2H, d ,, Hz, aromatic protons in the ortho-position to the OCH -group); 7.15 (2H, d , Hz, aromatic protons in the meta group of OH to the OH group); 7.26 (1H, d , Hz, H4 benzothiophene ring); 7 32 (1H, d , Hz, H7 benzothiophene ring); 7.64 (2H, d ,, Hz, aromatic protons in the ortho-palozhenie to CO-gsuppe); 9.70 (2H, broad singlet J OH). .  High resolution mass spectrum: calculated for C2, H.   489,199; found.   -, UV spectrum in ethanol Tk dtsts. (- v j. 290 them (32000).  IR spectrum in KBG: strip. at 1605 ,, attributed to cat. enol system.  The output at the stage of orajeni 70%.  The total yield of the acylation stages (7) and cleavage is 27%. For example, 23.  6-hydroxy-2- (4-oxyfencle) (2-corfolinoethoxy) benzon-benzo (b) thiophene.  3 g of the product (0. 0045 mol), obtained according to example 8, is hydrolyzed, processed and chromagrafted in accordance with example 22.  1.95 g (0.0041 mol) of a yellow foam is obtained, which does not crystallize, but according to HIIP-cneKTpa is identified as the desired product.  NMG spectrum (Dg-dnmetilsulfrksid. , 100 MHz), S 2.42 (4H, m , N (CH2CH2, O); 2.64 (2H, t. , Hz), 3.54 (4H, m , N (CH2CHj) 20); 4.08 (2Y, t. , 1, NCH CHgOAr); 6.64 (2H, d .   Hz, aromatic protons in the ortho position to the OH group); 6.82 (1H, q , H4-h5 I9-n 2 Hz, H5 benzothiophe: new ring); 6.89 (2H, d .   Hz aromatic protons in the ortho-, positk-w to OGH. -rpynfie) 5 7.15 (2H,. , Hz, aromatic protons in e-position to OH-rpymie); 7.23
    1711
    (1H, d., Hz, H4 of the benzothiophene ring); 7.31 (111, d., Hz, H7 of the benzothiophene ring; 7.63 (2H, d., Hz, aromatic protons in the ortho-position to CO); 9.68 (1H, s., OH); 9, 72 (1H, s ,, OH).
    High Resolution Mass Spectrum: calculated for 475.14533; found 475.14561.
    The yield of the cleavage stage is 91%. The overall yield of the acylation steps (Example 8) and elimination is 23%.
    EXAMPLE 24 6-Hydroxy-2- (4-hydroxyphenyl) (2-piperdinoetoxy) benzoyl benzo (b) thiophene.
    4 g (0.0061 mol) of 6-methanesulphonyloxy-2- (4-methanesulphonoxyphenyl) -3-4-2-piperidinoethoxy) benzoyl-benzo (b) thiophene hydrochloride is combined with 100 ml of denatured alcohol and 10 ml of 5 and. sodium hydroxide and stirred at reflux for 1.5 h under a nitrogen atmosphere. The reaction mixture is then evaporated to dryness in vacuo and the residue is dissolved in 200 ml of water and washed with 300 ml of diethyl ether. The aqueous phase is degassed under vacuum and then nitrogen is bubbled through it to remove traces of ether. The mixture is then acidified with 1N. hydrochloric acid and then made basic with an excess of sodium bicarbonate. The precipitate is collected by filtration and washed with cold water, thus obtaining 2.4 g of intermediate. Semi-pro (ukt is purified on a column of silica gel (cm): first elute 700 ml of 5% methanol in chloroform, and then 1 l of 10% solution of methanol in chloroform. First, impurities, fractions containing the desired product, It is combined and evaporated in vacuo to give 1.78 g of a yellow oil. The oil is dissolved in 6 ml of acetone, seeded and cooled in a refrigerator, to give 1.2 g (0.0025 mol) of purified product with mp 143-147 ° C. The ideality of the product is confirmed in the following manner.
    NMR spectrum (100 MHz, D-dimethyl sulfoxide),: 1.20-1.65 (6H, m., N CHiCH j) 3 CH2); 2.30 - 2.45 (4H, m, N (€ HiCHi) iCHj); 2.60 (2H, t., Hz OCHjCHjN); 4.06 (2H, t., Hz, OCHjCH N); 6.68 (2Y, d., Hz, aromatic protons in the ortho-position
    718
    to OH group); 6.85 (1H, d., 9 Hz, - benzothiophene ring); 6.90 (2H, d, Hz, aromatic protons in the ortho-position to k); 7.18 (2H, d., Hz, aromatic protons in the meta position to the OH group); 7.25 (1H, d., J 9 Hz, H5 of the benzothiophene ring); 7.66 (2H, A.j Hz, aromatic protons in the ortho-position to CO); 9.72 (2H, broad singlet, OH).
    UV spectrum in ethanol d (. (E): 290 them (34,000).
    Electronic shock mass spectrum: M at m / e 473. The yield at the cleavage stage is 42%,
    Example 25. 6-hydroxy-2- (4-hydroxyphenyl) (2-piperidinoethoxy) benzoyl benzo (k) thiophene,
    3.6 g (0.0054 mol) 6-methanesulfonyloxy-2- (4-methanesulfonyloxyphenyl) (2-piperidinoethoxy) benzoyl | The bezo (b) thiophene is dissolved in 100 ml of tegrahydrofuran and 4.0 ml of methanol and 10 ml of 5 N are added. sodium hydroxide solution. The mixture was stirred at room temperature for 16 hours and then treated as described in Example 24, yielding 3.5 g of a yellow solid. Dangerous product ochshtsen on a chromatographic column with silica gel, using eluent of variable composition; from 5% to 30% solution of methanol in chloroform. The fractions containing the product were evaporated, to give 1.85 g of an oily product, which was recrystallized from acetone, after which 1.25 g (0.0026 mol) of purified product were obtained with mp. 141-144 C. The yield at the cleavage stage is 49%.
    PRI me R 26. 6-hydroxy-2- (4-hydroxyphenyl) (2-piperidinoethoxy) benzoyl benzo (b) thiophene.
    The oily product obtained in Example 9 — 6-acetoxy2- (4-acetoxyphenyl) (2-piperidino-etoxy) benzoyl1-enzo (b) thiophene hydrochloride was dissolved in 700 ml of methanol and 100 ml of 5N. sodium hydroxide. The mixture is stirred at room temperature for 2 hours, then evaporated to an oil at a temperature below 40 ° C. The residue is dissolved in 500 ml of water and washed twice with 500 ml portions of diethyl ether. The aqueous phase is acidified to pH 2 with cold 50% methanesulfonic acid, diluted with 11 to a volume of about Zly and washed twice with 1-liter portions of diethyl ether. Then, the F1 phase is separated from the phase, thoroughly degassed under vacuum, and made basic aqueous ammonic solution. The resulting solids are collected by filtration and dried in vacuo at AO C, while 14.2 g of an inaccurate product are obtained, which is chromatographed on a 55 cm column of activity silica gel 1, eluting with a 15% solution of methanol in chloroform. The fractions containing the product are evaporated to dryness, and a yellow foam is obtained, which is recrystallized from acetone, to obtain 11.9 g (0.025 mol of the product, which is almost identical to the product described in example 24p according to NMR, UV- III1 ( -spectroscopy. Total yield by acylation (Example 9) and cleavage by 41%. EXAMPLE 27 6-Oxy-2- (4-hydroxyphenyl) (2-piperidinoethoxy) benzoyl benzo (b) thiophene. Intermediate as described in example 10, 6-benzoyloxy-2- (4-benzoyloxyphenyl-3- 4- (2-piperidinoethoxy) benzoyl benzo (1) thiophene hydrochloride, with 400 ml of water and 55 ml of methanesulfronic acid. The mixture is stirred with heating on a steam bath for 72 hours and then evaporated to an oil, which is diluted with water to 6 L. The aqueous solution is washed twice with 1 L of diethyl ether then it is completely degassed under vacuum, cooled to and the main way is added with aqueous ammonia, to a pH of 8.4. After precipitation, the product is separated by | and hydrochloride and dried under vacuum and then iderC1 installs from 11 | good about 80 14L of acetone. The product is dried in vacuum at which 18.1 g (0.038 mol of crystals) are obtained, which, according to NMR, mass spectra, LC, and UV analyzes, are almost {typical for the product, obtained in a 24 mgr. 25mjtfi yield of acrylate. example (Example 10) and 87% cleavage. EXAMPLE 28 6-Oxy-2- (4-hydroxy. phenyl) -3-14- (2-piperidnoneethoxy) benzoip-benz (b) thiophene. 6-Benzyl-hydrochloride oily with ultra-syphyl C-2 - (n-3-ol with ultrafine-7 hydroxyphenyl) (2-piperidne-ethoxy) benzoyl benzo (b) thiophene, prepared as described in Example 11, is added to 300 ml denatured ethanol and 30 ml of 5 ng and stirring under reflux for 2 hours. The mixture is then evaporated in vacuo and the residue is dissolved in 600 ml of water and then 800 ml of diethyl ether are added. The aqueous layer is acidified to pH 2.0 with methanesulfonic acid The mixture is diluted with water to 6 liters and twice the volume of diethyl ether is given in volumes of 2 liters each time. The aqueous phase is degassed under vacuum and the basic is made up to pH 8.4 with aqueous ammonia solution. The yellow brown crystals that form are separated, washed with water and dried under vacuum at 40 ° C to yield 7.4 g (0.016 mol) of the desired product. After the final re-crystallization from acetone, bright yellowish-brown crystals are obtained, which, according to the NMR and UV spectra, are almost identical to the desired product obtained in accordance with Example 24. The overall yield for acetal lithium research (Example 11) and the removal of 82Z. In the next group of examples, the protected dioxy-starting compound is acylated with an acylidene agent carrying the leaving group X, which is then replaced with an amine to create a main side chain. Example29. 6-Methanesulfonyloxy-2- (4-methanesulfonyloxyphenyl) 3-1.4- (2-chloroethoxy) benoneosHI benzo (b) thiophene. From 1.1 g (0.0048 mol) of 2- (chloroethoxy) benzoic acid, the acid chloride is obtained according to Example 9, and this acid chloride is combined with 1.2 g (0.0029 mol) of 6-methanesulfonyloxy-2- (4- methanesulfo-yloxyphenyl) benzo (1) thiophome dissolved in 25 ml of 1,2-dichloroethane in the presence of O, 5 ml of trifluoromethanesulphonic acid. The mixture is stirred under reflux for 2 h and then poured into ice-cold water. The organic phase is separated. V .f .4. “Vj 1X7 jr 4J l CJl / tlUX and extracted with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo, yielding 1.9 g of the crude product. Upon chromatography on a column (4-8 cm) with silica gel, eluting with a mixture of toluene / ethyl acetate 9/1, 1.2 (0.0021 mol) of the crude intermediate are obtained, which is recrystallized from methanol. you get crystals .pl. 123-124 ° C. The maximum absorption of the CO functional group is in the region of 1650 cm, the IR spectrum is taken in chloroform. Yield 71%. EXAMPLE 30 6-Methanesulfonyloxy-2- (4-methanesulfonyloxyphenyl) - (2-bromoethoxy) beisoyl benzo (k) thiophene. 1 g (0.00408 mol) of 4- (2-bromoethoxy) benzoic acid is converted to the acid chloride and combined with 1.2 g (0.0030 mol) of 6-methanesulfonyloxy-2 (4-methanesulfonyloxyphensh1) benzo (b) thiophene, 20 ml of dichloromethane and 0.5 m of trifluoromethanesulfonic acid. The mixture was stirred at reflux overnight and then poured into ice water. The organic phase is separated, washed with sodium carbonate solution, dried and evaporated in vacuo to give 2.1 g of a brown oil. The oil is chromatographed on a 48 cm column with silica gel using eluate toluene / ethyl acetate 9/1, the fractions containing the product are combined and evaporated in vacuo to give 1.8 g (0.0029 mol) of the purified product oils. The product is identified by the MH molecular ion, m / e 626, in the mass spectrum with field desorption, and by the position of the maximum absorption band in the IR spectrum, taken in chloroform at 1645, answers:; functional group WITH. A small amount of the substance is recrystallized from methanol, thus obtaining white crystals with so pl. 105-107 C Yield 97%. Example 31, 6-Methanesulfonyl oxy-2- (4-methanesulfonyloxyphenyl) (2-piperidinoethoxy) benzoshe1 benzo (I) thiophene hydrochloride. 1.5 g (0.024 mol) of 6-methanesulfonyloxy-2- (4-methanesulfonyloxy phenyl (2-bromoethoxy) benzoyl} benzo (t) thiophene is combined with 5. ml of piperidine, 25 ml of anhydrous dimetformamide and 150 ml of potassium iodide. The mixture is stirred evaporated to vacuum at room temperature for 2 hours, 1155 5722 dry, 25 ml of a saturated aqueous solution of sodium bicarbonate are added to the residue and the mixture is extracted with two portions of ethyl acetate with a volume of 25 ml each.The organic phases are combined and five times washed with portions of an aqueous solution of magnesium chloride, evaporated to dryness with forming a brown oil. 50 ml of a 3% solution of hydrogen chloride in methanol are added to the oil and the mixture is evaporated to dryness. Then 10 ml of methanol is added to the mixture and the mixture is heated and evaporated to a volume of 8 ml. Then it is cooled and a purified intermediate is precipitated M.P. 128-130 C. About 1.6 g (0.0024 mol) of the purified intermediate product is obtained. Yield 99%. EXAMPLE 32 6-methanesulfonyloxy-2- (4-methanesulfonic and 1-phenyl-3 hydrochloride - 4- (2-piperidinoethoxy) benzoyl benzo (b) thiophene. 0.58 g (0.0010 mol) of 6-methanesulfonyloxy-2- (4-methanesulfonyloxyphenyl) 3- {4- (2-chloroethoxy) benzoyl-1-yo (b) thiophene is combined with 20 ml of dimethylformamide, 4.8 ml of piperidine and 100 mg of potassium iodide, the mixture is stirred at 40 ° C, and C; hem for 2 hours at 50 ° C. The mixture was evaporated to give a brown oil in vacuo, the oil was treated by drinking it in 50 ml of a saturated aqueous solution of sodium bicarbonate and extracted twice with a mixture of 40 ml of ethyl acetate. The organic phases are combined, washed twice with portions of a saturated aqueous solution of sodium chloride in a volume of 100 ml, and concentrated in vacuo to an oil. 50 ml of a 3% solution of hydrogen chloride in methanol is added to the oily precipitate. The acidic mixture is concentrated again to an oil, which is dissolved in hot denatured ethanol and crystallized. The first portion of the purified crystals is 0.4 g (0.006 mol). The IR and UV spectra are identical to those of the products obtained in examples 12 and 31. Yield 60%. PRI me R 33. 6-methanesulfonyloxy-2- (4-methanesulfonyloxy-phenyl) -3- hydrochloride. 4- (2-p rrolidinoethoxy) benzoyl benzo (b) thiophene. 1.19 g of the product (0.00188 mol) obtained in accordance with Example 30, 20 ml of anhydrous dimethylformamide and 3.4 g (0.048 mol) are freshly distilled,
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING S- (4-AMINOETHOXYBENZOYL) BENZO (b) THIOPHENES OR THEIR SALTS.
    (57) A method for producing 3- (4-aminoethoxybenzoyl) benzo (b) thiophenes of general form, where R | and Rj- each C, .- C ¢ alkyl or together form polymethylene with 4-6 carbon atoms, a group ~ (CH z) 2 O (CH z) 2 or -CHjCHtCH ^ yCH ^ CHj-, or acylating derivative salts phenylbenzo (b) thiophene with a compound of the general formula J o
    K 3 -C - ^^ OSI g CH g 1C where R) is chlorine, bromine or iodine;
    R4 is X or —NR, —R 2 —rpynna, where X is chloro or bromo;
    R, and have the indicated meanings, under the conditions of the Friedel-Crafts reaction, in an inert organic solvent, such as 1,2-dichloroethane or dichloromethane, at a temperature of from room temperature to 100 ° C followed by sequential. if necessary, processing the obtained compound, where R ^ -X, with an amine of the formula
    -BN R 2 ,.
    where R and th ^ have the indicated meanings, and by hydrolysis, characterized in that, in order to increase the yield of the target product, a compound of the general formula is used as a phenylbenzo (b) thiophene derivative where R j is a group — COR ^;
    R e - unbranched or branched C * -C4 -alkyl or phenyl, or the group -SO 2 R where is r unbranched C (-C-alkyl or phenyl; and hydrolysis is carried out with a base such as sodium hydroxide at room temperature to the boiling point of the reaction medium in a solvent such as lower alcohol and / or tetrahydrofuran in case R f is -SO ^ R ^, or an aqueous lower alcohol, in the presence of methanesulfonic acid as an acid catalyst, in case R 5 is —COR fe .
    Priority by signs:
    04.03.81 R * and R 2 - each C * -C ^ ~ alkyl or together form polymethylene with 4-6 carbon atoms. And a group. - (CH 2 ) 2 O (CH 2 ) 2 -.
    12.16.81 R, and R together form a group - CH 2 CH (CH ) CH g g CH 2 -.
    gU-ll 55157
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    同族专利:
    公开号 | 公开日
    FI821160A0|1982-04-02|
    DK151282A|1982-10-04|
    EG15610A|1986-06-30|
    IL65378A|1986-02-28|
    GR76468B|1984-08-10|
    IE53187B1|1988-08-17|
    KR850001882B1|1985-12-28|
    GB2097392B|1985-04-24|
    HU191353B|1987-02-27|
    PT74692A|1982-05-01|
    ES8307240A1|1983-06-16|
    CS227348B2|1984-04-16|
    IE820786L|1982-10-03|
    DE3268227D1|1986-02-13|
    PL130867B1|1984-09-29|
    GB2097392A|1982-11-03|
    ES511124A0|1983-06-16|
    EP0062504A1|1982-10-13|
    PL235752A1|1982-11-22|
    EP0062504B1|1986-01-02|
    KR830010100A|1983-12-26|
    DD201793A5|1983-08-10|
    PT74692B|1985-01-08|
    IL65378D0|1982-05-31|
    FI821160L|1982-10-04|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US24633581A| true| 1981-04-03|1981-04-03|
    US06/246,334|US4358593A|1981-04-03|1981-04-03|Process for preparing 3-benzo[b]thiophenes|
    US33104581A| true| 1981-12-16|1981-12-16|
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