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SU554810A3 - The method of obtaining derivatives of biphenyl or their salts, or racemates, or optically active antipodes - Google Patents

The method of obtaining derivatives of biphenyl or their salts, or racemates, or optically active antipodes

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SU554810A3
SU554810A3 SU2069110A SU2069110A SU554810A3 SU 554810 A3 SU554810 A3 SU 554810A3 SU 2069110 A SU2069110 A SU 2069110A SU 2069110 A SU2069110 A SU 2069110A SU 554810 A3 SU554810 A3 SU 554810A3
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fluoro
biphenylyl
mol
acid
ethanol
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Энгель Вольфхард
Тойфель Хельмут
Зеегер Эрнст
Никкль Йозеф
Энгельгардт Гюнтер
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Д-Р Карл Томэ Гмбх (Фирма)
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Description

(54) СПОСОБ ПОЛУЧЕНИЯ ПРОИЗВОДНЫХ БИФЕИИЛА(54) METHOD FOR OBTAINING DERIVATIVES OF BEEPHEILE

ИЛИ ИХ СОЛЕЙ, ИЛИ РАЦЕМАТОВ, ИЛИ ОПТИЧЕСКИ АКТИВНЫХ АНТИПОДОВOR THEIR SALTS, OR RACEMATS, OR OPTICALLY ACTIVE ANTIPODS

- -

,«-.. ,.,, "- ..,.,

, , , ,-.- . ,,, -.-.

-kAsilJ -kAsilJ

. «- г s : --4 , - --- ,554810. "- g s: --4, - ---, 554810

Кислоты формулы I могут быть переведены в соли действием на них также неорганических или органических оснований. В качестве последних наиболее приемлемыми  вл ютс  диэтаноламин, морфолин, циклогексиламин и пиперазин.The acids of the formula I can be converted into salts by also inorganic or organic bases. As the latter, diethanolamine, morpholine, cyclohexylamine and piperazine are most suitable.

Производные бифенила формулы I могут быть выделены или в виде рацемата, или оптически активных антиподов, -последние могут быть получены путем фракционной кристаллизации их солей с оптически активными основани ми, желательно хинолином.The biphenyl derivatives of the formula I can be isolated either as a racemate or as optically active antipodes; the latter can be obtained by fractional crystallization of their salts with optically active bases, preferably quinoline.

Пример 1. 3-(2-Фтор-4-бифенилил)-масл на  кислота.Example 1. 3- (2-Fluoro-4-biphenylyl) -based acid.

а)Метиловый эфир 1,3-дитиан-2-карбоноБОИ кислоты.a) 1,3-Ditian-2-carbonoBOI acid methyl ester.

yj,8 г (0,498 моль) 1,3-пропандитиола и б/,и г (0,4УУ моль) метилового эфира диметоксиуксусной кислоты, растворенных в зии мл оезводного хлороформа, в течение 15 мин прикапывают к кип щему раствору из ни г (и,988 моль) эфирата трифторида Dopa в 100 мл сухого хлороформа, и смесь зате .1 кип т т еще 2 ц.yj, 8 g (0.498 mol) of 1,3-propanedithiol and b /, and g (0.4UU mol) of dimethoxyacetic acid methyl ester dissolved in ml of ozodvod chloroform, for 15 min, was added dropwise to a boiling solution of none (g and, 988 mol) of Dopa trifluoride etherate in 100 ml of dry chloroform, and the mixture is then boiled for another 2 centners.

После охлаждени  исходную реакционную смесь выливают в 400 мл лед ной воды, отдел ют органическую фазу и два раза промывают ее водой, насыщенным раствором оикарооната натри  и еще раз водой, сушат сульqjaroM натри  и выпаривают под вакуумом, иставшийс  остаток дистиллируют в вакууме. Т. кип. УЬ-98С/и,9 мм рт. сг.; т. пл. (петролейный эфир). Выход составл ет 35,0г от теоретического).After cooling, the initial reaction mixture is poured into 400 ml of ice-water, the organic phase is separated and washed twice with water, saturated sodium oikaronate solution and once again with water, dried with sodium sulfate and evaporated under vacuum, and the residue is distilled under vacuum. T. Kip. U-98S / i, 9 mm Hg. sg .; m.p. (petroleum ether). The yield is 35.0 g from theoretical).

б)(2-Фтор - 4 - бифенилил)- - ,3-дитиан-2-карОонова  кислота.b) (2-Fluoro-4-biphenylyl) - -, 3-dithian-2-carOonic acid.

К суспензии из 2,76 г (0,115 моль) гидрида натри  (3,45 г 80%-ной суспензии в минераль ,ном масле) в 150 мл безводного бензола в течение Приблизительно 30 мин прикапывают при поддержании температуры раствор из 20,0 г (.0,112 моль) метилового эфира 1,йдитиан-2-карбоновой кислоты и 35,0 г (0,125 моль) 1-бром-1-(2-фтор-4-бифенилил) -этана в 90 мл абсолютного диметилформамида. 11осле реакционную смесь перемешивают в течение 1 ч при -40С и в течение 12 ч при комнатной температуре, отгон ют большую часть бензола под уменьшенным давлением и нагревают после добавлени  100 мл безводного диметилформамида в течение 1 ч до . Исходную реакционную смесь смешивают с 500 мл лед ной воды, подкисл ют разбавленной сол ной кислотой, и раствор ют выпавший кристаллический продукт в этилацетате . Объединенные экстракты уксусного эфира промывают по очереди водой, насыщенным раствором бикарбоната натри  и еще раз водой, сушат сульфатом натри  и вьгпаривают . Оставшийс  остаток перекристаллизовывают из этилового эфира уксусной кислоты и получают продукт с т.  л. 151-152°С. Выход его составл ет 33,0 г (78% от теоретического).To a suspension of 2.76 g (0.115 mol) of sodium hydride (3.45 g of an 80% suspension in mineral oil) in 150 ml of anhydrous benzene for about 30 minutes, a solution of 20.0 g is added dropwise while maintaining the temperature ( .0,112 mol) methyl ester 1, iditian-2-carboxylic acid and 35.0 g (0.125 mol) of 1-bromo-1- (2-fluoro-4-biphenylyl) -ethane in 90 ml of absolute dimethylformamide. After the reaction mixture is stirred for 1 hour at -40 ° C and for 12 hours at room temperature, most of the benzene is distilled off under reduced pressure and heated after adding 100 ml of anhydrous dimethylformamide for 1 hour to. The initial reaction mixture is mixed with 500 ml of ice water, acidified with dilute hydrochloric acid, and the precipitated crystalline product is dissolved in ethyl acetate. The combined acetic ester extracts are washed in turn with water, with saturated sodium bicarbonate solution and again with water, dried with sodium sulfate and evaporated. The remaining residue is recrystallized from ethyl acetate to give the product with so-called l. 151-152 ° C. Its yield is 33.0 g (78% of the theoretical).

в)(2-Фтор-4-бифенилил) - 1-этил -1,3дитиан-2-карбоноБа  кислота.c) (2-Fluoro-4-biphenylyl) - 1-ethyl-1,3-dithian-2-carbonoBa acid.

Смесь из 20,0 г (0,0533 моль) метилового эфира (2-Фтор-4-бифенилил) -1 -этил -1,3дитиан-2-карбоновой кислоты, 8,9 г (0,16 моль) гидроокиси кали  и 20U мл этанола в течение 15 ч кип т т. Затем отгон ют приблизительно 2/3 растворител , выливают оставшуюс  смесь в 1 л воды и обрабатывают полученную смесь многократно эфиром. Эфирные экстракты удал ют. Воднощелочную фазу добавление.м разбавленной сол ной кислоты довод т до значени  рН 3 и затем еще обрабатывают этилацетатом. Объединенные экстракты уксусного эфира многократно промывают водой, сушат сульфатом натри  и выпаривают . Оставшеес  желтоватое .масло кристаллизуетс  после затирани  петролейны .м эфиром. Получаемый в количестве 16,0 г (83% от теоретического) продукт имеет т. пл. после перекристаллизации из циклогексана) метиленхлорида (объемное соотношение 8 ; 2) 157-158-С.A mixture of 20.0 g (0.0533 mol) of methyl (2-fluoro-4-biphenylyl) -1-ethyl-1,3 dithian-2-carboxylic acid methyl ester, 8.9 g (0.16 mol) of potassium hydroxide and 20U ml of ethanol is boiled for 15 hours. Then approximately 2/3 of the solvent is distilled off, the remaining mixture is poured into 1 liter of water and the mixture is treated several times with ether. The ether extracts are removed. The aqueous alkaline phase of the addition of m. Dilute hydrochloric acid is adjusted to pH 3 and then further treated with ethyl acetate. The combined acetic ester extracts are washed several times with water, dried with sodium sulfate and evaporated. The remaining yellowish oil crystallizes after mashing the petroleum m ether. Obtained in the amount of 16.0 g (83% of theoretical) product has so pl. after recrystallization from cyclohexane) methylene chloride (volume ratio 8; 2) 157-158-С.

г) 3-(2-Фтор-4-бифенилил)-масл на  кислота .d) 3- (2-Fluoro-4-biphenylyl) -buttonic acid.

Раствор из 7,20 г (0,0198 моль) 2-{1-(2фтор-4-бифенилил ) - 1-этил - 1,3-дитиан - 2карбоновой кислоты в 200 мл этаиола после добавлени  48 г (0,82 моль) никел . Рене  кип т т в течение 16 ч. Никель Рене  отфильтровывают , фильтрат концентрируют под вакуумом, остаток - масло зеленого цвета, обрабатывают 10%-иым едким натром, а затем многократно обрабатывают эфиром. Эфирные экстракты удал ют. Воднощелочную фазу подкисл ют разбавленной сол ной кислотой, выделившийс  продукт обрабатывают эфиром. Эфирный раствор про.мывают водой , сушат сульфатом натри  и выпаривают. Оставшийс  остаток очищают через соль циклогексиламмони  (т. пл. 163-164°С). Свободна  кислота имеет т. пл. после перекристаллизации из циклогексана 98-99°С.A solution of 7.20 g (0.0198 mol) of 2- {1- (2-fluoro-4-biphenylyl) -1-ethyl-1,3-dithian-2carboxylic acid in 200 ml of ethiol after adding 48 g (0.82 mol nickel The rene is boiled for 16 h. The Nickel of Rene is filtered off, the filtrate is concentrated under vacuum, the residue is green oil, treated with 10% sodium hydroxide and then repeatedly treated with ether. The ether extracts are removed. The aqueous alkaline phase is acidified with dilute hydrochloric acid, the separated product is treated with ether. The ether solution is washed with water, dried over sodium sulfate and evaporated. The remaining residue is purified via a cyclohexylammonium salt (m.p. 163-164 ° C). Free acid is m. Pl. after recrystallization from cyclohexane 98-99 ° C.

Выход составл ет 2,95 г (58% от теоретического ) .The yield is 2.95 g (58% of theory).

Аналогичным образом получают следующие масл ные кислоты;The following oil acids are prepared in a similar manner;

а)3-(4-фтор-4-бифенилил) - масл иа  кислота , т. пл. 141 - , (этанол), из 2-(1-(4фтор-4-бифенилил ) - 1-этил -1,3-дитиан-2-карооновой кислоты;a) 3- (4-fluoro-4-biphenylyl) - butyric acid, so pl. 141 -, (ethanol), from 2- (1- (4-fluoro-4-biphenylyl) -1-ethyl -1,3-dithian-2-caroic acid;

б)3-(2-хлор-4-бифенилил)-масл на  кислота , т. пл. 128-129°С, из 2-11-(2-хлор-4-бифенилил ) -1 -этил -1,3-дитиан-2-карбоновой кислоты .b) 3- (2-chloro-4-biphenylyl) -buttonic acid, so pl. 128-129 ° C, from 2-11- (2-chloro-4-biphenylyl) -1-ethyl -1,3-dithian-2-carboxylic acid.

в)3-(3-хлор-4-бифенилил) - масл на  кислота , т. пл. 106-108°С, из 2-11-(3-хлор-4-бифенилил )-1-этил -1,3 - дитиан-2 - карбоновой кислоты.c) 3- (3-chloro-4-biphenylyl) - butyric acid, so pl. 106-108 ° C, from 2-11- (3-chloro-4-biphenylyl) -1-ethyl -1.3 - dithian-2 - carboxylic acid.

Пример 2. Метиловый эфир 3-(2-фтор-4бифенилил ) - масл ной кислоты.Example 2. Methyl ester of 3- (2-fluoro-4biphenylyl) - butyric acid.

Claims (3)

В раствор из 48,0 г (0,202 моль) гексагидрата хлорида никел  в 180 мл этанола подают , размешива , по небольшим порци м 15,2 г (0,4 моль) боргидрида натри . Получаемую черную суспензию раз.мешивают еще 30 мин при комнатной температуре. Затем добавл ют 7,5 г (0,199 моль) метилового эфира 2-(1-(2фтор-4-бифенилил )-1-этил - 1,3-дитиан - 2карооновой кислоты и, размешива , кип т т в течение 70 мин с обратным холодильником. Охлажденную смесь фильтруют, сгущают и дистиллируют в среднем вакууме (т. кип. /0,0о мм рт. ст./ 124-ISO C), зате.м с небольшим количеством нетролейного эфира выкристаллизовывают и перекристаллизовывают из н-гексана. Получают 3,7о г (5У7о от теоретического ) бесцветных кристаллов с т. пл. 49- 50°С. Пример 3. Получение оптически активных антиподов -(2-фтор-4-бифенилил) - масл ной кислоты. 77,5 г {0,3 моль) 3-(2-фтор-4-бифенилил)масл ной кислоты раствор ют в 1,5 л этанола и смешивают с раствором из 97,2 г (0,3 моль) хинолина в 1,5 л этанола. Получают бесцветный осадок А, который отсасывают,, и фильтрат Б. Осадок А 15 раз перекристаллизовывают из этанола (всего 30 л), причем получают правовраш,ающу1О 3-(2-фтор-4 -бифенилил)масл ную кислоту с т. пл. 87-88 0 (из циклогексана ) af° +34,5°. Выход 5,5 г. Из фильтрата Б удал ют растворитель и остаток раствор ют в гор чем метаноле (500 мл). При охлаждении выпадает осадок, который отфильтровывают, а фильтрат 4 раза обрабатывают таким же образом метанолом . Оставшийс  при удалении метанола остаток раствор ют в 500 мл теплого этилацетата и получают при состо нии осадок, который отфильтровывают и перекристаллизовывают приблизительно из 500 мл этилацетата. Получают левовращающую 3-(2-фтор-4-бифенилил )-масл ную кислоту с т. пл. 85-87 0 ( из циклогексана) ,5° с выходом Пример 4. Натриева  соль 3-(2-фтор-4бифенилил )-масл ной кислоты. К теплому раствору из 193,0 г (2,297 моль) бикарбоната натри  в 4000 мл воды по порци м при перемешивании добавл ют 625,0 г (2,42 моль) 3-(2-фтор-4-бифенилил)-масл ной ислоты, котора  раствор етс  с сильным пеообразованием . Затем реакционн ю массу нагревают в течение 20 мин, охлаждают и п ть раз обрабатывают (каждый раз 1 л) тилового эфира с целью удалени  избыточой 3-(2-фтор-4-бифенилил)-масл ной кислоы . Водный раствор затем перегон ют в вакууме , масл нистый остаток постепенно раствор ют (каждый раз берут 1 л) в этаноле, отсасывают и сушат в вакууме при 70°С. Получают 600,0 г (93% от теоретического) бесцветных кристаллов, имеюших т. пл. 212- 213°С. Формула изобретени  1. Способ получени  производных бифенила обшей формулы I sv -CH-CHj-COB i где Ri - атом галогена; В - окси- или алкоксигруппа, или их солей, или рацематов, или оптически активных антиподов, отличающийс  тем, что соединение обшей формулы II где RI имеет указанное выше значение; JR2 - низший алкилрадикал, подвергают обработке сол ми ртути или серебра , никелем, или боридом никел  в среде растворител , полученный при этом продукт выдел ют в виде эфира, или кислоты, или соли , или рацематов, или оптически активных антиподов. To a solution of 48.0 g (0.202 mol) of nickel chloride hexahydrate in 180 ml of ethanol, 15.2 g (0.4 mol) of sodium borohydride are stirred in small portions. The resulting black suspension is stirred for another 30 minutes at room temperature. Then 7.5 g (0.199 mol) of 2- (1- (2-fluoro-4-biphenylyl) -1-ethyl-1,3-dithian-2-caronic acid) methyl ester is added and boiled for 70 minutes with stirring. reflux. The cooled mixture is filtered, concentrated and distilled under medium vacuum (mp. / 0.0 ° mm Hg. Art./124-ISO C), then crystallized out with a small amount of non-trace ether and recrystallized from n-hexane. Obtain 3.7o g (5U7o from theoretical) colorless crystals with mp 49-50 ° C. Example 3. Preparation of optically active antipodes - (2-fluoro-4-biphenylyl) - butyric acid. 77.5 g {0.3 mol) of 3- (2-fluoro-4-biphenylyl) butyric acid is dissolved in 1.5 l of ethanol and mixed with a solution of 97.2 g (0.3 mol) of quinoline in 1.5 l of ethanol . A colorless precipitate A is obtained, which is sucked off, and the filtrate B. Sediment A is recrystallized 15 times from ethanol (30 l in total), and a pravovrash is obtained, ayuchOO 3- (2-fluoro-4-biphenylyl) oleic acid with m.p. 87-88 0 (from cyclohexane) af ° + 34.5 °. Yield 5.5 g. Solvent is removed from filtrate B and the residue is dissolved in hot methanol (500 ml). Upon cooling, a precipitate formed, which was filtered off, and the filtrate was treated 4 times in the same way with methanol. The residue remaining during the removal of methanol is dissolved in 500 ml of warm ethyl acetate and a precipitate is obtained in the state, which is filtered and recrystallized from approximately 500 ml of ethyl acetate. A levorotatory 3- (2-fluoro-4-biphenylyl) -buttoned acid is obtained with a melting point of 200 g. 85-87 0 (from cyclohexane), 5 ° with the release of Example 4. Sodium salt of 3- (2-fluoro-4biphenylyl) -based acid. To a warm solution of 193.0 g (2.297 mol) of sodium bicarbonate in 4000 ml of water, 625.0 g (2.42 mol) of 3- (2-fluoro-4-biphenylyl) -based acid are added with stirring. which dissolves with strong re-formation. The reaction mass is then heated for 20 minutes, cooled, and treated five times (each time with 1 l) of ethyl ether in order to remove excess 3- (2-fluoro-4-biphenylyl) -based acid. The aqueous solution is then distilled in vacuo, the oily residue is gradually dissolved (1 l each time) in ethanol, sucked off and dried in vacuum at 70 ° C. Get 600,0 g (93% of theoretical) of colorless crystals, having so pl. 212-213 ° C. Claims 1. Process for the preparation of biphenyl derivatives of the general formula I sv -CH-CHj-COB i where Ri is a halogen atom; B is hydroxy or alkoxy, or their salts, or racemates, or optically active antipodes, characterized in that the compound of the general formula II is: where RI has the above meaning; JR2 is a lower alkyl radical, treated with salts of mercury or silver, nickel or nickel boride in a solvent, the resulting product is isolated in the form of an ester, or acid, or salt, or racemates, or optically active antipodes. 2.Способ по п. 1, отличающийс  тем, что в качестве растворител  используют низшие спирты. 2. A method according to claim 1, characterized in that lower alcohols are used as the solvent. 3.Способ по пп. 1 и 2, отличающийс  тем, что процесс ведут при температуре кипени  реакциоппой смеси.3. Method according to paragraphs. 1 and 2, characterized in that the process is carried out at the boiling point of the reaction mixture.
SU2069110A 1972-08-17 1974-10-21 The method of obtaining derivatives of biphenyl or their salts, or racemates, or optically active antipodes SU554810A3 (en)

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SU1958290A SU511846A3 (en) 1972-08-17 1973-08-15 The method of obtaining -biphenylbuttonic acids or their salts
SU2069774A SU552021A3 (en) 1972-08-17 1974-10-21 The method of obtaining derivatives of biphenyl or their salts
SU2069576A SU561505A3 (en) 1972-08-17 1974-10-21 The method of obtaining 3- (4-biphenylyl) -buttonic acid or its salts
SU2069110A SU554810A3 (en) 1972-08-17 1974-10-21 The method of obtaining derivatives of biphenyl or their salts, or racemates, or optically active antipodes
SU2069771A SU520030A3 (en) 1972-08-17 1974-10-21 Method for preparing substituted biphenylbutyric acid or its ester or its salt
SU7402069575A SU577967A3 (en) 1972-08-17 1974-10-21 Method of preparing substituted biphenylilbutyric acid or its esters,or its amides,or its salts
SU2069577A SU520907A3 (en) 1972-08-17 1974-10-21 Method for preparing substituted biphenylyl butyric acid or its salt
SU2069114A SU538658A3 (en) 1972-08-17 1974-10-21 The method of obtaining biphenylbutyric acids or their salts, or racemates, or optically active antipodes
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SU1958290A SU511846A3 (en) 1972-08-17 1973-08-15 The method of obtaining -biphenylbuttonic acids or their salts
SU2069774A SU552021A3 (en) 1972-08-17 1974-10-21 The method of obtaining derivatives of biphenyl or their salts
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SU2069114A SU538658A3 (en) 1972-08-17 1974-10-21 The method of obtaining biphenylbutyric acids or their salts, or racemates, or optically active antipodes
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