SU816399A3 - Method of preparing substituted dibenzylic ethers or their acid-additive salts - Google Patents
Method of preparing substituted dibenzylic ethers or their acid-additive salts Download PDFInfo
- Publication number
- SU816399A3 SU816399A3 SU792771698A SU2771698A SU816399A3 SU 816399 A3 SU816399 A3 SU 816399A3 SU 792771698 A SU792771698 A SU 792771698A SU 2771698 A SU2771698 A SU 2771698A SU 816399 A3 SU816399 A3 SU 816399A3
- Authority
- SU
- USSR - Soviet Union
- Prior art keywords
- ethers
- acid
- salts
- ethanol
- dibenzylic
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims description 7
- 150000002170 ethers Chemical class 0.000 title claims description 3
- 239000000654 additive Substances 0.000 title description 3
- 239000002253 acid Substances 0.000 claims abstract description 8
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims 1
- 229910052987 metal hydride Inorganic materials 0.000 claims 1
- 150000004681 metal hydrides Chemical class 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 4
- HLQZCRVEEQKNMS-UHFFFAOYSA-N 1-(chloromethyl)-4-phenylbenzene Chemical group C1=CC(CCl)=CC=C1C1=CC=CC=C1 HLQZCRVEEQKNMS-UHFFFAOYSA-N 0.000 abstract description 3
- RLFHPRWHJYDGSD-UHFFFAOYSA-N 1-(chloromethyl)-4-phenylsulfanylbenzene Chemical compound C1=CC(CCl)=CC=C1SC1=CC=CC=C1 RLFHPRWHJYDGSD-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- BMELCCDXEVUJTJ-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-3-imidazol-1-ylpropan-1-ol Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(O)CCN1C=CN=C1 BMELCCDXEVUJTJ-UHFFFAOYSA-N 0.000 abstract 1
- HZQLUIZFUXNFHK-UHFFFAOYSA-N 1-(bromomethyl)-4-phenylbenzene Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1 HZQLUIZFUXNFHK-UHFFFAOYSA-N 0.000 abstract 1
- WSLSNIMNEMCJPK-UHFFFAOYSA-N 1-(bromomethyl)-4-phenylsulfanylbenzene Chemical compound C1=CC(CBr)=CC=C1SC1=CC=CC=C1 WSLSNIMNEMCJPK-UHFFFAOYSA-N 0.000 abstract 1
- 241000233866 Fungi Species 0.000 abstract 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 abstract 1
- 241001148470 aerobic bacillus Species 0.000 abstract 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 abstract 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- -1 DIBENZYL ETHERS Chemical class 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 4
- UKVLTPAGJIYSGN-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-2-imidazol-1-ylethanol Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(O)CN1C=CN=C1 UKVLTPAGJIYSGN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 3
- 150000008046 alkali metal hydrides Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000006277 halobenzyl group Chemical group 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- XHEPANNURIQWRM-UHFFFAOYSA-N 2-chloro-1-(2,4-dichlorophenyl)ethanol Chemical compound ClCC(O)C1=CC=C(Cl)C=C1Cl XHEPANNURIQWRM-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000004111 Potassium silicate Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910052913 potassium silicate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
Abstract
Description
(54) СПОСОБ ПОЛУЧЕНИЯ ЗАМЕЩЕННЫХ ДИБЕНЗИЛОВЫХ ЭФИРОВ ИЛИ ИХ КИСЛОТНО-АДДИТИВНЫХ СОЛЕЙ(54) METHOD FOR OBTAINING SUBSTITUTED DIBENZYL ETHERS OR THEIR ACID ADDITIVE SALTS
Изобретение относитс к способу получени новых замещенных дибёнзиловых эфиров или их кислотно-аддити ных солей, которые могут найти применение в качестве физиологическиактивных соединений, обладающих антибактериальной активностью, в фармацевтической промышленности. Предлагаемый способ получени за мещенных дибензилоЕа:1х эфиров основан на известной реакции конденсации ароматических оксисоединений с галоидбензилом и переводе их извест ным способом в соли. Цель изобретени - разработка способа получени эфиров или их солей . Поставленна цель достигаетс те что, в способе получени замещенных дибензиловых эфиров общей формулы где R - CgHy или CjiHyS. или их кислотно-аддитивных солей, 1-(2,4 -дихлорфенил)-2-(М-имидазолилмeтил -этанол подвергают конденсации с галоидбензилом формулы где К С НуХ-С1,Вгв среде карбоксамида в присутствии гидрида щелочного металла, или в среде алифатического спирта Сз-С в присутствии алкогол та щелочного металла с выделением целевого продукта в виде оснований или их солей. В качестве карбоксамидов используют диметилформамид, гексаметилфосфорамид , но конденсаци протекает более полно, если используют диметилсульфоксид . Это приводит к более высокому выходу и к получению более чистого продукта. Полученное при конденсации основание не подвергают очистке хроматографией, потому что очистка вл етс необходимой только при применении в качестве растворителей диметилформамида или гексаметилфосфорамида . Фильтрование раствора основани через колонку с сйликагелем приводит к задержанию небольших количеств примесей. В случае соединени . в котором символ R представл ет собой фенильную группу, фильтрование не вл етс необходимом и кристаллизаци нитрата приводит к получению продукта, достаточно чистого дл фар мацевтических целей. При применении описанных апротонных растворителей употребл ют гидрид щелочного металла который способен образовывать соль с гидроксильной группой производного этанола. Растворитель, используемый при конденсации, представл ет собой али фатический спирт, содержащий от 3 до б углеродных атомов, такой, как трет-бутанол, и в этом случае гидрид щелочного металла замен ют алкогол том щелочного металла, например,трет бутилатом кали . Кислотно-аддитивные соли замещен ных дибензиловых эфиров получают известным способом, например путем при бавлени к основанию эквимолекул рного количества кислоты с последующей кристаллизацией полученной таким образом соли из- подход щего растворител . , ,, Исходных 1-(2 ,4 -диxлopфeнил)-2 -(N-имидазолил)-этанол получают-из 1-хлорацетил-2,4-дихлорбензола путем восстановлени последнего боргидридом натри и последующей конденсацией с имидазолилом. 2 ,4 -ДихлорПример 1.1фенил )-2-хлорэтанол. 49,5 г боргидрида натри медленно прибавл ют небольшими порци ми к суспензии 233 г 1-(1-окси-2-хлоро 3тил)-2,4-дихлорбензола в 1 л метано ла, перемешиваемого при комнатной температуре. Полученный раствор пере мешивают при комнатной температуре еще 2 ч и после этого выливают в 1л 5 н. сол ной кислоты, охлажденной льдом. После экстракции этилацетатом или хлороформом, экстракт промывают водой, 1 н. раствором гидрата окиси натри и снова водой до нейтральной реакции, и наконец, насьпценным раствором хлористого натри , Экстракт сушат, растворитель выпаривают и получаю .т 220 г масла1. Масло застывает при выдержке и полученное твердое вещество плавитс при 48-51°С. Н 3,19, Найдено,%: С 42,75, С)- 47,43. н, ciiO . С Вычислено,%: С 42,61, Н 3,13, 47,17. Пример 2, 1-(2,4-Дихлорфёнил )-2-{N-имидазолил)-этанол. 30 г натри прибавл ют к раствору 88,5 р имидаэола.и 60-0 мл метанола, после этого растворитель выпаривают . Остаток раствор ют в 300 мл диметилформамнда и нагревают до 115120с . К полученному раствору прибавл; гют по капл м и при перемешивании , раствор 225 г 1-(2,4--дихлорфенил )-2-хлороэтанола в 400 мл диметилформамида . Смесь нагревают до 115-120°С и выдерживают при этой температуре в течение 20 мин, и после последующего охлаждени до , при энергичном перемешивании прибавл ют 2500 мл лед ной воды. Продукт, осадившийс при перемешивании в течение периода времени около 2-х ч освобождают от верхнего сло жидкости, который декантируют, прибавл ют еще 2500 мл воды и, после выдержки,смесь фильтруют. Полученный осадок сушат и кристаллизуют из толуола. При этом получают 170 г целевого продукта , плав щегос при 134-135С. Найдено,%; С 51,62, Н 3,80, N 10,73, С1 27.76. С. Вычислено,: С 51,38, Н 3,92, N 10,89, С) 27,58., Пример 3. 2,4-Дихлор-4 тфенилтио- -(N-имидазолилметил) -дибензиловый простой эфир (1:R - C/Hr-S). Раствор 2,57 г 1-(2,4 -дихлорфенил )-2-(М-имидазол)-этанола, в 10 мл гексаметилфосфорамида прибавл ют по капл м, при , к суспензии 0,52 г гидрида натри (50%-ный раствор в масле) в- 5 мл гексаметилфосфорамида . После прекращени выделени водорода, образование соли завершают путем нагревани в течение 1 ч при . После охлаждени до 25°С, прибавл ют 2,58 г 1-хлорметил-4-фенилтиобензола . Температуру повышают до и смесь выдерживают при этой температуре в течение 12 ч. По завершении реакции, смесь выливают в 200 мл воды, продукт экстрагируют диэтиловым эфиром, растворитель выпаривают и остаток дважды очищают на колонке силикагел , с использованием в качестве элюента этилацетата и с проверкой различных фракций методом тонкослойной хроматографии. Растворитель выпаривают из средних фракций, дл получени 2,4 г целевого основани в форме желтоватого масла , дающего одно п тно на тонкослойной хроматограмме. Найдено,%: С 63,86, Н 4,24,N 6,41, С1 15,29, -S 6,97. 44420 2CoOS. Вычислено,: С 63,30, Н 4,44, N 6,13, С1 15,57, S 7,04. Пример 4. 2,4-Дихлор-4-фенил-о1- ( N -имидазолил-метил) -дибензиловый простой эфир (,1:R CgHy). Смесь, состо щую из 2,02 г третбу илата кали в 30 мл трет-бутанола готов т при , в атмосфере аз.ота. Прибавл ют 3,86 г 1-(2.4-. -диxпopфeнил)-2-(N-имидa-зoлил) -этанола . Раствор нагревают при температуре кипени с обратным холодильником в течение 1ч и затем охлаждают до 20-25 с. Прибавл ют 3,03 г 4-хлорметилбифенила и раствор снова нагревают при температуре кипени с обратным холодильником в течение 5ч.. Пос ле охлаждени до 20-25 с смесь выливают в воду и основание экстрагируют этилацетатом. Экстракт промывают диэтиловым эфиром и растворитель выпаривают . Остаток раствор ют в диэтиловом эфире (80 мл) и оставл ют на ночь. НераствориКые вацества отфильтровывают и фильтрат обрабатывают азотной кислотой, растворенной в диэтиловом эфире. При этом получают масло, эастываицее при выдержке. Остаток, состо щий из нитрата 2.,4-дихлор-4 -фенил-ot- (М-имидазолил-метил )-дибенз илового эфира, кристаллизуют из этанола или этйлацетата.Продукт (4,3 г) вл етс чистым, что доказываетс методом тонкослойной хроматОграфии и плавитс при 140-141 С.The invention relates to a process for the preparation of new substituted dibenzyl esters or their acid addition salts, which can be used as physiologically active compounds with antibacterial activity in the pharmaceutical industry. The proposed method for the preparation of substituted dibenzylEa: 1x ethers is based on the well-known condensation reaction of aromatic hydroxy compounds with halobenzyl and their conversion into salt in a known manner. The purpose of the invention is to develop a process for the preparation of esters or their salts. The goal is achieved by the fact that, in the method of producing substituted dibenzyl ethers of the general formula </ BR> where R is CgHy or CjiHyS. or their acid additive salts, 1- (2,4-dichlorophenyl) -2- (M-imidazolylmethyl-ethanol is subjected to condensation with halobenzyl formula where K C NuH-C1, Bv carboxamide in the presence of an alkali metal hydride, or in an aliphatic Cz-C alcohol in the presence of an alkali metal alcoholate with the release of the target product as bases or their salts. Dimethylformamide and hexamethylphosphoramide are used as carboxamides, but condensation proceeds more completely if dimethyl sulfoxide is used. This leads to a higher yield and a cleaner product. The base obtained by condensation is not purified by chromatography, because purification is necessary only when dimethylformamide or hexamethylphosphoramide is used as solvents. Filtration of the base solution through a column of sylcagel leads to retention of small amounts of impurities. wherein the symbol R represents a phenyl group, filtering is not necessary and crystallization of the nitrate results in a product sufficient internally clean headlamps for devel- purposes. When using the described aprotic solvents, an alkali metal hydride is used which is capable of forming a salt with a hydroxyl group of an ethanol derivative. The condensation solvent used is ali-phatic alcohol containing from 3 to b carbon atoms, such as tert-butanol, in which case the alkali metal hydride is replaced by an alkali metal alcohol, for example, potassium t-butylate. Acid addition salts of substituted dibenzyl esters are prepared in a known manner, for example, by adding an equimolar amount of acid to the base followed by crystallization of the salt thus obtained with a suitable solvent. , The starting 1- (2, 4-dichlorophenyl) -2- (N-imidazolyl) -ethanol is obtained from 1-chloroacetyl-2,4-dichlorobenzene by reduction of the latter with sodium borohydride and subsequent condensation with imidazolyl. 2, 4-Dichloro Example 1.1phenyl) -2-chloroethanol. 49.5 g of sodium borohydride are slowly added in small portions to a suspension of 233 g of 1- (1-hydroxy-2-chloro-3-ethyl) -2,4-dichlorobenzene in 1 l of methanol, stirred at room temperature. The resulting solution was stirred at room temperature for another 2 hours and then poured into 1L 5N. hydrochloric acid cooled with ice. After extraction with ethyl acetate or chloroform, the extract is washed with water, 1N. with a solution of sodium hydroxide and again with water until neutral, and finally, with an essential solution of sodium chloride, the extract is dried, the solvent is evaporated and I get. 220 g of oil1. The oil solidifies on aging and the resulting solid melts at 48-51 ° C. H 3.19, Found,%: C 42.75, C) - 47.43. n, ciiO. C Calculated,%: C 42.61, H 3.13, 47.17. Example 2, 1- (2,4-Dichlorophenyl) -2- {N-imidazolyl) -ethanol. 30 g of sodium are added to a solution of 88.5 p of imidaeol. And 60-0 ml of methanol, then the solvent is evaporated. The residue is dissolved in 300 ml of dimethylformamnd and heated to 115120 ° C. To the resulting solution added; With drops and under stirring, a solution of 225 g of 1- (2.4-dichlorophenyl) -2-chloroethanol in 400 ml of dimethylformamide. The mixture is heated to 115-120 ° C and maintained at this temperature for 20 minutes, and after further cooling, 2500 ml of ice water are added with vigorous stirring. The product precipitated with stirring for a period of time of about 2 hours is freed from the upper layer of liquid, which is decanted, another 2500 ml of water is added and, after aging, the mixture is filtered. The resulting precipitate is dried and crystallized from toluene. 170 g of the expected product are obtained, melting at 134-135 ° C. Found,%; C 51.62, H 3.80, N 10.73, C1 27.76. C. Calculated: C 51.38, H 3.92, N 10.89, C) 27.58., Example 3. 2,4-Dichloro-4 tphenylthio- (N-imidazolylmethyl) -dibenzyl ether ( 1: R - C / Hr-S). A solution of 2.57 g of 1- (2,4-dichlorophenyl) -2- (M-imidazole) -ethanol, in 10 ml of hexamethylphosphoramide is added dropwise, and, to a suspension, 0.52 g of sodium hydride (50% solution in oil) in 5 ml of hexamethylphosphoramide. After the evolution of hydrogen ceases, the salt formation is completed by heating for 1 h at. After cooling to 25 ° C, 2.58 g of 1-chloromethyl-4-phenylthiobenzene is added. The temperature is raised to and the mixture is kept at this temperature for 12 hours. Upon completion of the reaction, the mixture is poured into 200 ml of water, the product is extracted with diethyl ether, the solvent is evaporated and the residue is purified twice on a silica gel column using various ethyl acetate as a eluent. fractions by thin layer chromatography. The solvent is evaporated from the middle fractions to obtain 2.4 g of the desired base in the form of a yellowish oil, giving one spot on a thin layer chromatogram. Found: C, 63.86; H, 4.24; N, 6.41; C1, 15.29; -S, 6.97. 44420 2CoOS. Calculated: C 63.30, H 4.44, N 6.13, C1 15.57, S 7.04. Example 4. 2,4-Dichloro-4-phenyl-o1- (N-imidazolyl-methyl) -dibenzyl ether (, 1: R CgHy). A mixture consisting of 2.02 g of tert-potassium silicate in 30 ml of tert-butanol is prepared at, in an az. Atmosphere. 3.86 g of 1- (2.4-. -Dichlorophenyl) -2- (N-imide-zolyl) -ethanol is added. The solution is heated at reflux for 1 hour and then cooled to 20-25 seconds. 3.03 g of 4-chloromethylbiphenyl is added and the solution is heated again at reflux for 5 hours. After cooling to 20-25 seconds, the mixture is poured into water and the base is extracted with ethyl acetate. The extract is washed with diethyl ether and the solvent is evaporated. The residue was dissolved in diethyl ether (80 ml) and left overnight. The solvent is filtered off and the filtrate is treated with nitric acid dissolved in diethyl ether. An oil is obtained, which is an extract when aged. The residue consisting of nitrate 2., 4-dichloro-4-phenyl-ot- (M-imidazolyl-methyl) -dibenzyl ether, is crystallized from ethanol or ethyl acetate. The product (4.3 g) is pure, as evidenced by thin layer chromatography and melted at 140-141 C.
Найдено,%: С 59,17, Н 4,14, N 8,61, С1 14,46.Found,%: C 59.17, H 4.14, N 8.61, C1 14.46.
14«104 1,0. HNOj. Вычислено,%; С 59,25, Н 4,35, N 8,64, С1 14,57.14 "104 1.0. HNOj. Calculated,%; C 59.25, H 4.35, N 8.64, C1 14.57.
Пример 5. К раствору 3,86г 1-(2 ,4 -дихлорфенил)-2-(И-имидазолил )-этанола в 15 мл диметилсульфоксида (высушенного над гидридом кальци ) прибавл ют 0,66 г гидрида натри в атмосфере азота, при 2О-25 С. Смесь нагревают при 50-60 С до прекргицени выделени газа. После этогоExample 5. To a solution of 3.86 g of 1- (2, 4-dichlorophenyl) -2- (i-imidazolyl) -ethanol in 15 ml of dimethyl sulfoxide (dried over calcium hydride) was added 0.66 g of sodium hydride in a nitrogen atmosphere, with 2 ° -25 ° C. The mixture is heated at 50-60 ° C until the gas is pre-hygienic. Thereafter
смесь охлаждают до 20-25°С, прибавл ют 0,5 г йодистого кали .и раствор 3,03 г 4-хлорметилбифенила в 7 мл диметилсульфоксида (высушенного над гидридом кальци ), вводимый по капе л м. Смесь перемешивают примерно в течение 20 ч при 20-25 С и после этого выливают в воду. Продукт экстрагируют этилацетатом и после этого обрабатывают, какописано.the mixture is cooled to 20–25 ° C, 0.5 g of potassium iodide is added, and a solution of 3.03 g of 4-chloromethylbiphenyl in 7 ml of dimethyl sulfoxide (dried over calcium hydride) is added dropwise. The mixture is stirred for approximately 20 h at 20-25 C and then poured into water. The product is extracted with ethyl acetate and then treated as described.
Q Выход составл ет 4,6 г.Q Output is 4.6 g.
Соли 2 ,4-дихлор-4-фенилтио-с - (N-имидазалил-метил)-дибензилового простого эфира получают путем взаимодействи свободного основани , растворенного в этаноле, со спиртовымSalts of 2, 4-dichloro-4-phenylthio-c - (N-imidazalyl-methyl) -dibenzyl ether are obtained by reacting the free base, dissolved in ethanol, with an alcohol
раствором желательной кислоты с последующей кристсшлизацией полученной соли в подход щем растворителе. Свободное основание готов т в соответствии с примером 3. with a solution of the desired acid, followed by crystallization of the resulting salt in a suitable solvent. The free base is prepared in accordance with Example 3.
0 В табл. 1 приведены растворители, используемые дл кристаллизации,данные элементарного анализа и температуры плавлени некоторых солей соединений формулы 1 где R .0 In the table. 1 shows the solvents used for crystallization, the data of elemental analysis and the melting point of some salts of the compounds of the formula 1 where R.
5 В табл. 2 приведены некоторые данные дл р да солей 2,4-дихлор-4 -фенил-ot- (N -имидазолил-метил) -дибензилового простого эфира, полученных в соответствии с приведенными примеQ рами.5 In table. 2 shows some data for a number of salts of 2,4-dichloro-4-phenyl-ot- (N-imidazolyl-methyl) -dibenzyl ether, obtained in accordance with the examples given.
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
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| IT23546/78A IT1096361B (en) | 1978-05-18 | 1978-05-18 | THERAPEUTICALLY ACTIVE REPLACED BONDS |
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| JP (1) | JPS605592B2 (en) |
| AR (1) | AR219596A1 (en) |
| AT (1) | AT372950B (en) |
| AU (1) | AU523053B2 (en) |
| CA (1) | CA1115718A (en) |
| CH (1) | CH639075A5 (en) |
| DD (1) | DD143608A5 (en) |
| DE (1) | DE2917244C2 (en) |
| DK (1) | DK153838C (en) |
| EG (1) | EG14345A (en) |
| ES (1) | ES480552A1 (en) |
| FI (1) | FI71309C (en) |
| FR (1) | FR2426047A1 (en) |
| GB (1) | GB2025395B (en) |
| GR (1) | GR68396B (en) |
| HU (1) | HU182565B (en) |
| IE (1) | IE48372B1 (en) |
| IL (1) | IL57245A (en) |
| IT (1) | IT1096361B (en) |
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| NZ (1) | NZ190412A (en) |
| PH (1) | PH14782A (en) |
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| CA1155853A (en) * | 1980-06-06 | 1983-10-25 | Joseph A. Martin | Imidazole derivatives and preparation thereof |
| EP0117811A3 (en) * | 1983-02-23 | 1987-06-03 | Sanofi S.A. | Fungicidal pharmaceutical compositions for oral administration |
| FR2541114B1 (en) * | 1983-02-23 | 1986-04-11 | Sanofi Sa | ANTIFUNGAL PHARMACEUTICAL COMPOSITIONS FOR ORAL USE CONTAINING OMOCONAZOLE |
| CA1250586A (en) * | 1984-02-02 | 1989-02-28 | Manuel Raga | 1h-imidazole derivatives and process for their production |
| DE3413365A1 (en) * | 1984-04-09 | 1985-12-19 | Merz + Co GmbH & Co, 6000 Frankfurt | SUBSTITUTED PHENYLETHYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS |
| IT1200422B (en) * | 1985-03-19 | 1989-01-18 | Ripari Gero Ist Farm Biolog | COMPOUND WITH ANTIMICROBIA ACTIVITY, ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT |
| ES2249992B1 (en) | 2004-09-13 | 2007-03-01 | Ferrer Internacional, S.A. | A PROCEDURE FOR MANUFACTURING ENANTIOMERIC COMPOUNDS OF IMIDAZOL. |
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| GB1475271A (en) * | 1975-04-30 | 1977-06-01 | Pfizer Ltd | 1-aryl-2-1-imidazolyl-alkyl ethers and thioethers and their use as antifungal agents |
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