CS236550B1 - Method of esters preparation of piperazinoalkanoles of dibenzo(b,e)thiepine series and their salts with maleic acid - Google Patents
Method of esters preparation of piperazinoalkanoles of dibenzo(b,e)thiepine series and their salts with maleic acid Download PDFInfo
- Publication number
- CS236550B1 CS236550B1 CS76584A CS76584A CS236550B1 CS 236550 B1 CS236550 B1 CS 236550B1 CS 76584 A CS76584 A CS 76584A CS 76584 A CS76584 A CS 76584A CS 236550 B1 CS236550 B1 CS 236550B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- formula
- maleic acid
- salts
- thiepine
- preparation
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 13
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 239000011976 maleic acid Substances 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims abstract description 11
- 150000002148 esters Chemical class 0.000 title claims abstract description 8
- 150000003551 thiepines Chemical class 0.000 title claims abstract description 7
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 title claims description 5
- 150000003839 salts Chemical class 0.000 title abstract description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000000460 chlorine Chemical group 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 150000007513 acids Chemical class 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 150000001805 chlorine compounds Chemical class 0.000 claims abstract description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052801 chlorine Chemical group 0.000 claims abstract description 3
- 150000001414 amino alcohols Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002689 maleic acids Chemical class 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 13
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000006386 neutralization reaction Methods 0.000 abstract description 2
- 229940001470 psychoactive drug Drugs 0.000 abstract description 2
- 239000004089 psychotropic agent Substances 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- -1 3-bromopropylpropylidene Chemical group 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 5
- 239000003610 charcoal Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000000538 analytical sample Substances 0.000 description 2
- IPIVAXLHTVNRBS-UHFFFAOYSA-N decanoyl chloride Chemical compound CCCCCCCCCC(Cl)=O IPIVAXLHTVNRBS-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JJVDPWJWBAAPGG-UHFFFAOYSA-N 2-(4-propylpiperazin-1-yl)ethanol Chemical compound CCCN1CCN(CCO)CC1 JJVDPWJWBAAPGG-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 1
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Natural products COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 description 1
- BUHYMJLFRZAFBF-UHFFFAOYSA-N 3,4,5-trimethoxybenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC(OC)=C1OC BUHYMJLFRZAFBF-UHFFFAOYSA-N 0.000 description 1
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 1
- 241000272165 Charadriidae Species 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 1
- 239000003874 central nervous system depressant Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Chemical group 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000003102 mental depression Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000011120 plywood Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Vynález spadá do oboru synthetických léčiv.' Jeho předmětem je způsob přípravy esterů piperazinoalkanolů dibenzo(b,e) thiepinove řady obecného vzorce I, ve kterém R značí atom vodíku nebo •tom chloru a r' je alkyl β 1 až 9 uhlíkovými atomy nebo 3,4,5-trimethoxyfenyl, a jejich solí s kyselinou maleinovou. Látky vzorce 1 a jejich soli jsou meziprodukty přípravy psychotropních léčiv. Způsob přípravy podle vynálezu spočívá v reakci přísluSných (E)-1-(3/6,11-dihydrodibenzotb,e)thiepin-11-yliden/propyl) -4-(2-hydroxyethyl)piperazinů s chloridy nebo anhydridy přísluSných kyselin při teplotách 20 až 100 C v chloroformu nebo kyselině octové a v následující neutralizaci získaných basí kyselinou maleinovou.The invention is within the scope of synthetic drugs. ' His subject is a method of preparation dibenzo piperazinoalkanol esters (b, e) thiepine series of formula I, wherein R represents a hydrogen atom or Chlorine and r 'is alkyl β 1 to 9 carbon atoms or 3,4,5-trimethoxyphenyl, and salts thereof with maleic acid. The compounds of formula 1 and their salts are intermediates preparation of psychotropic drugs. The process of the invention is based on the invention in the reaction of the respective (E) -1- (3 / 6,11-dihydrodibenzothi, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazines with chlorides or anhydrides of the corresponding acids at at 20 to 100 ° C in chloroform or acetic acid and subsequent neutralization obtained with maleic acid.
Description
(54) Způsob přípravy esterů piperazinoalkanolů dibenzo(b,e)thiepinové řady a jejich solí s kyselinou maleinovou(54) A process for the preparation of dibenzo (b, e) thiepine series piperazinoalkanol esters and their maleic acid salts
Vynález spadá do oboru synthetických léčiv.' Jeho předmětem je způsob přípravy esterů piperazinoalkanolů dibenzo(b,e) thiepinove řady obecného vzorce I,The invention is in the field of synthetic drugs. It relates to a process for the preparation of piperazinoalkanol esters of the dibenzo (b, e) thiepine series of formula I,
ve kterém R značí atom vodíku nebo •tom chloru a r' je alkyl β 1 až 9 uhlíkovými atomy nebo 3,4,5-trimethoxyfenyl, a jejich solí s kyselinou maleinovou.wherein R is hydrogen or chlorine and r 'is alkyl of 1 to 9 carbon atoms or 3,4,5-trimethoxyphenyl, and maleic acid salts thereof.
Látky vzorce 1 a jejich soli jsou meziprodukty přípravy psychotropních léčiv. Způsob přípravy podle vynálezu spočívá v reakci přísluSných (E)-1-(3/6,11-dihydrodibenzotb,e)thiepin-11-yliden/propyl) -4-(2-hydroxyethyl)piperazinů s chloridy nebo anhydridy přísluSných kyselin při teplotách 20 až 100 C v chloroformu nebo kyselině octové a v následující neutralizaci získaných basí kyselinou maleinovou.The compounds of formula 1 and their salts are intermediates in the preparation of psychotropic drugs. The process according to the invention consists in reacting the corresponding (E) -1- (3 / 6,11-dihydrodibenzotb, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazines with the chlorides or anhydrides of the corresponding acids at temperatures 20 DEG-100 DEG C. in chloroform or acetic acid and subsequent neutralization of the bases obtained with maleic acid.
«0«0
Vynález se týká způsobu přípravy esterů piperazinoalkanolů dibenzo(b,e)thiepinové řady obecného vzorce I, oja (I), 1 — 1 CHjN_NCHjCMjOCOR’ ve kterém R značí atom vodíku nebo atom eUloru a R1 je alkyl s 1 až 9 uhlíkovými atomy nebo 3,4,5-trimethoxyfenyl, a jejich solí s kyselinou maleinovou. Jak je ve vzorci vyznačeno, příslušejí produkty (E) (trans)-řadě.The invention relates to a process for the preparation of piperazinoalkanol esters of the dibenzo (b, e) thiepine series of the general formula I, oja (I), 1 - 1 CH 3 NNCH 3 -C 1 JOCOR 'wherein R is hydrogen or fluorine and R 1 is alkyl of 1 to 9 carbon atoms; 3,4,5-trimethoxyphenyl, and maleic acid salts thereof. As indicated in the formula, the (E) (trans) -line products are assigned.
Látky podle vynálezu vzorce I a jejich soli s kyselinou maleinovou jsou meziprodukty přípravy psychotropních léčiv a také samy o sobě jsou vhodné k experimentům v oblasti therapie duševních depresí i za použití depotních injekčních forem. Jako taková, jsou látky podle vynálezu velmi málo toxické. Tak např. bis(hydrogenmalelnát) látky I, R = H,The compounds of the invention of formula I and their salts with maleic acid are intermediates for the preparation of psychotropic medicaments and are also suitable in themselves for experiments in the field of the therapy of mental depression using depot injection forms. As such, the substances according to the invention are of low toxicity. For example, bis (hydrogen maleatate) of I, R = H,
R1 = 3,4,5-trimethoxyfenyl, má při orálním podání hodnotu LD^q (akutní toxicita u myší) vyšší než 2,5 g/kg. Podobně netoxické jsou např; bis(hydrogenmaleinát) látky I, R “ Cl,R 1 = 3,4,5-trimethoxyphenyl, in oral administration has a value LD ^ Q (acute toxicity in mice) greater than 2.5 g / kg. Similarly, they are non-toxic; bis (hydrogen maleate) of substance I, R 'Cl,
R1 = 3,4,5-trimethoxyfenyl. Při orálních dávkách tšchto látek vyšších než 300 mg/kg se projevuje u myší jejich mírný centrálnš tlumivý diskoordinačni účinek. U některých látek podle vynálezu byl zjištěn antimikrobiální efekt v testech in vitro. Tak např. pro bis (hydrogenmaleinét) látky I, R = Cl, R1 = CH^, byly zjištěny tyto aktivity (uvedeny mikroorganismy a minimální inhibiční koncentrace vjjg/ml/ : Streptococcus p-haemolyticus 50, Streptococcus faecalis 100, Staphylococcus pyogenes aureus ,00, Escherichia coli 50, Mycobacterium tuberculosis 50, Trichophyton mentagrophytes 25.R @ 1 = 3,4,5-trimethoxyphenyl. At oral doses of these agents greater than 300 mg / kg, the mice exhibit a mild central depressant discoordination effect. Some of the compounds of the invention have been found to have antimicrobial effects in in vitro assays. For example, for the bis (hydrogen maleate) compounds I, R = Cl, R 1 = CH 2, the following activities have been observed (microorganisms and minimum inhibitory concentrations in µg / ml): Streptococcus p-haemolyticus 50, Streptococcus faecalis 100, Staphylococcus pyogenes aureus 00, Escherichia coli 50, Mycobacterium tuberculosis 50, Trichophyton mentagrophytes 25.
Způsob přípravy esterů vzorce 1 podle tohoto vynálezu spočívá v esterifikaci aminoalkoholů vzorce II.The process for the preparation of the esters of formula 1 according to the invention consists in the esterification of amino alcohols of formula II.
(II) ve kterém R značí totéž jako ve vzorci I, působením-reaktivních derivátů kyselin vzorce III,(II) wherein R denotes the same as in formula I, by the action of reactive acid derivatives of formula III,
R^COOH (III) ve kterém r’ značí rovněž totéž jako ve vzorci I. Jako reaktivních derivátů tšchto kyselin se použije s výhodou chloridů nebo anhydridů a reakce probíhají většinou již za teploty místnosti dostatečně rychle (lze je dokončit zahřátlm reakčních směsí k varu) ve vhodných rozpouštědlech, zejména v chloroformu. V případě esterifikaee octovým anhydridem je jak· reakční prostředí vhodná kyselina octová. Z výchozích látek vzorce II je látka s R = H známá (Holand.pat.přihl. 64/7758; Fr. pat. 88 751, 3. dodatek k pat. 1 449 569).R @ 4 COOH (III) in which r @ 1 is also the same as in formula I. The reactive derivatives of these acids are preferably chlorides or anhydrides and the reactions usually proceed at room temperature sufficiently quickly (they can be completed by heating the reaction mixtures to boiling). in suitable solvents, especially chloroform. In the case of esterified with acetic anhydride, acetic acid is suitable as the reaction medium. Of the starting materials of formula II, a substance with R = H is known (Dutch Patent Application 64/7758; Fr. Pat. 88 751, 3rd Amendment to Pat. 1,449,569).
Vzhledem k tomu, že tato látka je v citované literatuře jen chůd* charakterizována, je popia její přípravy zahrnut do příkladu. Látka vzorce II, R = Cl, je nová a její příprava je rovněž popsána v příkladu. Vzhledem k tomu, že příprava aminoalkoholů vzorce II vychází z příslušných 11-(3-brompropyliden)-1Ů,11-dihydrodibenzo(b,e)thieplnů, pro které byla pomocí IČ spektrum určena trans(E)-konfigurace na dvojné vazbě, je tato konfigurace přisuzována všem produktům, které z nich byly připraveny, tj. také esterům vzorce I. Pro některé z nich byla správnost tohoto přisouzení prověřena podrobným změřením ič spekter v oblasti mimorovinných vibrací aromatických C-H vazeb při 700 až 900 cm-1. Všechny nové látky v tomto vynálezu popsaná, a to jak konečné produkty, tak i meziprodukty, byly po stránce identity potvrzeny pomoci analys a spekter.Since this substance is only characterized in the cited literature by stilts *, it is included in the example in its preparation. The compound of formula II, R = Cl, is novel and its preparation is also described in the example. Since the preparation of amino alcohols of the formula II is based on the corresponding 11- (3-bromopropylpropylidene) -1H, 11-dihydrodibenzo (b, e) thiepines, for which the trans (E) -configuration at the double bond has been determined by IR spectrum, this configuration is attributed to all products prepared from them, ie esters of formula I. For some of them, the accuracy of this attribution was verified by a detailed measurement of the spectra in the area of extra-plane vibration of aromatic CH bonds at 700 to 900 cm -1 . All novel compounds described in this invention, both end products and intermediates, were confirmed in identity and by means of analyzes and spectra.
Další podrobnosti provedeni způsobu přípravy látek vzorce I podle tohoto vynálezu jsou uvedeny v příkladech provedení, které jsou samozřejmě jen ilustrací možnosti tohoto vynálezu, avšak není jejich účelem vynález omezovat jen na podmínky tam uvedené.Further details of the process for the preparation of the compounds of formula I according to the invention are given in the examples, which are of course only illustrative of the possibility of the invention, but are not intended to limit the invention to the conditions set forth therein.
P ří í klad, (E)-1-(3-/6,11-Dihydrodibenzo(b,e)thiepin-11-yliden/propyl)-4-(2-acetoxyethyl)piperazinExample, (E) -1- (3- / 6,11-Dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-acetoxyethyl) piperazine
Směs 5,0 g (£)-1-(3-/6,11-dihydrodibenzo(b,e)thiepin-11-yliden/própyl)-4-(2-hydroxyethyl)piperazinu, 7,0 ml acetanhydridu a 50 ml kyseliny octové se ponechá v klidu 24 h při teplotě místnosti..Potom se zředí vodou, zalkalizuje vodným amoniakem a extrahuje ze benzenem. Extrakt se vysuší uhličitanem draselným, odpaří za sníženého tlaku, Zbytek se rozpustí v 25 ml ethanolu a roztok se neutralizuje roztokem 3,2 g kyseliny maleinové v 10 ml ethanolu. Po stáni přes noc se odsátím získá 8,2 g (95 96) krystalického bis(hydrogenmaleinátu), který taje při 176 až 178 °C. Analyticky čistá látka se získá krystalizací z ethanolu, t.t. 182 až 183 °C.A mixture of 5.0 g of (E) -1- (3- / 6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazine, 7.0 ml acetic anhydride and 50 g ml of acetic acid was allowed to stand at room temperature for 24 h. The reaction mixture was then diluted with water, basified with aqueous ammonia and extracted with benzene. The extract is dried over potassium carbonate, evaporated under reduced pressure. The residue is dissolved in 25 ml of ethanol and neutralized with a solution of 3.2 g of maleic acid in 10 ml of ethanol. After standing overnight, 8.2 g (95 96) of crystalline bis (hydrogen maleate) melting at 176-178 ° C are obtained by suction. The analytically pure material was obtained by crystallization from ethanol, m.p. Mp 182-183 ° C.
Výchozí aminoalkohol byl sice v literatuře popsán (citováno), avšak při jeho přípravě je lépe postupovat déle uvedeným způsobem:Although the starting amino alcohol has been described (cited) in the literature, it is preferable to proceed in the following manner in its preparation:
Směs 25,0 g (E)-1l-(3-brompropyliden)-6,11-dihydrodibenzo(b,e)thiepinu (Bajšner M. et al., Collect. Czech. Chem. Commun. 44. 2536, 1979). 34,0 g 1-(2-hydroxyethyl)piperazinu a 65 ml chloroformu se míchá a vaří 3 h pod zpětným chladičem. Směs se zředí 100 ml chloroformu, zfiltruje se s aktivním uhlím, filtrát se promyje vodou a base se z něj vyextrahují třepáním do roztoku 25ml kyseliny chlorovodíkové ve 175 ml vody. Vodné vrstva se opět zfiltruje s aktivním uhlím, filtrát se zalkalizuje vodným amoniakem a produkt se extrahuje dichlormethanem. Extrakt se vysuší uhličitanem draselným a odpaří. Olejovitý zbytek, který představuje surový (E)-1-(3í/6,11-dihydrodibenzo(b,e)thiepin-11-ylíden/propyl-4-(2-hydroxyethyl)piperazin, se rozpustí ve 150 ml ethanolu a roztok se neutrslizuje pomocí roztoku ,6,8 g kyseliny maleinové v 60 ml ethanolu. Stáním a ochlazením vykrystaluje 28,2 g (6, 96) bis(hydrogenmaleinátu) tajícího při 154 až 155 °C. Analytický vzorek se získá rekrystalizaoí z ethanolu, t.t. ,55 až 156 °C. Čistá olejovité base se připraví v teoretickém výtěžku rozkladem této soli vodným amoniakem, extrakcí etherem a odpařením extraktu.A mixture of 25.0 g of (E) -1- (3-bromopropyl) -6,11-dihydrodibenzo (b, e) thiepine (Bajner M. et al., Collect. Czech. Chem. Commun. 44. 2536, 1979) . 34.0 g of 1- (2-hydroxyethyl) piperazine and 65 ml of chloroform are stirred and refluxed for 3 hours. The mixture is diluted with 100 ml of chloroform, filtered with charcoal, the filtrate is washed with water and the bases are extracted by shaking into a solution of 25 ml of hydrochloric acid in 175 ml of water. The aqueous layer was again filtered with charcoal, the filtrate basified with aqueous ammonia, and the product was extracted with dichloromethane. The extract was dried over potassium carbonate and evaporated. The oily residue representing crude (E) -1- (3H / 6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl-4- (2-hydroxyethyl) piperazine) was dissolved in 150 ml of ethanol and the solution 6.8 g of maleic acid in 60 ml of ethanol is crystallized by standing and cooling, 28.2 g of (96.9) bis (hydrogen maleate) melting at 154 DEG-155 DEG C. crystallize by standing and cooling. An analytical sample is obtained by recrystallization from ethanol, m.p. Mp 55 DEG -156 DEG C. Pure oily bases are prepared in theoretical yield by decomposition of the salt with aqueous ammonia, extraction with ether and evaporation of the extract.
Příklad 2 (É)-1-(3-/2-Chlor-6,11-dihydrodibenzo (b,e)thiepin-11-yliden/propyl-4-(2-aeetoxyethyl)plperazinExample 2 (E) -1- (3- / 2-Chloro-6,11-dihydrodibenzo (b, e) thiepin-11-ylidene) propyl-4- (2-ethoxyethyl) plperazine
Směs 4,2 g (E)-1-(3-/2-chlor-6,l1-dihydrodibenzo(b,e)thiepln.-11-yliden/propyl)-4-(2-hydroxyethyDpiperazinu, 5,0 ml acetanhydridu a 15 ml kyseliny octové se ponechá v klidu 48 h při teplotě místnosti a potom se zahřívá 2 h ne 100 °C. Podobným zpracováním jako v příkladu 1 se získá 5,6 g (80 %)bis(hydrogenmaleinátu) tajícího při 190 až ,92 °C. Analytický vzorek se získá rekrystaiizaci z etanolu, t.t. 192 až ,93 °C. Čistá olejovité báze se získá rozkladem této soli vodným amoniakem, extrakcí éterem a odpařením extraktu.A mixture of 4.2 g of (E) -1- (3- / 2-chloro-6,11-dihydrodibenzo (b, e) thien-11-ylidene / propyl) -4- (2-hydroxyethylpiperazine), 5.0 ml of acetic anhydride and 15 ml of acetic acid are allowed to stand at room temperature for 48 h and then heated at 100 DEG C. for 2 h. A similar treatment as in Example 1 yields 5.6 g (80%) of bis (hydrogen maleate) melting at 190 DEG. 92 DEG C. An analytical sample was obtained by recrystallization from ethanol, mp 192 DEG -93 DEG C. The pure oily base was obtained by decomposition of the salt with aqueous ammonia, extraction with ether and evaporation of the extract.
Výchozí aainoalkohol je látkou novou, kterou lze připravit dále uvedeným postupem ze známého 2-chlordibenzo(b,e)thiepin-11(6H)-onu (Rajšner M. et al., česk. Fara. H,The starting alcohol is a novel substance which can be prepared by the following procedure from the known 2-chlorodibenzo (b, e) thiepin-11 (6H) -one (Rajsner M. et al., Czech Fara. H,
451, 12É2)í451, 12 (12);
Reakcí 4,7 g hořčíku s 25,0 g cyklopropylbromidu (Meek J. S., Osuga D. T.,,Org. Syn., Coll. Vol. 2, 126, 1973) ve 100 ml tetrahydrofuranu se připraví roztok Grignardova činidla (viz Rajšner U. et al., Collefct. Czech. Commun. 44. 2536, 1979). Roztok činidla se ochladí na teplotu místnosti a za míchání se k nšau po kapkách přidá během 1 h teplý roztok 25,0 g 2-chlordibenzo(b,e)thiepin-l1(6H)-onu ve 100 ml tetrahydrofuranu. Směs se vaří 1 h pod zpětným chladičem, ochladí se ledovou lázní a za míchání se rozloží pomalým přidáním 135 ml nasyceného roztoku chloridu amonného.A solution of Grignard reagent is prepared by reacting 4.7 g of magnesium with 25.0 g of cyclopropyl bromide (Meek JS, Osuga DT, Org. Syn., Coll. Vol. 2, 126, 1973) in 100 ml of tetrahydrofuran (see Rajsner U. et. al., Collefct. Czech. Commun. 44, 2536 (1979). The reagent solution was cooled to room temperature and a warm solution of 25.0 g of 2-chlorodibenzo (b, e) thiepin-11 (6H) -one in 100 ml of tetrahydrofuran was added dropwise over 1 hour to the stirring solution. The mixture was refluxed for 1 h, cooled in an ice bath, and quenched with slow addition of 135 mL of saturated ammonium chloride solution with stirring.
Směs se extrahuje, extrakt se promyje nasyceným roztokem chloridu sodného, vysuší se síranem sodným a odpaří. Stáním odparku přes noc proběhne krystalizace a získá se 26,7 g (92 %) krystalického 2-chlor-11-cyklopropyl-6,11-dihydrodibenzo(b,e)thiepin-11-olu tajícího při 124 až 127 °C. Rekrystalizací vzorku ze směsi benzenu a petroletheru se získá analyticky čietá látka tající při 129 až 131 °C.The mixture was extracted, the extract was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Upon standing the residue crystallized overnight to give 26.7 g (92%) of crystalline 2-chloro-11-cyclopropyl-6,11-dihydrodibenzo (b, e) thiepin-11-ol melting at 124-127 ° C. Recrystallization of the sample from a mixture of benzene and petroleum ether gave an analytically pure material, melting at 129-131 ° C.
K míchanému roztoku 10,0 g předešlého alkoholu ve 170 ml kyseliny octové se během 30 minut při 10 až 15 °C přikape 85 ml 15% roztoku bromvodíku v kyselině octové. Směs se ponechá 24 h při teplotě místnosti, zfiltruje se s aktivním uhlím, filtrát se zředí 200 ml vody a extrahuje se benzenem. Extrakt se promyje vodou, vysuší se síranem hořečnatým a odpaří. Zbytek krystaluje po zředění cyklohexanem. Získá se 9,0 g (75 %) surového (E)-11(3-brompropyliden)-2-ehlor-6,11-dihydrodibenzo(b,e)thiepinu, který se překrystaluje ze směsi cyklohexanu a hexanu a získá se potom v čistém stavu jako látka tající při 109 až 111 °G.To a stirred solution of 10.0 g of the preceding alcohol in 170 ml of acetic acid was added dropwise over 30 minutes at 10-15 ° C 85 ml of a 15% solution of hydrogen bromide in acetic acid. The mixture is left at room temperature for 24 h, filtered with charcoal, the filtrate is diluted with 200 ml of water and extracted with benzene. The extract was washed with water, dried (MgSO4) and evaporated. The residue crystallizes upon dilution with cyclohexane. 9.0 g (75%) of crude (E) -11 (3-bromopropyl) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine are obtained, which is recrystallized from a mixture of cyclohexane and hexane and is then obtained in the pure state as a substance melting at 109-111 ° C.
Směs 5,0 g předešlého bromderivátu, 6,0 g 1-(2-hydroxyethyl)piperazinu a 10 ml chloroformu se míchá a vaří 3 h pod zpětným chladičem. Směs se potom zředí 50 ml chloroformu, zfiltruje se s aktivním uhlím, filtrát se promyje vodou a potom se extrahuje roztokem kyseliny chlorovodíkové (10 ml) v 60 ml vody. Vodná vrstva se zfiltruje s aktivním uhlím, filtrát se zalkalizuje vodným amoniakem a produkt se extrahuje dichlormethanem. Extrakt se vysuší uhličitanem draselným a odpaří. Olejovitý zbytek se rozpustí v 50 ml ethanolu a roztok pa neutralizuje roztokem vypočteného množství kyseliny maleinové v ethanolu. Stání a chlazení vede ke krystalizaci, kterou se získá 5,2 g (59»%)bis(hydrogen maleinátu) (E)-.,-(3-/2~chlor-6,11-dihydrodibenzo(b,e)thlepin-1-yliden/propyl)-4-(2-hydroxyethyDpiperazinu, t.t. ,63 až 165 °C.A mixture of 5.0 g of the above bromo derivative, 6.0 g of 1- (2-hydroxyethyl) piperazine and 10 ml of chloroform was stirred and refluxed for 3 h. The mixture was then diluted with 50 ml of chloroform, filtered with charcoal, the filtrate was washed with water and then extracted with a solution of hydrochloric acid (10 ml) in 60 ml of water. The aqueous layer was filtered with charcoal, the filtrate basified with aqueous ammonia, and the product was extracted with dichloromethane. The extract was dried over potassium carbonate and evaporated. The oily residue is dissolved in 50 ml of ethanol and neutralized with a solution of a calculated amount of maleic acid in ethanol. Standing and cooling results in crystallization to give 5.2 g (59%) of bis (hydrogen maleate) (E) - .- (3- / 2-chloro-6,11-dihydrodibenzo (b, e) thlepin) -1-ylidene / propyl) -4- (2-hydroxyethylpiperazine) mp, 63-165 ° C.
Krystalizaci ze směsi ethanolu a etheru se získá čistá sůl tající při ,65 až 166 °C. Rozkladem této soli vodným amoniakem a extrakcí chloroformem se získá krystalická base tající při 12, až 122 °C (benzen-petrolether). Neutralizací této base kyselinou methansulfonovou v ethanolu lze připravit krystalický dimethansulfonát tající při 206 až 208 °C (ethanol-ether).Crystallization from ethanol / ether gives a pure salt, m.p. 65-166 ° C. Decomposition of this salt with aqueous ammonia and extraction with chloroform gave a crystalline base melting at 12 to 122 ° C (benzene-petroleum ether). By neutralizing this base with methanesulfonic acid in ethanol, crystalline dimethane sulfonate melting at 206-208 ° C (ethanol-ether) can be prepared.
Příklad 3 (E)-1-(3-/6,1l-Dihydrodibenzo(b,e)thiepin-11-yliden(propyl)-4-(2-dekanoyloxyethyl)piperazinExample 3 (E) -1- (3- / 6,11-Dihydrodibenzo (b, e) thiepin-11-ylidene (propyl) -4- (2-decanoyloxyethyl) piperazine
Směs 5,0 g (E)-1-(3-/6,11-dihydrodibenzo(b,e)thiepin-11-yliden/propyl)-4-(2~hydroxyethyUpiperazinu (viz příklad 1), 5,1 g dekanoylchloridu (Fierz-David Η. E., Kuster W., Helv, Ghim.Acta 22. 82, 1939). 8 ml chloroformu a 25 ml benzenu se ponechá stát 24 h při teplotě místnosti a potom se vaří 3 h pod zpětným chladičem. Po ochlazení se rozdělí třepáním mezi zředěný vodný amoniak a benzen, benzenová vrstva se vysuší uhličitanem draselným a odpaří se za sníženého tlaku. Zbytek se neutralizuje pomocí 3,2 g kyseliny maleino vé v 35 ml ethanolu. Získá se 8,9 g (88 %) krystalického bis(hydrogenmaleinátu), t.t.A mixture of 5.0 g of (E) -1- (3- / 6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethylpiperazine (see Example 1), 5.1 g) decanoyl chloride (Fierz-David DavidE., Kuster W., Helv, Ghim.Acta 22, 82, 1939) 8 ml of chloroform and 25 ml of benzene are allowed to stand at room temperature for 24 hours and then refluxed for 3 hours. After cooling, it was partitioned by shaking between dilute aqueous ammonia and benzene, the benzene layer was dried over potassium carbonate and evaporated under reduced pressure, and the residue was neutralized with 3.2 g maleic acid in 35 ml ethanol to give 8.9 g (88 g). %) of crystalline bis (hydrogen maleate), mp
,68 až 169 °C (ethanol).68 DEG-169 DEG C. (ethanol).
Homogenní olejovité base se získá rozkladem soli vodným amoniakem, extrekcí etherem a odpařením extraktu.Homogeneous oily bases are obtained by decomposing the salt with aqueous ammonia, extracting with ether and evaporating the extract.
P ř.ll k l 'a d 4 (E)-1-(3-/2-Chlor-6,I1-dihydrodibenzo(b,e)thiepin-11-yliden/propyl)-4-(2-dekanoyloxy ethyl)piperazinEXAMPLE 4 4 (E) -1- (3- / 2-Chloro-6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-decanoyloxyethyl) piperazine
Směs 4,2 g (B)-l-(3-/2-chlor-6,11-d£hydrodibenzo(b,e)thiepin-11-yliden/propyl)-4-(2-hydroxyethyl)piperazínu (viz přiklad 1), 3,9 g dekanoylchloridu, (citováno), 6 ml chloroformu a 20 ml benzenu se zpracuje podobně jako v příkladu 3. Získá se 6,5 g (80 %)bis(hydro genmaleinátu), t.t. 178 až 179 °C (ethanol). Homogenní plejovitá base se získá rozkladem táto soli vodným amoniakem, extrakcí etherem a odpařením extraktu.A mixture of 4.2 g of (B) -1- (3- / 2-chloro-6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazine (see Example 1), 3.9 g of decanoyl chloride (cited), 6 ml of chloroform and 20 ml of benzene were treated as in Example 3. 6.5 g (80%) of bis (hydro-maleate), m.p. 178 DEG-179 DEG C. (ethanol). A homogeneous plywood base is obtained by decomposing this salt with aqueous ammonia, extracting with ether and evaporating the extract.
Příkladě (E)-i-(3-/6,11-Difaydrodibenzo(b,e)thiepin-11-yliden/propyl)-4-(2-/3,4,5-trimethoxybenzoyloxy/ethyl)piperazinExample (E) -i- (3- / 6,11-Difaydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2- / 3,4,5-trimethoxybenzoyloxy / ethyl) piperazine
Směs 5,0 g (E)-1-(3-/6,1l-dihydrodibenzo(b,e)thlepin-11yllden/propyl)-4-(2-hydroxy“ ethyl)piperazinu (viz příklad 1), 6,1 g 3,4,5-trimethoxybenzoylchloridu (Marsh J. T., Stephen H., J. Chem. Soc. 127. 1635, 1925). 25 ml benzenu a 10 ml chloroformu se ponechá 36 h v klidu při teplotě místnosti a potom se rozdělí třepáním mezi zředěný vodný amoniak a benzen. Benzenová vrstva se promyje nasyceným roztokem chloridu amonného, vysuěí se síranem hořeSnatým a odpaří za sníženého tlaku. Zbytek se neutralizuje pomocí 3,2 g kyseliny maleinové v 35 ml horkého ethanolu. Krystalizaci se získé 9,5 g (90 %)bis(hydrogenmaleinátu) tajícího při 149 až 151 °C. Rekrystalizací z ethanolu se získá zcela Sisté látka, t.t. 153 až 154 °C.A mixture of 5.0 g of (E) -1- (3- / 6,11-dihydrodibenzo (b, e) thlepin-11-yllden / propyl) -4- (2-hydroxyethyl) piperazine (see Example 1), 6, 1 g of 3,4,5-trimethoxybenzoyl chloride (Marsh JT, Stephen H., J. Chem. Soc. 127. 1635, 1925). 25 ml of benzene and 10 ml of chloroform were left to stand at room temperature for 36 hours and then partitioned by shaking between dilute aqueous ammonia and benzene. The benzene layer was washed with saturated ammonium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was neutralized with 3.2 g of maleic acid in 35 ml of hot ethanol. Crystallization yielded 9.5 g (90%) of bis (hydrogen maleate) melting at 149-151 ° C. Recrystallization from ethanol gave the pure product, m.p. 153-154 ° C.
P ř í klad 6 (E)-1-(3-/2-Chlor-6,11-dihydrodibenzo(b,e)thiepin-11yliden/propyl)-4-(2-/3,4,5~trimethoxybenzoyloxy/ethyl)piperazinExample 6 (E) -1- (3- / 2-Chloro-6,11-dihydrodibenzo (b, e) thiepine-11-ylidene / propyl) -4- (2- (3,4,5-trimethoxybenzoyloxy)) ethyl) piperazine
Směs 3,1 g kyseliny 3,4,5-trimethoxybenzoová (Mautnner ř., Org. Syn., Coll. Vol. 1, 537, 12W, 25 ml benzenu a 3,0 ml thionylchloridu se vaří 6 h pod zpětným chladičem a potom se odpaří za sníženého tlaku. Zbytek (chlorid kyseliny) se zředí 30 ml benzenu a odpařování se opakuje. Potom se přidá 3,0 g (E)-1-(3-/2chlor-6,1Í-dihydrodibenzo(b,e)thiepin-11-yliden/propyl)-4-(2hydroxyethyl)piperazinu (viz příklad 2), 15 ml benzénu a 5 ml chloroformu a směs se zpracuje podobně jako v příkladu 5. Získá se 4,7 g (80 SS) bis(hydrcgenmaleinátu) tajícího při 166 až 169 °C (ethanol).A mixture of 3.1 g of 3,4,5-trimethoxybenzoic acid (Mautnner r., Org. Syn., Coll. Vol. 1, 537, 12W, 25 ml of benzene and 3.0 ml of thionyl chloride is refluxed for 6 hours and The residue (acid chloride) is diluted with 30 ml of benzene and the evaporation is repeated and then 3.0 g of (E) -1- (3- / 2-chloro-6,11-dihydrodibenzo (b, e) are added. (thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazine (see Example 2), 15 ml of benzene and 5 ml of chloroform, and the mixture was treated as in Example 5. 4.7 g (80 SS) of bis were obtained. (hydrene maleate) melting at 166-169 ° C (ethanol).
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS76584A CS236550B1 (en) | 1984-02-02 | 1984-02-02 | Method of esters preparation of piperazinoalkanoles of dibenzo(b,e)thiepine series and their salts with maleic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS76584A CS236550B1 (en) | 1984-02-02 | 1984-02-02 | Method of esters preparation of piperazinoalkanoles of dibenzo(b,e)thiepine series and their salts with maleic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS236550B1 true CS236550B1 (en) | 1985-05-15 |
Family
ID=5340380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS76584A CS236550B1 (en) | 1984-02-02 | 1984-02-02 | Method of esters preparation of piperazinoalkanoles of dibenzo(b,e)thiepine series and their salts with maleic acid |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS236550B1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7732459B2 (en) | 2002-11-13 | 2010-06-08 | Millennium Pharmaceuticals, Inc. | CCR1 antagonists and methods of use therefor |
| US8653096B2 (en) | 2001-11-21 | 2014-02-18 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use thereof |
-
1984
- 1984-02-02 CS CS76584A patent/CS236550B1/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8653096B2 (en) | 2001-11-21 | 2014-02-18 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use thereof |
| US9663537B2 (en) | 2001-11-21 | 2017-05-30 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use |
| US7732459B2 (en) | 2002-11-13 | 2010-06-08 | Millennium Pharmaceuticals, Inc. | CCR1 antagonists and methods of use therefor |
| US7977350B2 (en) | 2002-11-13 | 2011-07-12 | Millennium Pharmaceuticals, Inc. | CCR1 antagonists and methods of use therefor |
| US8394817B2 (en) | 2002-11-13 | 2013-03-12 | Millennium Pharmaceuticals, Inc. | CCR1 antagonists and methods of use therefor |
| US9334283B2 (en) | 2002-11-13 | 2016-05-10 | Millennium Pharmaceuticals, Inc. | CCR1 antagonists and methods of use thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4110337A (en) | Triazolobenzodiazepines | |
| DE2733868C2 (en) | New 1,2,4,5-tetrahydro-3H-2-benzazepin-3-ones, processes for their preparation and medicaments containing them | |
| Gilmore Jr et al. | Seven-membered Ring Compounds. I. 7, 8, 9, 10-Tetrahydrocyclohepta [de] naphthalene | |
| Horowitz et al. | A cleavage reaction of α-Allylbenzylamines | |
| JPS6339587B2 (en) | ||
| EP0174910B1 (en) | Process for the preparation of 4-phenyl-pyrrole derivatives | |
| US3956374A (en) | Aryl-oxo-heptenoic acids | |
| EP0087655B1 (en) | Process for the preparation of acemetacin | |
| CS236550B1 (en) | Method of esters preparation of piperazinoalkanoles of dibenzo(b,e)thiepine series and their salts with maleic acid | |
| JONES | Reaction of some heterocyclic vic-dicarboxamides with alkaline hypobromite | |
| US3055888A (en) | 2-alkylmercapto-9-[2'-(n-alkylpiperidyl-2" and pyrrolidyl-2")-ethylidene-1']-thiaxanthenes | |
| US3481972A (en) | Substituted hydroxyethyl acid hydrazides | |
| EP0056617B1 (en) | Cycloheptene derivatives, process and intermediates for their preparation, and pharmceuticals containing them | |
| Speckamp et al. | Dihydroquinolones I: Reactions of substituted 4‐oxo‐1, 2, 3, 4‐tetrahydroquinoline | |
| FRONK et al. | Ethyl N-methyl-2-pyridone-4-carboxylate and derivatives | |
| EP3091000A1 (en) | Synthetic process of carprofen | |
| US4082764A (en) | Methods for the production of 4H-s-triazolo[4,3-a][1,4]benzodiazepine 5N-oxides | |
| Balenovic et al. | Synthesis of Aminomethylglyoxal Derivatives | |
| US4258211A (en) | 4-Aminoaliphatic-2,3,5,6-[dibenzobicyclo[5.1.0]octanes] and salts thereof | |
| Overberger et al. | The Synthesis of Optically Active C-Methyl-2-oxoheptamethylenimines and C-Methyl-7-aminoheptanoic Acids | |
| US4334088A (en) | 2-Alkynyl-5-indanyloxyacetic acids | |
| Kung et al. | Association phenomena. 5. Synthesis and properties of 1, 4-dipolar substituted cyclohexenes | |
| US2868836A (en) | 2, 4-dihydroxy-3-methylphenylglyoxylic acid and derivatives thereof | |
| SU501668A3 (en) | The method of obtaining derivatives of 2-aminobenzylamine | |
| DE1136709B (en) | Process for the preparation of 2-oxo-1, 2-dihydro-1, 4-benzodiazepines |