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FI73680B - PROCEDURE FOR THERAPEUTIC VERIFICATION OF 5,11-DIHYDRO-11 - / (4-METHYL-1-PIPERAZINYL) -ACETYL / -6H-PYRIDO / 2,3-B // 1,4 / BENZODIAZEPIN-6-ON. - Google Patents

  • ️Fri Jul 31 1987
PROCEDURE FOR THERAPEUTIC VERIFICATION OF 5,11-DIHYDRO-11 - / (4-METHYL-1-PIPERAZINYL) -ACETYL / -6H-PYRIDO / 2,3-B // 1,4 / BENZODIAZEPIN-6-ON. Download PDF

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Publication number
FI73680B
FI73680B FI833349A FI833349A FI73680B FI 73680 B FI73680 B FI 73680B FI 833349 A FI833349 A FI 833349A FI 833349 A FI833349 A FI 833349A FI 73680 B FI73680 B FI 73680B Authority
FI
Finland
Prior art keywords
dihydro
methyl
pyrido
benzodiazepin
piperazinyl
Prior art date
1982-09-28
Application number
FI833349A
Other languages
Finnish (fi)
Other versions
FI833349L (en
FI833349A0 (en
FI73680C (en
Inventor
Wolfgang Eberlein
Gerhard Breuer
Original Assignee
Thomae Gmbh Dr K
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1982-09-28
Filing date
1983-09-20
Publication date
1987-07-31
1983-09-20 Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
1983-09-20 Publication of FI833349A0 publication Critical patent/FI833349A0/en
1984-03-29 Publication of FI833349L publication Critical patent/FI833349L/en
1987-07-31 Publication of FI73680B publication Critical patent/FI73680B/en
1987-11-09 Application granted granted Critical
1987-11-09 Publication of FI73680C publication Critical patent/FI73680C/en

Links

  • YZPAKBGVJIVPEU-UHFFFAOYSA-N 1,2-benzodiazepin-6-one Chemical compound N1=NC=CC=C2C(=O)C=CC=C21 YZPAKBGVJIVPEU-UHFFFAOYSA-N 0.000 title claims description 9
  • -1 (4-METHYL-1-PIPERAZINYL) -ACETYL Chemical class 0.000 title claims description 8
  • 238000000034 method Methods 0.000 title claims description 7
  • 230000001225 therapeutic effect Effects 0.000 title claims description 3
  • 238000012795 verification Methods 0.000 title 1
  • 150000001875 compounds Chemical class 0.000 claims abstract description 12
  • 150000003839 salts Chemical class 0.000 claims abstract description 9
  • 150000007522 mineralic acids Chemical class 0.000 claims abstract description 6
  • 150000007524 organic acids Chemical class 0.000 claims abstract description 6
  • 235000005985 organic acids Nutrition 0.000 claims abstract description 6
  • 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
  • JCXZKUZXVQKENT-UHFFFAOYSA-N 2-(4-methylpiperazin-1-ium-1-yl)acetate Chemical compound CN1CCN(CC(O)=O)CC1 JCXZKUZXVQKENT-UHFFFAOYSA-N 0.000 claims abstract description 4
  • 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
  • 125000003884 phenylalkyl group Chemical group 0.000 claims abstract description 4
  • 125000004432 carbon atom Chemical group C* 0.000 claims abstract 3
  • 238000004519 manufacturing process Methods 0.000 claims abstract 2
  • 238000006243 chemical reaction Methods 0.000 claims description 10
  • 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
  • 239000003960 organic solvent Substances 0.000 claims description 4
  • KSSXNHGPIDAUAS-UHFFFAOYSA-N 1,4-benzodiazepin-6-one Chemical compound N1=CC=NC=C2C(=O)C=CC=C21 KSSXNHGPIDAUAS-UHFFFAOYSA-N 0.000 claims description 2
  • 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
  • 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
  • 125000004344 phenylpropyl group Chemical group 0.000 claims description 2
  • 150000002148 esters Chemical class 0.000 claims 2
  • 239000006188 syrup Substances 0.000 claims 1
  • 235000020357 syrup Nutrition 0.000 claims 1
  • 229910052744 lithium Inorganic materials 0.000 abstract description 11
  • RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 abstract description 7
  • MIRBIZDDMSFTKY-UHFFFAOYSA-N 5,11-dihydropyrido[2,3-b][1,4]benzodiazepin-6-one Chemical compound O=C1NC2=CC=CN=C2NC2=CC=CC=C12 MIRBIZDDMSFTKY-UHFFFAOYSA-N 0.000 abstract description 5
  • 239000002904 solvent Substances 0.000 abstract description 3
  • 238000006138 lithiation reaction Methods 0.000 abstract 1
  • OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
  • WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
  • VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
  • XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
  • RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
  • YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
  • MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
  • 239000000047 product Substances 0.000 description 5
  • WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
  • ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
  • 239000000203 mixture Substances 0.000 description 4
  • 229960004633 pirenzepine Drugs 0.000 description 4
  • 238000002360 preparation method Methods 0.000 description 4
  • UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
  • 125000003118 aryl group Chemical group 0.000 description 3
  • UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
  • 150000003222 pyridines Chemical class 0.000 description 3
  • 239000011541 reaction mixture Substances 0.000 description 3
  • 238000003756 stirring Methods 0.000 description 3
  • 239000000725 suspension Substances 0.000 description 3
  • QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
  • IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
  • OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
  • HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
  • XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
  • VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
  • KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
  • VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
  • 238000004440 column chromatography Methods 0.000 description 2
  • 239000012043 crude product Substances 0.000 description 2
  • QETJQVJIERQYIQ-UHFFFAOYSA-N ethyl 2-(4-methylpiperazin-1-yl)acetate Chemical compound CCOC(=O)CN1CCN(C)CC1 QETJQVJIERQYIQ-UHFFFAOYSA-N 0.000 description 2
  • 229910003002 lithium salt Inorganic materials 0.000 description 2
  • 159000000002 lithium salts Chemical class 0.000 description 2
  • 238000002844 melting Methods 0.000 description 2
  • 230000008018 melting Effects 0.000 description 2
  • BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
  • 238000000746 purification Methods 0.000 description 2
  • 238000001953 recrystallisation Methods 0.000 description 2
  • 239000000741 silica gel Substances 0.000 description 2
  • 229910002027 silica gel Inorganic materials 0.000 description 2
  • RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
  • PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
  • VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
  • PHGMLCRXRGZJCD-UHFFFAOYSA-N 3-phenylpropyl 2-(4-methylpiperazin-1-yl)acetate Chemical compound CN1CCN(CC1)CC(=O)OCCCC1=CC=CC=C1 PHGMLCRXRGZJCD-UHFFFAOYSA-N 0.000 description 1
  • YFACHVCFIDNDNQ-UHFFFAOYSA-N CC1CNCCN1CC(=O)OCC1=CC=CC=C1 Chemical compound CC1CNCCN1CC(=O)OCC1=CC=CC=C1 YFACHVCFIDNDNQ-UHFFFAOYSA-N 0.000 description 1
  • 201000004624 Dermatitis Diseases 0.000 description 1
  • 229910052770 Uranium Inorganic materials 0.000 description 1
  • 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
  • 239000008346 aqueous phase Substances 0.000 description 1
  • 208000010668 atopic eczema Diseases 0.000 description 1
  • 238000004587 chromatography analysis Methods 0.000 description 1
  • 238000007796 conventional method Methods 0.000 description 1
  • 239000006184 cosolvent Substances 0.000 description 1
  • 229940043279 diisopropylamine Drugs 0.000 description 1
  • SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical class [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 description 1
  • HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
  • 230000000694 effects Effects 0.000 description 1
  • 239000012467 final product Substances 0.000 description 1
  • 238000003818 flash chromatography Methods 0.000 description 1
  • 229910052736 halogen Inorganic materials 0.000 description 1
  • GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
  • QSOFJTPEADTCHW-UHFFFAOYSA-N hexyl 2-(4-methylpiperazin-1-yl)acetate Chemical compound CCCCCCOC(=O)CN1CCN(C)CC1 QSOFJTPEADTCHW-UHFFFAOYSA-N 0.000 description 1
  • 238000002329 infrared spectrum Methods 0.000 description 1
  • UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
  • DBYQHFPBWKKZAT-UHFFFAOYSA-N lithium;benzene Chemical compound [Li+].C1=CC=[C-]C=C1 DBYQHFPBWKKZAT-UHFFFAOYSA-N 0.000 description 1
  • 229910052757 nitrogen Inorganic materials 0.000 description 1
  • 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
  • 238000005580 one pot reaction Methods 0.000 description 1
  • 239000012074 organic phase Substances 0.000 description 1
  • 238000006053 organic reaction Methods 0.000 description 1
  • 150000002902 organometallic compounds Chemical class 0.000 description 1
  • 229910000027 potassium carbonate Inorganic materials 0.000 description 1
  • 239000002244 precipitate Substances 0.000 description 1
  • 238000000926 separation method Methods 0.000 description 1
  • 239000007787 solid Substances 0.000 description 1
  • 239000011877 solvent mixture Substances 0.000 description 1
  • 239000007858 starting material Substances 0.000 description 1
  • 238000010626 work up procedure Methods 0.000 description 1

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

1. Process for preparing 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- -pyrido[2,3-b][1,4]-benzodiazepin-6-one or the salts thereof with inorganic or organic acids, characterised in that 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one of formula I see diagramm : EP0104566,P8,F1 is reacted in a solvent conventionally used for lithiation reactions first with at least two equivalents of a lithium alkyl or lithium aryl at temperatures of between -60 and 0 degrees C and subsequently with a (4-methyl-1-piperazinyl)-acetate of general formula III see diagramm : EP0104566,P8,F2 wherein R represents an alkyl group with 1 to 10 carbon atoms, a phenyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, and the compound thus obtained is isolated and, if desired, converted into the salts thereof with inorganic or organic acids.

Description

1 736801 73680

Menetelmä valmistaa terapauttisesti vaikuttavaa 5,11-dihydro-ll-[(4-metyy1i-l-piperatsinyyli)asetyyli]-6H-pyrido[2,3-b]{1,4]— bentsodiatsepin-6-onia - Förfarande för framställning av terapeutiskt verksam 5,ll-dihydro-ll-[(4-metyl-l-piperazinyl)-acetyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-onThe process for the preparation of a therapeutically active 5,11-dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] {1,4] benzodiazepin-6-one is preferred for the preparation of 5,11-Dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

Keksinnön kohteena on menetelmä valmistaa terapeuttisesti vaikuttavaa 5.11- dihydro-11-[(4-metyy1i-l-piperatsinyyli)asetyyli]-6H-pyrido[2,3-d][1,4]bentsodiatsepin-6-onia, jonka kaava IV on cöo 0 ^CH2 (IV) 0 ch3 tai sen suoloja epäorgaanisten tai orgaanisten happojen kanssa. Tällä yhdisteellä on suuri terapeuttinen merkitys erinomaisen ulkkusten vastaisen vaikutuksensa vuoksi.The present invention relates to a process for the preparation of a therapeutically active 5,11-dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-d] [1,4] benzodiazepin-6-one of formula IV is c 0 0 CH 2 (IV) 0 ch 3 or its salts with inorganic or organic acids. This compound is of great therapeutic importance due to its excellent anti-eczema activity.

Pirentsepiinin valmistus on kuvattu patenttijulkaisussa DE-PS 17 95 183 kaksivaiheisena menetelmänä, jossa lähdetään 5.11- dihydro-6H-pyrido[2,3-b] [1,4]bentsod iatsepin-6-onista. Tällöin muunnetaan lähtöyhdiste ensin halogeeni asetyylihalo-genidilla 11-halogeeniasetyyli-5,11-dihydro-6H-pyrido12,3-oj-[1,4]bentsodiatsepin-6-oni-välituotteeksi, mikä sen jälkeen saatetaan reagoimaan N-metyylipiperatsiinin kanssa lopputuotteeksi .The preparation of pirenzepine is described in DE-PS 17 95 183 as a two-step process starting from 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one. In this case, the starting compound is first converted with halogen acetyl halide to 11-haloacetyl-5,11-dihydro-6H-pyrido12,3-o- [1,4] benzodiazepin-6-one intermediate, which is then reacted with N-methylpiperazine to give the final product.

Tähän mennessä on jo toistuvasti yritetty liittää sivuketju 2 73680 yhdessä vaiheessa (kts. esimerkiksi EP-A-0 022 174 tai DE-A-31 09 769), mutta väitettyjä menetelmiä ei voida kuitenkaan lainkaan käytännössä toteuttaa.To date, there have been repeated attempts to connect the side chain 2 73680 in one step (see, for example, EP-A-0 022 174 or DE-A-31 09 769), but the claimed methods cannot be implemented in practice at all.

Nyttemmin on havaittu, että pirentsepiini voidaan saada yksivaiheisessa reakiossa hyvällä saannolla ja yksinkertaisella tavalla siten, että kaavan I mukainen 5,ll-dihydro-6H-pyrido-[2,3-b] [1,4]bentsod iatsepin-6-onin cöoIt has now been found that pirenzepine can be obtained in a one-step reaction in good yield and in a simple manner so that the 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one of formula I

HB

dilitiumsuola saatetaan orgaanisessa liuottimessa reagoimaan lämpötilassa välillä -60°C ja huoneenlämpötila (4-metyy1i-1-piperatsinyyli)-etikkahappoesterin kanssa, jonka kaava III on /-\ 0 ch3-n_- CH2-C-OR (III) jossa R on alkyyliryhmä, fenyyli- tai fenyylialkyyliryhmä, ja haluttu yhdiste eristetään ja mahdollisesti muunnetaan suoloik-seen epäorgaanisten tai orgaanisten happojen kanssa. Fenyyli-alkyyliryhminä tulevat tällöin ensi sijassa kysymykseen fenyyli-metyyli-, fenyylietyyli- tai fenyylipropyyliryhmä ja aryyli-ryhmänä fenyyliryhmä.the dilithium salt is reacted in an organic solvent at a temperature between -60 ° C and room temperature with (4-methyl-1-piperazinyl) -acetic acid ester of formula III is / -? 0 ch 3 -n_-CH 2 -C-OR (III) wherein R is an alkyl group , a phenyl or phenylalkyl group, and the desired compound is isolated and optionally converted into its salts with inorganic or organic acids. Suitable phenylalkyl groups are primarily a phenylmethyl, phenylethyl or phenylpropyl group and an aryl group is a phenyl group.

5,11-dihydro-6H-pyrido[2,3-b] [1,4]bentsod iätsepin-6-onin5,11-Dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

IIII

3 73680 (kaava I) muuntaminen 1itiumsuolaksi onnistuu 1 itiumalkyyleillä, erityisesti kuitenkin n-butyylilitiumilla, n-butyylilitiumilla tetrametyylietyleenidiamiinin läsnäollessa, tert.-butyyliliti-umilla, litiumdi-isopropyyliamidilla tai litiumdisykloheksyyli-amidilla tai litiumaryyleillä, esimerkiksi 1itiumfenyylillä. Muuntainen 1itiumsuolaksi ja myöhempi reaktio pirentsepiiniksi tapahtuu orgaanisessa liuottimessa lämpötiloissa välillä -60°C ja 0°C, parhaiten kuitenkin -10°C:ssa. Orgaaniseksi liuottimeksi sopivat sellaiset liuottimet, joita voidaan käyttää litiumalkyyleillä tai 1itiumaryyleillä suoritettavissa reaktioissa; erityisen edullisesti käytetään tetrahydrofuraania tai eetteriä, kuten dietyylieetteriä, alifaattisia hiilivetyjä, kuten heksaania tai niiden seoksia, mahdollisesti myös kun mukana on ko-1iuottimen heksametyylifosforiamidia. Litium-alkyylin tai -aryylin lisäämisen jälkeen lisätään lyhyen ajan kuluttua stökiömetrinen määrä tai sen ylimäärä yleiskaavan III mukaista (4-metyyli-l-piperatsinyyli)-etikkahappoesteriä ja reaktioseoksen annetaan lämmetä hitaasti, esimerkiksi 2 tunnin sisällä, huoneen lämpötilaan reaktion saattamiseksi loppuun. Muodostunut kaavan IV mukainen pirentsepiini eristetään tavanomaisilla menetelmillä reaktioseoksesta. Saatu vapaa yhdiste voidaan tämän jälkeen haluttaessa muuntaa suoloikseen.Conversion of 3,73680 (formula I) to the lithium salt is possible with 1-lithium alkyls, in particular n-butyllithium, n-butyllithium in the presence of tetramethylethylenediamine, tert-butyllithium, lithium diisopropylamide or lithium dicyclohexylamide, for example lithium arylarylamide or lithium arylarylamide. The conversion to the lithium salt and the subsequent reaction to pirenzepine take place in an organic solvent at temperatures between -60 ° C and 0 ° C, but preferably at -10 ° C. Suitable organic solvents are those which can be used in reactions with lithium alkyls or lithiumaryls; particularly preferably tetrahydrofuran or an ether such as diethyl ether, aliphatic hydrocarbons such as hexane or mixtures thereof are used, optionally also in the presence of hexamethylphosphoramide of the co-solvent. After the addition of lithium alkyl or aryl, a stoichiometric amount or excess of (4-methyl-1-piperazinyl) -acetic acid ester of general formula III is added after a short time and the reaction mixture is allowed to slowly warm, for example within 2 hours, to room temperature to complete the reaction. The resulting pirenzepine of formula IV is isolated from the reaction mixture by conventional methods. The resulting free compound can then be converted to its salts, if desired.

Kaavan I mukaisen yhdisteen reaktio litiumalkyylin tai -aryylin kanssa litium-välituotteeksi ei ollut ennalta odotettavissa, koska pyridiinien ja kondensoitujen pyridiinien reaktio metal-liorgaanisten yhdisteiden kanssa johtaa tunnetusti ensi siiassa alkyylisubstituoituihin pyridi ini johdannaisiin (vrt. H.W. Gschwend ja H.R. Rodriquez, Heteroatom-Faci1itated Lithiations, Organic Reactions, 26., 27 (1979)).The reaction of a compound of formula I with a lithium alkyl or aryl to form a lithium intermediate was not expected because the reaction of pyridines and condensed pyridines with organometallic compounds is known to lead primarily to alkyl-substituted pyridine derivatives (cf. HW Gschwend, Het Rodit , Organic Reactions, 26, 27 (1979)).

Seuraavat esimerkit selventävät lähemmin keksintöä: 4 73680The following examples further illustrate the invention: 4,73680

Esimerkki 1 5.11- dihydro-ll-/(4-metyyli-l-piperatsinyyli)-asetyyli/-6H-pyrido/2,3-b//l,4/bentsodiatsepin-6-oniExample 1 5.11-Dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] 1,4] benzodiazepin-6-one

Suspensioon, joka sisältää 21 g (0,1 moolia) 5,ll-dihydro-6H-pyrido/2,3-b//l,4/bentsodiatsepin-6-onia 400 mmlrssa tetra-hydrofuraania, lisätään hitaasti tipottain ja samalla sekoittaen -10°Csssa 200 ml 1,5-molaarista n-butyylilitiumin liuosta heksaanissa. Lisäyksen jälkeen seosta sekoitetaan vielä 30 minuuttia -10°C:ssa. Tämän jälkeen lisätään tipottain liuos, joka sisältää 20,4 g (0,11 moolia) (4-metyyli-l-pipe-ratsinyyli)-etikkahappoetyyliesteriä 100 mlrssa absoluuttista tetrahydrofuraania. Panoksen annetaan lämmetä huoneen lämpötilaan ja sekoitetaan vielä 2 tuntia. Tämän jälkeen reaktioseos laimennetaan etikkahappoetyyliesterillä ja lisätään 250 ml 10-prosenttista suolahappoa. Saostunut sakka erotetaan imulla. Orgaanisen faasin erottamisen jälkeen vesifaasi säädetään alkaliseksi lisäämällä kiinteää kaliumkarbonaattia ja uutetaan useita kertoja kloroformilla. Suodatetaan aktiivi-hiilen läpi ja haihdutetaan kuiviin pyöröhaihduttimessa. Puhdistamaton tuote puhdistetaan py1väskromatograafisesti piihappogeelillä käyttämällä etikkahappoetyyliesteri/metanolia tilavuussuhteessa 9:1. Saadaan 21,1 g (60 % teoreettisesta) väritöntä tuotetta, jonka sulamispiste metanolista uudelleen-kitey ttämisen jälkeen on 222 -225°C ja joka ohu t1 e v y k ro ma -togrammin IR- ja NMR-spektrien perusteella on täysin identtinen paten11iju lkaιussa DL-PS 1 795 183, esimerkki 7, kuvatun yhdisteen kanssa.To a suspension of 21 g (0.1 mol) of 5,11-dihydro-6H-pyrido [2,3-b] 1,4] benzodiazepin-6-one in 400 ml of tetrahydrofuran is slowly added dropwise with stirring At -10 ° C 200 ml of a 1.5 molar solution of n-butyllithium in hexane. After the addition, the mixture is stirred for another 30 minutes at -10 ° C. A solution of 20.4 g (0.11 mol) of (4-methyl-1-piperazinyl) -acetic acid ethyl ester in 100 ml of absolute tetrahydrofuran is then added dropwise. The batch is allowed to warm to room temperature and stirred for a further 2 hours. The reaction mixture is then diluted with ethyl acetate and 250 ml of 10% hydrochloric acid are added. The precipitated precipitate is separated by suction. After separation of the organic phase, the aqueous phase is made alkaline by adding solid potassium carbonate and extracted several times with chloroform. Filter through activated carbon and evaporate to dryness on a rotary evaporator. The crude product is purified by flash chromatography on silica gel using acetic acid ethyl ester / methanol 9: 1 by volume. 21.1 g (60% of theory) of a colorless product are obtained, having a melting point of 222-225 [deg.] C. after recrystallization from methanol and which, on the basis of the IR and NMR spectra of the thin-layer chromatogram, are completely identical to those obtained in DL. PS 1 795 183, Example 7.

Esimerkki 2 5.11- dihydro-ll-/(4-metyyli-l-piperatsinyyj[1)asetyyli/-6H-pyrido/2,3-b//l,4/bentsodiatsepin-6-oniExample 2 5.11-Dihydro-11 - [(4-methyl-1-piperazinyl] (1) acetyl] -6H-pyrido [2,3-b] 1,4] benzodiazepin-6-one

Suspensio, joka sisältää 21 g (0,1 moolia) 5,11-dihydro-6H-Suspension containing 21 g (0.1 mol) of 5,11-dihydro-6H-

IIII

3 73680 py rido/2,3-b//l, 4/benl.oodia tsep i n-6-on ia 6 00 ml : son Letrahydro-f u r a a n i a , jäähdytetään typen alin - 6 ϋ ° C : e e n ja tämän jälkeen lisätään tipottain myös -60°('reen jäähdytetty liuos, joka sisältää 200 ml litiumdi-isopropyyliamidin, jonka valmistuksessa on käytetty 20,2 q di-isupropyy1iamiinιa ja 13 3,8 ml 1,3-molaa-rista n-bu t y y 1 i 1 i t i umin liuosta (»oksaan issa . Sekoitetaan 30 minuuttia samassa lämpötilassa ja lisätään sen jälkeen tipottain liuos, joka sisältää 26,7 g (0,10 moolia) (6-metyyli-l-piperatsinyyli)-etikkahappobentsyyliesteriä 100 ml rssa tetrahydrofuraania. Sekoittamista jatketaan vielä 2 tuntia ja annetaan tämän jälkeen lämmetä huoneen lämpötilaan. Reaktio-panoksen jatkokäsittely tapahtuu samalla tavoin kuin mitä on kuvattu esimerkissä 1. Raakatuote puhdistetaan kromatograa-fisesti piihappogeelillä käyttämällä etikkahappoetyylieste-ri/metanolia tilavuussuhteessa 3 r1. Muodostunut väritön tuote on ohutlevykromatogrammin, IR- ja MMR-spektrien perusteella täysin identtinen esimerkissä 1 kuvatun yhdisteen kanssa.3,73680 pyrido [2,3-b] 1,4 / benod.odia cepin-6-one and 6 00 ml of Letrahydro-uranium, cooled to -6 ° C under nitrogen and then a solution cooled to -60 ° (200 ml) containing 200 ml of lithium diisopropylamide prepared using 20.2 g of diisopropylamine and 13 ml of 3.8 ml of 1,3-molar n-butyl chloride is also added dropwise. A solution of 26.7 g (0.10 mol) of (6-methyl-1-piperazinyl) -acetic acid benzyl ester in 100 ml of tetrahydrofuran is added dropwise over 30 minutes at the same temperature. is continued for a further 2 hours and then allowed to warm to room temperature The reaction batch is worked up in the same manner as described in Example 1. The crude product is purified by chromatography on silica gel using ethyl acetate / methanol in a volume ratio of 3 to 1. The colorless product formed is a TLC chromatogram. and MMR spec completely identical to the compound described in Example 1.

Saanto: 21,8 g (62 % teoreettisesta).Yield: 21.8 g (62% of theory).

Esimerkki 3 5.11- dihydro-ll-/(4-metyyli-l-piperatinyyli)asetyyli/-6H-pyrido/2,3-b//l,4/bentsodlatsepin-6-oniExample 3 5.11-Dihydro-11 - [(4-methyl-1-piperatinyl) acetyl] -6H-pyrido [2,3-b] 1,4] benzodazazin-6-one

Esimerkin 1 mukaisesti saadaan 20,2 g (37 ?ά teoreettisesta) haluttua yhdistettä käyttämällä 17,2 g (0,10 moolia) 6-metyyli-1-piperatsinyylietikkahappo-metyyliesteriä.According to Example 1, 20.2 g (37% of theory) of the desired compound are obtained using 17.2 g (0.10 mol) of 6-methyl-1-piperazinyl-acetic acid methyl ester.

Vastaava tulos saadaan käyttämällä ( 4-metyy 1 i- 1 -pipera L sinyy Hiet ikkahappo-n-propyy1l- tai -2-fenyy1ietyy1iesteriä.A similar result is obtained by using (4-methyl-1-piperazine) Acetic acid n-propyl or -2-phenylethyl ester.

Esimerkki 6 5.11- dihydro-ll-/(6-metyyli-l-piperatsinyyli)asetyyli/-6H-pyrido/2,3-b//l,4/bentsodiatsepin-6-oni 6 7 3 6 8 0Example 6 5.11-Dihydro-11 - [(6-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] 1,4] benzodiazepin-6-one 6 7 3 6 8 0

Esimerkin 1 mukaisesti saatetaan reagoimaan 21 g (0,1 moolia) 5.11- dihdro-6H- pyndo/2,3-0//1,4/bent sod iät su pin -6-oni a ja 36 g (0,15 moolia) (4-metyyli-l-piperatsinyyli)-etikkahappo-heksyyliesteriä. Pylväskromatograafisen puhdistamisen jälkeen saadaan 11,9 g (34,7 % teoreettisesta) väritöntä tuotetta, jonka sulamispiste metanolista uudelleenkiteyttämisen jälkeen on 222 - 224°C ja joka spektroskooppisten arvojen perusteella on täysin identtinen esimerkissä 1 kuvatun yhdisteen kanssa.According to Example 1, 21 g (0.1 mol) of 5.11-dihydro-6H-pyndo [2,3-O] [1,4] benthosin-pin-6-one and 36 g (0.15 mol) are reacted. ) (4-Methyl-1-piperazinyl) -acetic acid hexyl ester. Purification by column chromatography gives 11.9 g (34.7% of theory) of a colorless product, melting at 222-224 ° C after recrystallization from methanol, which is completely identical in spectroscopic values to the compound described in Example 1.

Esimerkki 5 5.11- dihydro-ll-/(4-metyyli-l-piper.itsinyyli)asetyyli/-6H-pyrido/2,3-b//l,4/bentsodiatsepin-6-oniExample 5 5.11-Dihydro-11 - [(4-methyl-1-piperizinyl) acetyl] -6H-pyrido [2,3-b] 1,4] benzodiazepin-6-one

Esimerkin 1 mukaisesti saatetaan reagoimaan keskenään 21 g (0,1 moolia) 5,11-dihydro-6-H-pyr ido/2 , 3-b// 1,4/bentsodi-atsepin-6-onia ja 41,4 g (0,15 moolia) (4-metyyli-l-piperatsinyy-li)-etikkahappo-3-fenyylipropyyliesteriä. Pylväskromatograafisen puhdistamisen jälkeen saadaan 14,5 g (41,4 % teoreettisesta) väritöntä tuotetta, joka metanolista uude 11 eenk i t ei y 11 am i sen jälkeen sulaa 222 - 225°C:ssa ja joka spektroskooppisten arvojen perusteella on täysin identtinen esimerkissä 1 kuvatun yhdisteen kanssa.According to Example 1, 21 g (0.1 mol) of 5,11-dihydro-6-H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 41.4 g are reacted with each other. (0.15 mol) of (4-methyl-1-piperazinyl) -acetic acid 3-phenylpropyl ester. Purification by column chromatography gives 14.5 g (41.4% of theory) of a colorless product which does not melt at 222-225 ° C from methanol and which is completely identical in spectroscopic values to that described in Example 1. with the compound.

Esimerkki 6 5.11- dihydro-ll-/(4-metyyli-I-piperatsinyyli )asetyyli/-6H-pyrido/213-b//l,4/bentsodiatsepin-6-oniExample 6 5.11-Dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [213-b] 1,4] benzodiazepin-6-one

Suspensioon, joka sisältää 21 g (0,1 moolia) 5 , ll-dihydro-5H-pyrido/2,3-b//1,4/bentsodiatsepin-6-onia 400 ml:ssa tetra-hydrofuraan ia, lisätään hitaasti tipottain ja samalla sekoittaen -10°C:ssa 150 ml noin 2-molaarista fenyylilitiumin liuosta bentseenin ja eetterin seoksessa (75/25). Lisäyksen jälkeen seosta sekoitetaan vielä 30 minuuttia -10°C:ssa. Tämän jälkeen lisätään tipottain liuos, joka sisältää 20,4 g (0,11 moolia) (4-metyyli-l-piperatsinyyli)-etikkahappoetyyliesteriä 100To a suspension of 21 g (0.1 mol) of 5,11-dihydro-5H-pyrido [2,3-b] [1,4] benzodiazepin-6-one in 400 ml of tetrahydrofuran is slowly added dropwise and while stirring at -10 ° C 150 ml of a solution of about 2 molar phenyllithium in a mixture of benzene and ether (75/25). After the addition, the mixture is stirred for another 30 minutes at -10 ° C. A solution of 20.4 g (0.11 mol) of (4-methyl-1-piperazinyl) -acetic acid ethyl ester 100 is then added dropwise.

IIII

7 73680 mlrssa absoluutt tctrahydrofuraan ia . I’anuksen annetaan lämmetä huoneen lämpötilaan ja sekoitetaan vielä ? tuntia. Jatkokäsittely tapahtuu esimerkin 1 mukaisesti, Saadaan 11,3 g (32,2 % teoreettisesta) väritöntä tuotetta, joka spektroskooppisten a r v u j e n p e r u s t e e 1 la ii π I a y s i n identtinen esimerkissä 1 saadun yhdisti?en kanssa.7 73680 ml of absolute tetrahydrofuran. Letananus be allowed to warm to room temperature and stir further? hours. Further work-up is carried out according to Example 1. 11.3 g (32.2% of theory) of a colorless product are obtained which is identical to the compounds obtained in Example 1 in terms of spectroscopic a r v u e e p e r u s t e e 1 la ii π I a y s i

Esimerkk i 7Example i 7

Tetrahyd ro f uraanin asemesta voidaan esimerkissä 1 käyttää edullisesti myös muita liuottimia tai vastaavasti liuotin-seoksia, joita tavanomaisesti käytetään litiumalkyylien tai litiumaryvlien kanssa suoritettavissa reaktioissa.Instead of tetrahydrofuran, other solvents or solvent mixtures, respectively, which are customarily used in the reactions with lithium alkyls or lithium anvils, can also be advantageously used in Example 1.

Seuraa vaan taulukkoon on koottu eräitä esimerkkejä: (Pa inomäärät ovat samat kuin mitä on annettu esimerk is s;i 1).Follow but the table summarizes some examples: (The amounts are the same as given in Example 1; 1).

Liuotin Saanto (q) teorettisestaSolvent Yield (q) from theoretical

Glykoli-dimetyylieetteri 15,8 44Glycol dimethyl ether 15.8 44

Dioksaani/glykolidimo- tyylieetteri(l:l) 9,7 27Dioxane / glycol dimethyl ether (1: 1) 9.7 27

Heksaani/tetrametyy li- etyleenidiomiini (2:1) 5,8 18Hexane / tetramethylethylenediamine (2: 1) 5.8 18

Claims (5)

7 3 6 8 07 3 6 8 0 1. Menetelmä valmistaa terapeuttisesti vaikuttavaa 5,11-dihydro-ll-[(4-metyyli-l-piperatsinyyli)asetyyli]-6H-pyrido{2,3-d] [1,4] — bentsodiatsepin-6-onia, jonka kaava IV on cöo Λ 0 ^«2 (IV) 0 CH3 tai sen suoloja epäorgaanisten tai orgaanisten happojen kanssa, tunnettu siitä, että kaavan I mukainen 5,1l-dihydro-6H-pyrido[2,3-b] [1,4]bentsodiatsepin-6-on in CCO H diiitiumsuola saatetaan orgaanisessa lieottimessa reagoimaan lämpötilassa välillä -60°C ja huoneenlämpötila {4-metyyli-i-piperatsinyyli)-etikkahappoesterin kanssa, jonka kaava III on /—S J CH3-N^_J - CH2-C-0R (III) II 9 73680 jossa R on alkyyliryhmä, fenyyli- tai fenyylialkyyliryhmä, ja halutta yhdiste eristetään ja mahdollisesti muunnetaan suoloik-seen epäorgaanisten tai orgaanisten happojen kanssa.A process for preparing a therapeutically active 5,11-dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido {2,3-d] [1,4] benzodiazepin-6-one, which Formula IV is c 6 O-O 2 (IV) O CH 3 or its salts with inorganic or organic acids, characterized in that the 5,1'-dihydro-6H-pyrido [2,3-b] [1,4 The benzodiazepin-6-one CCO H dithium salt is reacted in an organic solvent at a temperature between -60 ° C and room temperature with (4-methyl-1-piperazinyl) -acetic acid ester of formula III -SJ CH 3 -N 2 -J-CH 2 -. C-OR (III) II 9 73680 wherein R is an alkyl group, a phenyl or phenylalkyl group, and the desired compound is isolated and optionally converted into salts with inorganic or organic acids. 2. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että reaktio suoritetaan -10°C:ssa.Process according to Claim 1, characterized in that the reaction is carried out at -10 ° C. 3. Patenttivaatimuksen 1 ja 2 mukainen menetelmä, tunnet-t u siitä, että esterinä käytetään sellaista yleiskaavan III mukaista esteriä, jossa R on alkyyliryhmä, jossa on 1 - 4 hiili-atomia tai fenyylimetyyli-, fenyylietyyli- tai fenyy1ipropyyli-ryhmä.Process according to Claims 1 and 2, characterized in that the ester used is an ester of the general formula III in which R is an alkyl group having 1 to 4 carbon atoms or a phenylmethyl, phenylethyl or phenylpropyl group. 1. Förfarande för framställning av terapeutiskt verksam 5,11-dihydro-11-[(4-mety1-1-piperazinyl) acetyl]-6H-pyrido[2,3-b]-t1,4]benzodiazepin-6-on med formeln IV cCo A 0 fH2 UV) N O t CH3 eller dess salter med oorganiska eller organiska syror, k ä n -netecknat därav, att ett dilitiumsalt av 5,11-dihydro-A compound for the therapeutic treatment with 5,11-dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] -t1,4] benzodiazepin-6-one Form IV IV cCo A 0 fH2 UV) NO t CH3 or a salt of an organic or organic syrup, whether or not containing 5,11-dihydro-

FI833349A 1982-09-28 1983-09-20 Process for the preparation of therapeutically active 5,11-dihydro-11- [(4-methyl-1-piperazinyl) -acetyl] -6H-pyrido / 2,3-b // 1,4 / benzodiazepin-6-one. FI73680C (en)

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DE3235795 1982-09-28

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