DE10057996A1 - New diurethane-protected benzotriazole-1-carboxamidine derivatives, are highly reactive guanidylation reagents, useful e.g. in drug synthesis - Google Patents
New diurethane-protected benzotriazole-1-carboxamidine derivatives, are highly reactive guanidylation reagents, useful e.g. in drug synthesisInfo
- Publication number
- DE10057996A1 DE10057996A1 DE10057996A DE10057996A DE10057996A1 DE 10057996 A1 DE10057996 A1 DE 10057996A1 DE 10057996 A DE10057996 A DE 10057996A DE 10057996 A DE10057996 A DE 10057996A DE 10057996 A1 DE10057996 A1 DE 10057996A1
- Authority
- DE
- Germany
- Prior art keywords
- protected
- benzotriazole
- diurethane
- reagents
- tert
- Prior art date
- Legal status (The legal status 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 status listed.)
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Links
- PYLUJEDSEQRWTK-UHFFFAOYSA-N benzotriazole-1-carboximidamide Chemical class C1=CC=C2N(C(=N)N)N=NC2=C1 PYLUJEDSEQRWTK-UHFFFAOYSA-N 0.000 title abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 title description 12
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 229940079593 drug Drugs 0.000 title description 2
- 239000003814 drug Substances 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims abstract 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 150000003335 secondary amines Chemical class 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- -1 tert-butoxycarbonyl (Boc) Chemical group 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical class C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 claims description 2
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- ZZNAXOGUNJNTMP-UHFFFAOYSA-N tert-butyl N-[[(2-methylpropan-2-yl)oxycarbonylamino]-methylsulfanylmethylidene]carbamate methyl carbamimidothioate Chemical compound CSC(N)=N.C(C)(C)(C)OC(=O)NC(SC)=NC(=O)OC(C)(C)C ZZNAXOGUNJNTMP-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 150000003141 primary amines Chemical class 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 description 7
- 230000009257 reactivity Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- JEEPGQDKVCACHZ-UHFFFAOYSA-N tert-butyl n-[benzotriazol-1-yl-[(2-methylpropan-2-yl)oxycarbonylamino]methylidene]carbamate Chemical compound C1=CC=C2N(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)N=NC2=C1 JEEPGQDKVCACHZ-UHFFFAOYSA-N 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LCXGSLYZGOSULT-UHFFFAOYSA-N tert-butyl n-[[(2-methylpropan-2-yl)oxycarbonylamino]-(6-nitrobenzotriazol-1-yl)methylidene]carbamate Chemical compound C1=C([N+]([O-])=O)C=C2N(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)N=NC2=C1 LCXGSLYZGOSULT-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RBZRMBCLZMEYEH-UHFFFAOYSA-N 1h-pyrazol-1-ium-1-carboximidamide;chloride Chemical compound Cl.NC(=N)N1C=CC=N1 RBZRMBCLZMEYEH-UHFFFAOYSA-N 0.000 description 2
- AOCDQWRMYHJTMY-UHFFFAOYSA-N 5-nitro-2h-benzotriazole Chemical compound C1=C([N+](=O)[O-])C=CC2=NNN=C21 AOCDQWRMYHJTMY-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002357 guanidines Chemical class 0.000 description 2
- 238000010327 methods by industry Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- MWDUVTFOBWMHFL-UHFFFAOYSA-N tert-butyl (nz)-n-[anilino-[(2-methylpropan-2-yl)oxycarbonylamino]methylidene]carbamate Chemical compound CC(C)(C)OC(=O)NC(=NC(=O)OC(C)(C)C)NC1=CC=CC=C1 MWDUVTFOBWMHFL-UHFFFAOYSA-N 0.000 description 2
- CSOJECDGWHHWRS-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylcarbamothioyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C CSOJECDGWHHWRS-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 1
- MTAQWWUHEAXKFE-UHFFFAOYSA-N 3,5-dimethylpyrazole-1-carboxamide;nitric acid Chemical compound O[N+]([O-])=O.CC=1C=C(C)N(C(N)=O)N=1 MTAQWWUHEAXKFE-UHFFFAOYSA-N 0.000 description 1
- PZBQVZFITSVHAW-UHFFFAOYSA-N 5-chloro-2h-benzotriazole Chemical compound C1=C(Cl)C=CC2=NNN=C21 PZBQVZFITSVHAW-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- MDFRYRPNRLLJHT-UHFFFAOYSA-N methyl carbamimidate;sulfuric acid Chemical compound COC(N)=N.OS(O)(=O)=O MDFRYRPNRLLJHT-UHFFFAOYSA-N 0.000 description 1
- NNBBQNFHCVVQHZ-UHFFFAOYSA-N methyl carbamimidothioate;sulfuric acid Chemical compound CSC(N)=N.OS(O)(=O)=O NNBBQNFHCVVQHZ-UHFFFAOYSA-N 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229930010796 primary metabolite Natural products 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- UUSXNQWTGNNGSU-UHFFFAOYSA-N tert-butyl n-[n'-benzyl-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamimidoyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(NC(=O)OC(C)(C)C)=NCC1=CC=CC=C1 UUSXNQWTGNNGSU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Die vorliegende Erfindung betrifft Diurethan-geschützte 1H-Benzotriazol-1- carboxamidinderivate mit einer hohen Guanidierungsreaktivität, ein Verfahren zu ihrer Herstellung und ein Verfahren zur Umwandlung von primären und sekundären Aminen in die entsprechenden N,N'-geschützten Guanidinverbindungen.The present invention relates to diurethane-protected 1H-benzotriazole-1- carboxamidine derivatives with a high guanidation reactivity Process for their preparation and a process for the conversion of primary and secondary amines into the corresponding N, N'-protected Guanidine.
Es ist bekannt, dass die Guanidingruppe der Aminosäure Arginin in Peptiden und Proteinen in physiologische und pathophysiologische molekulare Erkennungsprozesse verwickelt ist. Ferner sind Guanidingruppen wesentliche Bestandteile der strukturell sehr unterschiedlichen primären und sekundären Metaboliten lebender Organismen. Guanidingruppen finden Anwendung als Komponenten in vielen synthetisch hergestellten Medikamenten, in der Erforschung und dem Design von Enzyminhibitoren und Rezeptorantagonisten als auch in synthetischen Verfahren an festen Trägersubstanzen. Aufgrund der zunehmenden Verwendung der synthetischen Verfahren an festen Trägersubstanzen werden nach wie vor hochwirksame Amidinierungsreagenzien benötigt.[1-3] It is known that the guanidine group of the amino acid arginine in peptides and proteins is involved in physiological and pathophysiological molecular recognition processes. Furthermore, guanidine groups are essential components of the structurally very different primary and secondary metabolites of living organisms. Guanidine groups are used as components in many synthetically produced drugs, in the research and design of enzyme inhibitors and receptor antagonists, as well as in synthetic processes on solid carriers. Due to the increasing use of synthetic methods on solid carriers, highly effective amidination reagents are still required. [1-3]
In der Vergangenheit fanden Guanidierungsreagenzien wie Cyanamid, O- Methylisoharnstoffhydrogensulfat, S-Methylisothioharnstoffhydrogensul fat, 3,5-Dimethyl-pyrazol-1-carboxamidinnitrat und 1H-Pyrazol-1- carboxamidinhydrochlorid [7] breite Anwendung. Ihre Umsetzung mit primären und sekundären Aminen führte zur Bildung von ungeschützten Mono- und insbesondere Polyguanidinderivaten. Die Aufreinigung der gebildeten ungeschützten Guanidinderivate und insbesondere die Abtrennung der nicht umgesetzten Aminvorstufe gestaltet sich jedoch als äußerst schwierig.[4,5] Die jüngsten Arbeiten auf diesem Gebiet konzentrierten sich daher hauptsächlich auf die Entwicklung von N-mono- und N,N'-bis-geschützten Guanidierungsreagenzien, um die Aufreinigung der entstehenden Mono- bzw. Bis-geschützten Guanidinverbindungen zu erleichtern. Die zusätzliche Verwendung von elektronenziehenden Schutzgruppen - wie sie z. B. in Mono- und Diurethan-geschützten Carboxamidinderivaten vorhanden sind - führt zu einer Zunahme der Elektrophilie am Amidinokohlenstoffatom und somit zu einer verstärkten Reaktivität gegenüber Aminen. Die Guanidierungsreagenzien 1 bis 4 ermöglichen eine unmittelbare Herstellung von N-mono- und N,N'-bis- geschützten Guanidinderivaten sowohl in Lösung als auch auf festen Trägersubstanzen.[8-23] In the past, guanidation reagents such as cyanamide, O-methylisourea hydrogen sulfate, S-methylisothiourea hydrogen sulfate, 3,5-dimethylpyrazole-1-carboxamide nitrate and 1H-pyrazole-1-carboxamidine hydrochloride [7] have been widely used. Their reaction with primary and secondary amines led to the formation of unprotected mono- and especially polyguanidine derivatives. However, the purification of the unprotected guanidine derivatives formed, and in particular the removal of the unreacted amine precursor, is extremely difficult. [4,5] The most recent work in this area has therefore focused mainly on the development of N-mono- and N, N'-bis-protected guanidation reagents to facilitate the purification of the resulting mono- and bis-protected guanidine compounds. The additional use of electron-withdrawing protective groups - as z. B. are present in mono- and diurethane-protected carboxamidine derivatives - leads to an increase in electrophilicity at the amidino carbon atom and thus to an increased reactivity towards amines. The guanidation reagents 1 to 4 enable an immediate production of N-mono- and N, N'-bis-protected guanidine derivatives both in solution and on solid carriers. [8-23]
Die Mono- und Diurethan-geschützten Guanidierungsreagenzien 1 bis 4 weisen aufgrund der erhöhten Elektrophilie ihres Amidinokohlenstoffatoms eine verstärkte Reaktivität gegenüber primären und sekundären Aminen auf. Jedoch haben selbst die jüngst entwickelten Guanidierungsreagenzien nicht die erwartete große Anwendung gefunden.The mono- and diurethane-protected guanidation reagents 1 to 4 exhibit due to the increased electrophilicity of their amidino carbon atom increased reactivity to primary and secondary amines on. However, even the most recently developed guanidation reagents not found the expected big application.
Der vorliegenden Erfindung lag das Ziel zugrunde, Diurethan-geschützte 1H-Benzotriazol-1-carboxamidinderivate für die Guanidierung von primären und sekundären Aminen bereitzustellen, welche die genannten Nachteile entsprechend dem Stand der Technik nicht aufweisen und sich durch eine hohe Guanidierungsreaktivität auszeichnen.The present invention was based on the goal of being protected by diurethane 1H-Benzotriazole-1-carboxamidine derivatives for guanidation of primary and to provide secondary amines which have the disadvantages mentioned according to the prior art and do not have a high guanidation reactivity.
Diese Aufgabe wurde erfindungsgemäß durch die Bereitstellung der N,N'-
Diurethan-geschützten 1H-Benzotriazol-1-carboxamidinderivate der
allgemeinen Formel I
This object was achieved in accordance with the invention by providing the N, N'-diurethane-protected 1H-benzotriazole-1-carboxamidine derivatives of the general formula I
gelöst, worin X H oder einen elektronenanziehenden Substituenten und R1 und R2 jeweils eine Urethan-Schutzgruppe, vorzugsweise eine tert- Butoxycarbonyl-(Boc)- oder Benzyloxycarbonyl-(Z)-Gruppe bedeuten. Die elektronenanziehenden Substituenten sind beschrieben in Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, J. March, 1992, S. 88, John Wiley & Sons und in Tetrahedron Letters 37, 1973, S. 3627-3630, Pergamon Press.solved, wherein XH or an electron-withdrawing substituent and R 1 and R 2 each represent a urethane protective group, preferably a tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z) group. The electron attracting substituents are described in Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, J. March, 1992, p. 88, John Wiley & Sons and in Tetrahedron Letters 37, 1973, pp. 3627-3630, Pergamon Press.
Es hat sich überraschenderweise gezeigt, dass die erfindungsgemäßen N,N'-Diurethan-geschützten 1H-Benzotriazol-1-carboxamidinderivate eine neue Klasse von hochreaktiven Guanidierungsreagenzien bilden. Die Elektrophilie des Amidinokohlenstoffatoms ist in den N,N'-Diurethan geschützten 1H-Benzotriazol-1-carboxamidinderivaten aufgrund der elektronenziehenden Boc- bzw. Z-Gruppen stark erhöht. Dies führt zu einer elektronenziehenden Boc- bzw. Z-Gruppen stark erhöht. Dies führt zu einer erhöhten Reaktivität gegenüber primären und sekundären Aminen. Zusätzlich weisen die erfindungsgemäßen N,N'-Diurethan-geschützten 1H- Benzotriazol-1-carboxamidinderivate sehr gute Abgangsgruppen auf, wodurch ihre Reaktivität bei der Umsetzung der primären und sekundären Aminen in die entsprechenden N,N'-Guanidinderivate zusätzlich erhöht wird.It has surprisingly been found that the inventive N, N'-diurethane-protected 1H-benzotriazole-1-carboxamidine derivatives form a new class of highly reactive guanidation reagents. The Electrophilicity of the amidino carbon atom is in the N, N'-diurethane protected 1H-benzotriazole-1-carboxamidine derivatives due to the electron-withdrawing Boc or Z groups greatly increased. This leads to a electron-withdrawing Boc or Z groups greatly increased. This leads to a increased reactivity to primary and secondary amines. In addition, the N, N'-diurethane-protected 1H- Benzotriazole-1-carboxamidine derivatives have very good leaving groups, which increases their reactivity in the implementation of the primary and secondary Amines in the corresponding N, N'-guanidine derivatives additionally increased becomes.
Gemäß einer bevorzugten Ausführungsform wurden die Verbindungen N,N'-Di-(tert-butoxycarbonyl)-1H-benzotriazol-1-carboxamidin und N,N'-Di- (tert-butoxycarbonyl)-6-nitro-1H-benzotriazol-1-carboxamidin bereitge stellt. Beide Verbindungen zeichnen sich durch ihre extrem hohe Reaktivität gegenüber primären und sekundären Aminen aus und sind daher sehr gut für eine quantitative Amidinierung von Aminogruppen sowohl in Lösung als auch auf festen Trägersubstanzen geeignet. Diese Tatsache ist besonders für die kombinatorische Chemie von großer Bedeutung.In a preferred embodiment, the compounds N, N'-di- (tert-butoxycarbonyl) -1H-benzotriazole-1-carboxamidine and N, N'-di- (tert-Butoxycarbonyl) -6-nitro-1H-benzotriazole-1-carboxamidine ready provides. Both compounds are characterized by their extremely high reactivity towards primary and secondary amines and are therefore very good for quantitative amidination of amino groups both in solution and also suitable on solid substrates. This fact is special of great importance for combinatorial chemistry.
Die Herstellung der erfindungsgemäßen N,N'-Diurethan-geschützten 1H- Benzotriazol-1-carboxamidin-Derivate erfolgt durch Umsetzung von einem gegebenenfalls durch einen elektronenanziehenden Substituenten sub stituiertes 1H-Benzotriazol mit einem Diurethan-geschützten Thioharnstoff oder dem entsprechenden S-Methylisothioharnstoffderivat in einem wasserfreien organischen Lösungsmittel in Gegenwart einer organischen Hilfsbase und von Quecksilber(II)chlorid. Vorzugsweise wird als Lösungsmittel ein polares aprotisches organisches Lösungsmittel, vorzugsweise Dimethylformamid oder N-Methylpyrrolidon und als organische Hilfsbase Triethylamin verwendet.The preparation of the N, N'-diurethane-protected 1H- Benzotriazole-1-carboxamidine derivatives are made by reacting one optionally by an electron-withdrawing substituent sub substituted 1H-benzotriazole with a diurethane-protected thiourea or the corresponding S-methylisothiourea derivative in one anhydrous organic solvent in the presence of an organic Auxiliary base and of mercury (II) chloride. Preferably, as Solvent a polar aprotic organic solvent, preferably dimethylformamide or N-methylpyrrolidone and as organic auxiliary base triethylamine used.
Als Diurethan-geschützte S-Methylisothioharnstoffe wurden bevorzugt N,N'-Di(benzyloxycarbonyl)- und N,N'-Di-(tert-butoxycarbonyl)-S- methylisothioharnstoffe und als Diurethan-geschützter Thioharnstoff das entsprechende N,N'-Di-(tert-butoxycarbonyl)-Derivat verwendet. Preferred as diurethane-protected S-methylisothioureas N, N'-di (benzyloxycarbonyl) - and N, N'-di- (tert-butoxycarbonyl) -S- methyl isothioureas and as a diurethane-protected thiourea corresponding N, N'-di- (tert-butoxycarbonyl) derivative used.
Vorzugsweise wurde als substituiertes 1H-Benzotriazol 6-Nitro-1H- benzotriazol und 6-Chlor-1H-benzotriazol eingesetzt.The preferred substituted 1H-benzotriazole was 6-nitro-1H- benzotriazole and 6-chloro-1H-benzotriazole used.
Die Einzelheiten der Durchführung des erfindungsgemäßen Herstellungsver fahrens bieten keine besonderen Schwierigkeiten und diese kann nach an sich bekannten Methoden und in bekannten verfahrenstechnischen Apparaturen erfolgen. Auf diese Weise werden N,N'-Diurethan-geschützte 1H-Benzotriazol-1-carboxamidinderivate erhalten. Die hohe Reinheit der erfindungsgemäßen N,N'-Diurethan-geschützten 1H-Benzotriazol-1- carboxamidinderivate wurde durch Schmelzpunktbestimmung, Dünnschichtchromatographie, HPLC, ESI-MS, 1H-NMR und 13C-NMR bestätigt.The details of the implementation of the manufacturing process according to the invention do not present any particular difficulties and these can be carried out according to methods known per se and in known process engineering apparatus. In this way, N, N'-diurethane-protected 1H-benzotriazole-1-carboxamidine derivatives are obtained. The high purity of the N, N'-diurethane-protected 1H-benzotriazole-1-carboxamidine derivatives according to the invention was confirmed by melting point determination, thin-layer chromatography, HPLC, ESI-MS, 1 H-NMR and 13 C-NMR.
Die erfindungsgemäßen N,N'-Diurethan-geschützten 1H-Benzotriazol-1- carboxoamidinderivate bilden eine neue Klasse von hochreaktiven Guanidie rungsreagenzien und finden Anwendung bei der Amidinierung von primären und sekundären Aminen sowohl in Lösung als auch auf festen Trägersub stanzen. Die Umsetzung der erfindungsgemäßen N,N'-Diurethan-geschütz ten 1H-Benzotriazol-1-carboxamidinderivate mit primären und sekundären Aminen zu N,N'-geschützten Guanidinderivaten erfolgt in Gegenwart eines organischen Lösungsmittels. Vorzugsweise wird die Umsetzung in Dichlormethan durchgeführt.The N, N'-diurethane-protected 1H-benzotriazole-1- according to the invention carboxoamidine derivatives form a new class of highly reactive guanidia reagent and are used in the amidation of primary and secondary amines both in solution and on a solid support punch. The implementation of the N, N'-diurethane protected according to the invention ten 1H-benzotriazole-1-carboxamidine derivatives with primary and secondary Amines to N, N'-protected guanidine derivatives take place in the presence of a organic solvent. Preferably the implementation in Dichloromethane performed.
Die Durchführung der erfindungsgemäßen Guanidierungsreaktion bereitet keine besonderen Schwierigkeiten und kann nach an sich bekannten Methoden und in bekannten verfahrenstechnischen Apparaturen erfolgen. Auf diese Weise werden N,N'-geschützte Guanidinderivate in extrem hoher Ausbeute (bis zu 100%) und hoher Reinheit erhalten. Durch Schmelzpunktbestimmung, Dünnschichtchromatographie, ESI-MS, 1H-NMR und 13C-NMR können die hergestellten N,N'-geschützten Guanidinderivate eindeutig charakterisiert und ihre hohe Reinheit bestimmt werden. Carrying out the guanidation reaction according to the invention is not particularly difficult and can be carried out by methods known per se and in known process engineering apparatus. In this way, N, N'-protected guanidine derivatives are obtained in extremely high yield (up to 100%) and high purity. The N, N'-protected guanidine derivatives produced can be clearly characterized and their high purity determined by melting point determination, thin layer chromatography, ESI-MS, 1 H-NMR and 13 C-NMR.
Gemäß einer bevorzugten Ausführungsform wird bei der Guanidierungs reaktion als N,N'-Diurethan-geschütztes 1H-Benzotriazol-1- carboxamidinderivat N,N'-Di-(tert-butoxycarbonyl)-1H-benzotriazol-1- carboxamidin und N,N'-Di-(tert-butoxycarbonyl)-6-nitro-1H-benzotriazol-1- carboxamidin verwendet. Mit beiden Reagenzien wird eine einfache und quantitative Umwandlung der primären und sekundären Amine in N,N'- Diurethan-geschützte Guanidinderivate erreicht.According to a preferred embodiment, the guanidation reaction as N, N'-diurethane-protected 1H-benzotriazole-1- carboxamidine derivative N, N'-di- (tert-butoxycarbonyl) -1H-benzotriazole-1- carboxamidine and N, N'-di- (tert-butoxycarbonyl) -6-nitro-1H-benzotriazole-1- carboxamidin used. With both reagents, a simple and quantitative conversion of the primary and secondary amines into N, N'- Diurethane-protected guanidine derivatives achieved.
Es ist besonders zu erwähnen, dass mit den erfindungsgemäßen Guanidie rungsreagenzien auch schwach nukleophile Amine wie z. B. Anilin in extrem hoher Ausbeute amidiniert werden. Die Guanidierung von schwach nukleophilen Aminen verlief hingegen mit den bekannten Guanidierungs reagenzien nicht zufriedenstellend, wodurch eine breite Anwendung der Guanidierung bisher verhindert wurde.It is particularly worth mentioning that with the guanidia according to the invention tion reagents also weakly nucleophilic amines such. B. aniline in extreme can be amidinated in high yield. The guanidation of weak nucleophilic amines, however, proceeded with the known guanidation reagents unsatisfactory, resulting in widespread use of the Guanidation has so far been prevented.
Die nachfolgenden Beispiele sollen die Erfindung näher veranschaulichen.The following examples are intended to illustrate the invention in more detail.
Zu einer rührenden Lösung aus 1H-Benzotriazol (357 mg, 3 mmol), N,N'-Di-
(tert-butoxycarbonyl)-Thioharnstoff (829 mg, 3 mmol) und TEA (1,38 ml,
9,9 mmol) in trockenem Dimethylformamid (6 ml) wurde bei 0°C HgCl2
(896 mg, 3,3 mmol) gegeben. Nach 12 Stunden bei Raumtemperatur
wurde die Reaktion unter vermindertem Druck konzentriert, mit EtOAc (100 ml)
verdünnt und durch einen Celite-Bett gefiltert. Das Filtrat wurde mit
H2O (20 ml), 5% aq Na2CO3 (20 ml), H2O (20 ml), Kochsalzlösung (20 ml)
gewaschen und getrocknet (Na2SO4). Das Lösungsmittel wurde entfernt
und das Produkt aus Hexan (40 ml) kristallisiert; Ausbeute: 730 mg (67
%).
Schmelzpunkt (mp) 143-144°C; homogen in der Dünnschichtchromatogra
phie (TLC) (Hexan/Methyltert-butylether/AcOH, 40 : 10 : 2) und HPLC
(linearer Gradient (12 min) aus Acetonitril/2% H3PO4 von 5 : 95 bis 80 : 20)
(tR = 11,70); ESI-MS: m/z = 362,2 [M + H]+; Mr = 361,40 berechnet für
C17H23N5O4; 1H-NMR (CDCl3; 400 MHz): δ 9,038 (s, 1H, NH), 8,381, 8,110
(2d, 2H, C4H, C7H); 7,651, 7,501 (2 t, 2H, C5H, C6H), 1,602, 1,565,
1,548 (8H, 6CH3); 13C-NMR (CDCl3; 100 MHz): d 115,285, 120,234,
126,022, 130,192 (4C, C4,5,6,7) 28,093 (6C, 6CH3).To a stirring solution of 1H-benzotriazole (357 mg, 3 mmol), N, N'-di- (tert-butoxycarbonyl) thiourea (829 mg, 3 mmol) and TEA (1.38 ml, 9.9 mmol) in dry dimethylformamide (6 ml) HgCl 2 (896 mg, 3.3 mmol) was added at 0 ° C. After 12 hours at room temperature, the reaction was concentrated under reduced pressure, diluted with EtOAc (100 ml) and filtered through a bed of Celite. The filtrate was washed with H 2 O (20 ml), 5% aq Na 2 CO 3 (20 ml), H 2 O (20 ml), brine (20 ml) and dried (Na 2 SO 4 ). The solvent was removed and the product crystallized from hexane (40 ml); Yield: 730 mg (67%).
Melting point (mp) 143-144 ° C; homogeneous in thin layer chromatography (TLC) (hexane / methyl tert-butyl ether / AcOH, 40: 10: 2) and HPLC (linear gradient (12 min) from acetonitrile / 2% H 3 PO 4 from 5: 95 to 80: 20) (t R = 11.70); ESI-MS: m / z = 362.2 [M + H] + ; M r = 361.40 calculated for C 17 H 23 N 5 O 4 ; 1 H NMR (CDCl 3 ; 400 MHz): δ 9.038 (s, 1H, NH), 8.381, 8.110 (2d, 2H, C 4 H, C 7 H); 7.651, 7.501 (2t, 2H, C 5 H, C 6 H), 1.602, 1.565, 1.548 (8H, 6CH 3 ); 13 C NMR (CDCl 3 ; 100 MHz): d 115.285, 120.234, 126.022, 130.192 (4C, C 4.5.6.7 ) 28.093 (6C, 6CH 3 ).
Zu einer rührenden Lösung aus 6-Nitro-1H-benzotriazol (630 mg, 3,5 mmol),
N,N'-Di-(tert-butoxycarbonyl)-Thioharnstoff (980 mg, 3,5 mmol)
und TEA (1,62 ml, 11,55 mmol) in trockenem Dimethylformamid (12 ml)
wurde bei 0°C HgCl2 (1,045 g, 3,85 mmol) gegeben. Nach 4 Stunden bei
Raumtemperatur wurde die Reaktion unter vermindertem Druck
konzentriert, mit EtOAc (100 ml) verdünnt und durch einen Celite-Bett
filtriert. Das Filtrat wurde mit H2O (20 ml), 5% aq Na2CO3 (20 ml), H2O
(20 ml), Kochsalzlösung (20 ml) gewaschen und getrocknet (Na2SO4). Das
Lösungsmittel wurde entfernt und das Produkt durch Flashchromatographie
(90 g Silikagel in Hexan/Methyltert-butylether, 3 : 1) gereinigt und aus
Methyltert-butylether/Hexan kristallisiert; Ausbeute: 700 mg (50%).
Schmelzpunkt (mp) 126-128°C; homogen in der Dünnschichtchromatogra
phie (TLC) (Hexan/Methyltert-Butylether/AcOH, 40 : 10 : 2) und HPLC
(linearer Gradient (12 min) aus Acetonitril/2% H3PO4 von 5 : 95 bis 80 : 20)
(tR = 11,96); ESI-MS: m/z = 497,2, [M + H]+; Mr = 406,40 berechnet für
C17H22N6O6; 1H-NMR (CDCl3; 400 MHz): δ 9,061 (s, 1H, NH) 8,531 (d, 2H,
C4H, C5H) 8,528 (s, 1H, H7); 13C-NMR (CDCl3; 100 MHz): δ 15,957,
117,055, 124,877 (3C, C4,5,7) 28,061 (6C, 6CH3).To a stirring solution of 6-nitro-1H-benzotriazole (630 mg, 3.5 mmol), N, N'-di- (tert-butoxycarbonyl) thiourea (980 mg, 3.5 mmol) and TEA (1, 62 ml, 11.55 mmol) in dry dimethylformamide (12 ml) was added at 0 ° C. HgCl 2 (1.045 g, 3.85 mmol). After 4 hours at room temperature, the reaction was concentrated under reduced pressure, diluted with EtOAc (100 ml) and filtered through a bed of Celite. The filtrate was washed with H 2 O (20 ml), 5% aq Na 2 CO 3 (20 ml), H 2 O (20 ml), brine (20 ml) and dried (Na 2 SO 4 ). The solvent was removed and the product was purified by flash chromatography (90 g silica gel in hexane / methyl tert-butyl ether, 3: 1) and crystallized from methyl tert-butyl ether / hexane; Yield: 700 mg (50%).
Melting point (mp) 126-128 ° C; homogeneous in thin layer chromatography (TLC) (hexane / methyl tert-butyl ether / AcOH, 40: 10: 2) and HPLC (linear gradient (12 min) from acetonitrile / 2% H 3 PO 4 from 5: 95 to 80: 20) (t R = 11.96); ESI-MS: m / z = 497.2, [M + H] + ; M r = 406.40 calculated for C 17 H 22 N 6 O 6 ; 1 H NMR (CDCl 3 ; 400 MHz): δ 9.061 (s, 1H, NH) 8.531 (d, 2H, C 4 H, C 5 H) 8.528 (s, 1H, H 7 ); 13 C NMR (CDCl 3 ; 100 MHz): δ 15.957, 117.055, 124.877 (3C, C 4.5.7 ) 28.061 (6C, 6CH 3 ).
Benzylamin (26 µl, 0,24 mmol) wurde zu einer rührenden Lösung aus N,N'-
Di-(tert-butoxycarbonyl)-1H benzotriazol-1-carboxamidin(72 mg, 0,2 mmol)
in trockenem CH2Cl2 (1 ml) bei Raumtemperatur gegeben. Nach 30 Minuten
wurde die Mischung mit Diisopropylether (12 ml) verdünnt und mit 0,25 M
aq KHSO4 (3 ml), H2O (2 × 2 ml) und Kochsalzlösung (1 ml) gewaschen.
Die organische Phase wurde getrocknet (Na2SO4), filtriert und konzentriert.
Das Rohprodukt wurde durch Flashchromatographie (18 g Silikagel in
Hexan/Methyltert-butylether, 4 : 1) gereinigt; Ausbeute: 70 mg (100%).
Schmelztemperatur (mp) 125-126°C; Lit.: Drake, B., Patek, M., Lebl, M.,
Synthesis, 1994, 579-582: 126-127°C; homogen in der Dünnschicht
chromatographie (TLC) (Hexan/Methyltert-butylether/AcOH, 40 : 10 : 2); ESI-
MS: m/z = 350,2 [M + H]+; Mr = 349,33 berechnet für C18H27N3O4; 1H-
NMR und 13C-NMR sind mit der zugewiesenen Struktur übereinstimmend.Benzylamine (26 µl, 0.24 mmol) became a stirring solution of N, N'-di- (tert-butoxycarbonyl) -1H benzotriazole-1-carboxamidine (72 mg, 0.2 mmol) in dry CH 2 Cl 2 (1 ml) at room temperature. After 30 minutes the mixture was diluted with diisopropyl ether (12 ml) and washed with 0.25 M aq KHSO 4 (3 ml), H 2 O (2 × 2 ml) and brine (1 ml). The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was purified by flash chromatography (18 g silica gel in hexane / methyl tert-butyl ether, 4: 1); Yield: 70 mg (100%).
Melting temperature (mp) 125-126 ° C; Lit .: Drake, B., Patek, M., Lebl, M., Synthesis, 1994, 579-582: 126-127 ° C; homogeneous in the thin layer chromatography (TLC) (hexane / methyl tert-butyl ether / AcOH, 40: 10: 2); ESI-MS: m / z = 350.2 [M + H] + ; M r = 349.33 calculated for C 18 H 27 N 3 O 4 ; 1 H-NMR and 13 C-NMR are consistent with the assigned structure.
-
A) Anilin (44 µl, 0,48 mmol) wurde bei Raumtempertur zu einer rührenden
Lösung aus N,N'-Di-(tert-butoxycarbonyl)-1H-benzotriazol-1-carboxamidin
(145 mg, 0,4 mmol) in trockenem CH2Cl2 (2 ml) bei Raumtemperatur
gegeben. Nach 2 Stunden wurde die Mischung mit Diisopropylether (12 ml)
verdünnt und mit 0,25 M aq KHSO4 (3 ml), H2O (2 × 2 ml) und Kochsalzlö
sung (1 ml) gewaschen. Die organische Phase wurde getrocknet (Na2SO4),
filtriert und konzentriert. Das Rohprodukt wurde durch Flashchromatogra
phie (18 g Silikagel in Hexan/Methyltert-butylether, 4 : 1) gereinigt;
Ausbeute: 120 mg (90%).
Schmelzpunkt (mp) 131-133°C; Lit.: Feichtinger, K., Sings, H. L., Baker, T. J., Matthews, K., Goodman, M. J., Org. Chem. 63, 1998, 8432-8439: 132-134°C; homogen in der Dünnschichtchromatographie (TLC) (Hexan/Methyltert-butylether/AcOH, 40 : 10 : 2); ESI-MS: m/z = 3336,4 [M + H]+; Mr = 335,41 berechnet für C17H25N3O4; 1H-NMR und 13C-NMR sind mit der zugewiesenen Struktur übereinstimmend.A) Aniline (44 µl, 0.48 mmol) at room temperature became a stirring solution of N, N'-di- (tert-butoxycarbonyl) -1H-benzotriazole-1-carboxamidine (145 mg, 0.4 mmol) in dry CH 2 Cl 2 (2 ml) at room temperature. After 2 hours the mixture was diluted with diisopropyl ether (12 ml) and washed with 0.25 M aq KHSO 4 (3 ml), H 2 O (2 × 2 ml) and brine (1 ml). The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was purified by flash chromatography (18 g silica gel in hexane / methyl tert-butyl ether, 4: 1); Yield: 120 mg (90%).
Melting point (mp) 131-133 ° C; Lit .: Feichtinger, K., Sings, HL, Baker, TJ, Matthews, K., Goodman, MJ, Org. Chem. 63, 1998, 8432-8439: 132-134 ° C; homogeneous in thin layer chromatography (TLC) (hexane / methyl tert-butyl ether / AcOH, 40: 10: 2); ESI-MS: m / z = 3336.4 [M + H] + ; M r = 335.41 calculated for C 17 H 25 N 3 O 4 ; 1 H-NMR and 13 C-NMR are consistent with the assigned structure. - B) N,N'-Di-(tert-butoxycarbonyl)-N''-phenylguanidin wurde wie in der oben beschriebenen Methode A) aus Anilin (44 µl, 0,48 mmol) und N,N'-Di-(tert butoxycarbonyl)-6-nitro-1H-benzotriazol-1-carboxamidin (164 mg, 0,4 mmol) hergestellt. Nach 1 Stunde wurde die Reaktionsmischung wie oben beschrieben aufgearbeitet; Ausbeute: 134 mg (100%).B) N, N'-di- (tert-butoxycarbonyl) -N "phenylguanidine was as in the above described method A) from aniline (44 ul, 0.48 mmol) and N, N'-Di- (tert butoxycarbonyl) -6-nitro-1H-benzotriazole-1-carboxamidine (164 mg, 0.4 mmol) manufactured. After 1 hour the reaction mixture became as above described worked up; Yield: 134 mg (100%).
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[7] Paquette, LA, Encyclopedia of Reagents for Organic Synthesis, Wiley, Sussex UK, 1996.
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[9] Kim, KS, Qian, L., Tetrahedron Lett. 34, 1993, 7677-7680.
[10] Verdini, AS, Lucietto, P., Fossati, G., Giordani, C., Tetrahedron Lett. 33, 1992, 6541-6542.
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[13] Tian, Z., Edwards, P., Roeske, RW, Int. J. Pept. Protein Res. 40, 1992, 119-126.
[14] Lal, B., Gangopadhyay, AK, Tetrahedron Lett. 37, 1996, 2483-2486.
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Claims (8)
worin X H oder einen elektronenanziehenden Substituenten und R1 und R2 jeweils eine Urethan-Schutzgruppe bedeuten.1. Compound of the general formula I
wherein XH or an electron-withdrawing substituent and R 1 and R 2 each represent a urethane protective group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10057996A DE10057996A1 (en) | 2000-11-23 | 2000-11-23 | New diurethane-protected benzotriazole-1-carboxamidine derivatives, are highly reactive guanidylation reagents, useful e.g. in drug synthesis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10057996A DE10057996A1 (en) | 2000-11-23 | 2000-11-23 | New diurethane-protected benzotriazole-1-carboxamidine derivatives, are highly reactive guanidylation reagents, useful e.g. in drug synthesis |
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| Publication Number | Publication Date |
|---|---|
| DE10057996A1 true DE10057996A1 (en) | 2002-06-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE10057996A Withdrawn DE10057996A1 (en) | 2000-11-23 | 2000-11-23 | New diurethane-protected benzotriazole-1-carboxamidine derivatives, are highly reactive guanidylation reagents, useful e.g. in drug synthesis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10230780A1 (en) * | 2002-07-09 | 2004-02-05 | Degussa Ag | Process for the preparation of 1-methylcyclopropylguanidine or its salts |
| WO2010074591A1 (en) * | 2008-12-24 | 2010-07-01 | Закрытое Акционерное Общество "Beptekc" | Creatine amides, a method for the production thereof and an agent exhibiting a neuroprotective action |
-
2000
- 2000-11-23 DE DE10057996A patent/DE10057996A1/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10230780A1 (en) * | 2002-07-09 | 2004-02-05 | Degussa Ag | Process for the preparation of 1-methylcyclopropylguanidine or its salts |
| WO2010074591A1 (en) * | 2008-12-24 | 2010-07-01 | Закрытое Акционерное Общество "Beptekc" | Creatine amides, a method for the production thereof and an agent exhibiting a neuroprotective action |
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