EP1525195A2 - Verfahren zur herstellung von phenylalanin-derivaten - Google Patents
Verfahren zur herstellung von phenylalanin-derivatenInfo
- Publication number
- EP1525195A2 EP1525195A2 EP03771103A EP03771103A EP1525195A2 EP 1525195 A2 EP1525195 A2 EP 1525195A2 EP 03771103 A EP03771103 A EP 03771103A EP 03771103 A EP03771103 A EP 03771103A EP 1525195 A2 EP1525195 A2 EP 1525195A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- cyanophenylalanine
- reaction
- halide
- tipps
- protected
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
Definitions
- the invention relates to an improved process for the preparation of 3-amidino or 3-guanidinophenylalanine derivatives, in particular of triisopropylphenyl-sulfonyl-substituted 3-amidino or 3-guanidino-phenylalanine derivatives.
- the present invention relates to novel urokinase inhibitors of the general formula I derived from 3-amidino- or 3-guanidinophenylalanine, X
- X is an amidino or guanidino group
- R 1 is a group of the formula
- R 2 is a phenyl radical optionally substituted, for example, with C 6 -C 6 alkyl, C 6 -C 6 alkoxy, hydroxyl, carboxyl, sulfonyl, nitro, cyano, oxo or / and halogen-substituted phenoxy or benzyloxycarbonyl radical
- R 2 is a phenyl radical optionally substituted, for example, with C 6 -C 6 alkyl, C 6 -C 6 alkoxy, hydroxyl, carboxyl, sulfonyl, nitro, cyano, oxo or / and halogen, such as, for example, phenyl, 4-methylphenyl, 2, 4,6-trimethylphenyl, 2,4,6-triisopropylphenyl, 4-methoxy-2,3,6-trimethylphenyl,
- R 3 is H or branched or unbranched C, -C 4 alkyl and n is 0 or 1,
- ZN or CR 9 means, wherein R 9 is H or branched or unbranched CC ⁇ alkyl, and their preparation.
- the compounds can also be used as salts, preferably as physiologically acceptable acid salts, e.g. as salts of mineral acids, particularly preferably as hydrochlorides, or as salts of suitable organic acids.
- Z represents CH are also preferred.
- the compound of the formula (I) is particularly preferably N ⁇ - (2,4,6-triisopropylphenylsulfonyl) -3-amidino- (D, L) -phenylalanine-4-ethoxycarbonyl-piperazide, N ⁇ - (2 , 4,6-Triisopropyl-phenylsulfonyl) -3- guanidino- (D, L) -phenylalanine-4-ethoxycarbonyl-piperazide, umdiel_ enantiomers thereof or pharmaceutically acceptable salts of these compounds.
- an N-acyl-protected amino malonic acid diester in particular an N-acetyl-protected amino malonic acid diester, such as, for example, diethyl acetamido-malonic acid, is used.
- the use of the acetyl-estimated diester is preferred since the corresponding acetylphenylalanine can be converted into isomerically pure intermediates in the further synthesis.
- the starting materials 3-cyanobenzyl bromide and the N-protected aminomalonate are commercially available and can be converted into an N-protected 3-cyanophenylalanine in high yield.
- a sterically hindered phenylsulfonyl halide in particular TIPPS-CI
- an essentially qualitative separation of the undesired phenylsulfonyl hydroxide, in particular TIPPS-OH is achieved in a simple manner.
- Suitable substituents on the phenylsulfonyl halide are, for example, one or more in particular C T -Cg alkyl radicals, which in turn can be substituted one or more times, for example with halogen (eg trichloromethyl, trifluoromethyl), C 1 -C 6 alkoxy radicals or / and halogens.
- halogen eg trichloromethyl, trifluoromethyl
- 3-cyanophenylalanine in particular the (L) -3-cyanophenylalanine, becomes an N-protected derivative, for example a tBOC protected derivative.
- the reaction then takes place with a piperazine derivative, for example ethoxycarbonylpiperazide, to form an N-protected 3-cyanophenylalanine piperazide.
- this product is then reacted with an optionally substituted, for example a sterically hindered, phenylsulfonyl halide, in particular TIPPS-CI.
- This reaction does not take place via the formation of the by-product TIPPS-OH and therefore does not require any additional purification steps for the desired product.
- 3-cyanophenylalanine in particular (L) -3-cyanophenylalanine
- a quaternary ammonium hydroxide compound such as, for example, benzyltrimethylammonium hydroxide (Triton B)
- Triton B benzyltrimethylammonium hydroxide
- This product is then treated with an optionally substituted, e.g. a sterically hindered phenylsulfonyl halide, in particular TIPPS-CI, without significant formation of the by-product TIPPS-OH to the desired product TIPPS-3-cyanophenylalanine.
- Preferred phenylsulfonyl halides are those given under measure (b) above.
- 3-cyanophenylalanine in particular (L) -3-cyanophenylalanine
- a trialkylsilane compound Compounds in which the alkyl radicals are identical or different and each have 1 to 20, preferably 1 to 4, carbon atoms are preferably used as the trialkylsilane compound. Trimethylsilane is particularly preferably used.
- the reaction is advantageously carried out in an anhydrous solvent, for example in dichloromethane.
- the free amino acid 3-cyanophenylalanine is preferably suspended in the solvent, for example in dichloromethane, with an excess of trialkylsilane compound, for example 2 to 4, in particular 2.5 to 3, equivalents thereof.
- the water-sensitive trialkylsilyl ester forms as an intermediate as protection against dimerization and through the simultaneous silylation of the amino group increases the nucleophilicity, which accelerates the subsequent reaction with an optionally substituted phenylsulfonyl halide.
- Preferred phenylsulfonyl halides are those given under measure (3) b above.
- the 3-cyanophenylalanine trialkylsilyl ester formed as an intermediate is then reacted with an optionally substituted phenylsulfonyl halide, in particular with triisopropylphenylsulfonyl chloride (TIPPS-CI) to give the desired product TIPPS-3-cyanophenylaIanine.
- a base for example diisopropylethylamine (DIPEA), is advantageously added.
- DIPEA diisopropylethylamine
- Figure 1 shows a first embodiment of the method according to the invention, comprising the use of measure (a), i.e. Use of 3-cyanobenzyl bromide and acetamidomalonate diethyl ester as starting materials.
- measure (a) i.e. Use of 3-cyanobenzyl bromide and acetamidomalonate diethyl ester as starting materials.
- the reaction mixture in the reaction of (L) -3-cyanophenylalanine and TIPPS-CI can be worked up in an aqueous medium (measure (b)).
- FIG. 2 shows a further embodiment of the method according to the invention according to measure (c).
- a solution of (L) -3-cyanophenyl-alanine is reacted with di-tert-butyl pyrocarbonate (BOC 2 O) under Schotten-Baumann conditions to give the corresponding BOC-protected amino acid (BOC-L-Phe (3- CN) -OH, which is converted into the corresponding amide BOC-L-Phe (3-CN) -Pip with N-ethoxycarbonylpiperazine and a suitable coupling reagent (such as DCC, HBTU, PyBOP or other reagents commonly used in peptide chemistry) -COOEt
- strong acids eg trifluoroacetic acid, HCl gas in dioxane or methanol
- the resulting free amino group can be converted with the addition of organic bases (e.g. triethylamine or diisopropylethylamine) in an anhydrous solvent with triisopropylphenylsulfonyl chloride (TIPPS-CI) to the corresponding sulfonamide TIPPS-L-Phe (3-CN) -Pip-COOEt.
- organic bases e.g. triethylamine or diisopropylethylamine
- TIPPS-CI triisopropylphenylsulfonyl chloride
- Figure 3 shows a further embodiment of the method according to measure (d).
- the free amino acid L-3CN-Phe is dissolved in methanol together with an equivalent of an ammonium hydroxide compound, for example benzyltrimethylammonium hydroxide, and the solvent is then stripped off in vacuo.
- an ammonium hydroxide compound for example benzyltrimethylammonium hydroxide
- the mixture is rotated again with toluene, since water forms an azeotrope with toluene.
- the resulting colorless oil is then soluble in dichloromethane.
- the reaction with TIPPS-CI (slow addition with cooling) with the addition of a tertiary amine, for example diisopropylethylamine takes place quantitatively without any noteworthy side reactions within a few hours.
- FIG. 4 shows a further embodiment of the method according to the invention in accordance with measure (e).
- the free amino acid L-3-CN-Phe is suspended together with an excess of trimethylsilane in dichloromethane and refluxed for 1.5 hours with stirring.
- the extremely water-sensitive trimethylsilyl ester forms as a protection against dimerization.
- the simultaneous silylation of the amino group increases the nucleophilicity, which accelerates the subsequent reaction with TIPPS-CI.
- the reaction solution is then cooled in an ice bath and DIPEA is added as the base. TIPPS-CI can be added all at once without special precautions (e.g. no loosening or dripping is necessary).
- the reaction solution is stirred at 0 ° C. for 30 minutes and then at room temperature for 1 to 2 hours. The solvent can then be removed in vacuo. The residue is stirred in water for 5 minutes to split off the silylester and then partitioned between 10 ml of ethyl acetate + 30 ml of ether and 5% KHSO 4 .
- the organic phase is washed twice with acid and twice with distilled water, dried and the solvent removed in vacuo.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10233919 | 2002-07-25 | ||
DE10233919 | 2002-07-25 | ||
DE10238048A DE10238048A1 (de) | 2002-07-25 | 2002-08-20 | Verfahren zur Herstellung von Phenylalanin-Derivaten |
DE10238048 | 2002-08-20 | ||
PCT/EP2003/008230 WO2004011449A2 (de) | 2002-07-25 | 2003-07-25 | Verfahren zur herstellung von phenylalanin-derivaten |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1525195A2 true EP1525195A2 (de) | 2005-04-27 |
Family
ID=31189298
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03771103A Withdrawn EP1525195A2 (de) | 2002-07-25 | 2003-07-25 | Verfahren zur herstellung von phenylalanin-derivaten |
Country Status (4)
Country | Link |
---|---|
US (1) | US7247724B2 (de) |
EP (1) | EP1525195A2 (de) |
AU (1) | AU2003253326A1 (de) |
WO (1) | WO2004011449A2 (de) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100701811B1 (ko) | 2002-05-29 | 2007-04-02 | 머크 앤드 캄파니 인코포레이티드 | 탄저병의 치료 및 치사 인자의 억제에 유용한 화합물 |
DE10323898A1 (de) | 2003-05-26 | 2004-12-23 | Wilex Ag | Hydroxyamidin- und Hydroxyguanidin-Verbindungen als Urokinase-Hemmstoffe |
JP2007537256A (ja) | 2004-05-11 | 2007-12-20 | メルク エンド カムパニー インコーポレーテッド | N−スルホン化アミノ酸誘導体調製のためのプロセス |
DE102004045720A1 (de) * | 2004-09-21 | 2006-03-23 | Wilex Ag | Stabile Dosierungsform von Phenylalanin-Derivaten |
DE102004057195A1 (de) * | 2004-11-26 | 2006-06-01 | Wilex Ag | Kristalline Modifikationen von N-Alpha-(2,4,6-Triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanin-4-ethoxycarbonylpiperazid und/oder Salzen davon |
WO2021181157A1 (en) | 2020-03-10 | 2021-09-16 | Redhill Biopharma Ltd. | Treatment of coronavirus infection |
US11471448B2 (en) | 2020-12-15 | 2022-10-18 | Redhill Biopharma Ltd. | Sphingosine kinase 2 inhibitor for treating coronavirus infection in moderately severe patients with pneumonia |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5518735A (en) * | 1990-11-15 | 1996-05-21 | Pentapharm Ag | Meta-substituted phenylalanine derivatives |
CA2338073C (en) * | 1998-07-20 | 2010-09-21 | Wilex Biotechnology Gmbh | Novel urokinase inhibitors |
DE10117381A1 (de) | 2001-04-06 | 2002-10-10 | Wilex Biotechnology Gmbh | Herstellung polyklonaler, monospezifischer Antikörper gegen die uPAR-Varianten del4, del5 und del4+5 sowie deren Verwendung für diagnostische und therapeutische Zwecke |
-
2003
- 2003-07-25 WO PCT/EP2003/008230 patent/WO2004011449A2/de not_active Application Discontinuation
- 2003-07-25 AU AU2003253326A patent/AU2003253326A1/en not_active Abandoned
- 2003-07-25 US US10/522,218 patent/US7247724B2/en not_active Expired - Lifetime
- 2003-07-25 EP EP03771103A patent/EP1525195A2/de not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO2004011449A3 * |
Also Published As
Publication number | Publication date |
---|---|
US7247724B2 (en) | 2007-07-24 |
WO2004011449A3 (de) | 2004-04-08 |
US20050245757A1 (en) | 2005-11-03 |
WO2004011449A2 (de) | 2004-02-05 |
AU2003253326A1 (en) | 2004-02-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0885204B1 (de) | Neue arylglycinamidderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende pharmazeutische zusammensetzungen | |
DE69629789T2 (de) | Aminoalkohol Derivate und ein Verfahren zu ihrer Herstellung | |
CH635066A5 (de) | Verfahren zur herstellung cyclischer aminosaeuren. | |
EP1525195A2 (de) | Verfahren zur herstellung von phenylalanin-derivaten | |
EP0206993A1 (de) | Neue Sulfonsäureester | |
DE69909165T2 (de) | Verfahren zur Herstellung von N-Glycyltyrosin | |
EP0094633B1 (de) | Spiro-2-aza-alkan-3-carbonitrile, Verfahren zu ihrer Herstellung und ihre Verwendung | |
EP0217018B1 (de) | Verfahren zur Herstellung von 3-Aminoacrylsäureestern | |
DE60210696T2 (de) | Optisch aktive 4-(tert-Butoxycarbonyl)piperazin Derivate und Verfahren zu ihrer Herstellung | |
DE1239692B (de) | Verfahren zur Herstellung von 3-(alpha-Arylalkyl)-sydnoniminen, ihren Salzen und N-Acylderivaten | |
EP1073634B1 (de) | Verfahren zur herstellung von enantiomerenreinem n-methyl- n- (1s)- 1-phenyl- 2-((3s)-3- hydroxypyrrolidin- 1-yl)ethyl]- 2,2- diphenylacetamid | |
DE10238048A1 (de) | Verfahren zur Herstellung von Phenylalanin-Derivaten | |
EP0382114A2 (de) | Phosphinesterhaltige N-Acyl-2-aminosäureamide, Verfahren zu ihrer Herstellung und N-Acyl-2-aminosäurenitrile als Vorprodukte | |
DD247217A5 (de) | Verfahren zur herstellung von 2,6,-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridin-3,5-dicarbonsaeure-3 beta (n-benzyl-n-methylamino)-ethylester-5-methylester und dessen hydrochlorid-salz | |
EP1799665B1 (de) | Verfahren zur reinigung von 3-hydroxy-amidino-phenylalanin-derivaten durch ausfällung und umkristallisation eines salzes mit einer aromatischen sulfonsäure | |
DE2725732C2 (de) | Bestatin-Analoga, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Präparate | |
AT395976B (de) | Verfahren zur herstellung von dihydropyridinverbindungen oder ihren salzen | |
CH651017A5 (de) | Verfahren zur herstellung von amiden, peptiden, penicillinen und cephalosporinen. | |
CH624396A5 (de) | ||
AT400844B (de) | Abreicherungsverfahren des e-isomeren in z/e-7-amino-3-(2-(4-methyl-5-thiazolyl)vinyl)-3 cephem-4-carbonsäure | |
EP0704438A2 (de) | Verfahren zur Herstellung von 2-Cyaniminothiazolidin | |
DE19647538A1 (de) | Verfahren zur Herstellung von enantiomerenreinem N-Methyl-N-[1-phenyl-2-(-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamid | |
EP0565969A1 (de) | Tricyclische Lactole, ihre Verwendung als Racematspaltungsmittel und Verfahren zu ihrer Herstellung | |
DE2833174A1 (de) | P-substituierte n,n'-bis-(3-oxazolidinyl-2-on)-phosphoramide und verfahren zu ihrer herstellung | |
EP0470702A1 (de) | Optisch aktives Morpholinooxobutansäure-Hydroxybinaphthalinderivat und seine Herstellung |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20050121 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK |
|
DAX | Request for extension of the european patent (deleted) | ||
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: SOMMER, JOACHIM Inventor name: SPERL, STEFAN Inventor name: WOSIKOWSKI-BUTERS, KATJA |
|
17Q | First examination report despatched |
Effective date: 20081107 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20120526 |