WO2004011449A2 - Verfahren zur herstellung von phenylalanin-derivaten - Google Patents
Verfahren zur herstellung von phenylalanin-derivaten Download PDFInfo
- Publication number
- WO2004011449A2 WO2004011449A2 PCT/EP2003/008230 EP0308230W WO2004011449A2 WO 2004011449 A2 WO2004011449 A2 WO 2004011449A2 EP 0308230 W EP0308230 W EP 0308230W WO 2004011449 A2 WO2004011449 A2 WO 2004011449A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyanophenylalanine
- reaction
- halide
- tipps
- protected
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 150000002993 phenylalanine derivatives Chemical class 0.000 title description 2
- ZIHWPYSIZIGNDJ-QMMMGPOBSA-N (2s)-2-amino-3-[3-(diaminomethylideneamino)phenyl]propanoic acid Chemical class OC(=O)[C@@H](N)CC1=CC=CC(NC(N)=N)=C1 ZIHWPYSIZIGNDJ-QMMMGPOBSA-N 0.000 claims abstract description 7
- -1 N-protected aminomalonic acid diester Chemical class 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 32
- ZHUOMTMPTNZOJE-VIFPVBQESA-N (2s)-2-amino-3-(3-cyanophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC(C#N)=C1 ZHUOMTMPTNZOJE-VIFPVBQESA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 5
- CVKOOKPNCVYHNY-UHFFFAOYSA-N 3-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC(C#N)=C1 CVKOOKPNCVYHNY-UHFFFAOYSA-N 0.000 claims description 4
- 239000000908 ammonium hydroxide Substances 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 4
- 150000004885 piperazines Chemical class 0.000 claims description 4
- ZYPDAVAXIWVERD-FVGYRXGTSA-N azanium;(2s)-2-amino-3-(3-cyanophenyl)propanoate Chemical compound [NH4+].[O-]C(=O)[C@@H](N)CC1=CC=CC(C#N)=C1 ZYPDAVAXIWVERD-FVGYRXGTSA-N 0.000 claims description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 3
- LNOQURRKNJKKBU-UHFFFAOYSA-N ethyl piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNCC1 LNOQURRKNJKKBU-UHFFFAOYSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- ISOLMABRZPQKOV-UHFFFAOYSA-N diethyl 2-acetamidopropanedioate Chemical compound CCOC(=O)C(NC(C)=O)C(=O)OCC ISOLMABRZPQKOV-UHFFFAOYSA-N 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- CWHBCTLVWOCMPQ-UHFFFAOYSA-L disodium;2-[(3,5-diiodo-4-oxidophenyl)-(3,5-diiodo-4-oxocyclohexa-2,5-dien-1-ylidene)methyl]benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C(C=1C=C(I)C([O-])=C(I)C=1)=C1C=C(I)C(=O)C(I)=C1 CWHBCTLVWOCMPQ-UHFFFAOYSA-L 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 2
- ZWOFHHFUPIWBRO-ZETCQYMHSA-N (2s)-2-(3-cyanoanilino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC(C#N)=C1 ZWOFHHFUPIWBRO-ZETCQYMHSA-N 0.000 description 1
- MJIDYLIDXWGFRN-QMMMGPOBSA-N (2s)-2-[2-(diaminomethylidene)hydrazinyl]-3-phenylpropanoic acid Chemical class NC(=N)NN[C@H](C(O)=O)CC1=CC=CC=C1 MJIDYLIDXWGFRN-QMMMGPOBSA-N 0.000 description 1
- NIOKQPJRXDRREF-QMMMGPOBSA-N (2s)-2-amino-3-(3-carbamimidoylphenyl)propanoic acid Chemical class OC(=O)[C@@H](N)CC1=CC=CC(C(N)=N)=C1 NIOKQPJRXDRREF-QMMMGPOBSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CBQJSKKFNMDLON-JTQLQIEISA-N N-acetyl-L-phenylalanine Chemical compound CC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-JTQLQIEISA-N 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- JINBYESILADKFW-UHFFFAOYSA-N aminomalonic acid Chemical compound OC(=O)C(N)C(O)=O JINBYESILADKFW-UHFFFAOYSA-N 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- ISJSHQTWOHGCMM-NDEPHWFRSA-N ethyl 4-[(2s)-3-(3-carbamimidoylphenyl)-2-[[2,4,6-tri(propan-2-yl)phenyl]sulfonylamino]propanoyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(=O)[C@@H](NS(=O)(=O)C=1C(=CC(=CC=1C(C)C)C(C)C)C(C)C)CC1=CC=CC(C(N)=N)=C1 ISJSHQTWOHGCMM-NDEPHWFRSA-N 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000000951 phenoxy group Chemical class [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03771103A EP1525195A2 (de) | 2002-07-25 | 2003-07-25 | Verfahren zur herstellung von phenylalanin-derivaten |
US10/522,218 US7247724B2 (en) | 2002-07-25 | 2003-07-25 | Method for the production of phenylalanine derivatives |
AU2003253326A AU2003253326A1 (en) | 2002-07-25 | 2003-07-25 | Method for the production of phenylalanine derivatives |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10233919.8 | 2002-07-25 | ||
DE10233919 | 2002-07-25 | ||
DE10238048.1 | 2002-08-20 | ||
DE10238048A DE10238048A1 (de) | 2002-07-25 | 2002-08-20 | Verfahren zur Herstellung von Phenylalanin-Derivaten |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004011449A2 true WO2004011449A2 (de) | 2004-02-05 |
WO2004011449A3 WO2004011449A3 (de) | 2004-04-08 |
Family
ID=31189298
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/008230 WO2004011449A2 (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) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004103984A1 (de) | 2003-05-26 | 2004-12-02 | Wilex Ag | Hydroxyamidin- und hydroxyguanidin-verbindungen als urokinase-hemmstoffe |
WO2006056448A1 (de) * | 2004-11-26 | 2006-06-01 | Wilex Ag | KRISTALLINE MODIFIKATIONEN VON N-α-(2,4,6-TRIISOPROPYLPHENYLSULFONYL)-3-HYDROXYAMIDINO-(L)-PHENYLALANIN-4-ETHOXYCARBONYLPIPERAZID UND/ODER SALZEN DAVON |
US7504425B2 (en) | 2002-05-29 | 2009-03-17 | Merck & Co., Inc. | Compounds useful in the treatment of anthrax and inhibiting lethal factor |
US7579487B2 (en) | 2004-05-11 | 2009-08-25 | Merck & Co., Inc. | Process for making N-sulfonated-amino acid derivatives |
CN1993144B (zh) * | 2004-09-21 | 2012-05-30 | 威丽克斯股份公司 | 苯丙氨酸衍生物的稳定剂型 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL295658A (en) | 2020-03-10 | 2022-10-01 | 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 |
---|---|---|---|---|
WO1992008709A1 (de) | 1990-11-15 | 1992-05-29 | Pentapharm Ag | Meta-substituierte phenylalanin-derivate |
BR9912327B1 (pt) * | 1998-07-20 | 2013-11-12 | Inibidores da uroquinase | |
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 EP EP03771103A patent/EP1525195A2/de not_active Withdrawn
- 2003-07-25 US US10/522,218 patent/US7247724B2/en not_active Expired - Lifetime
- 2003-07-25 AU AU2003253326A patent/AU2003253326A1/en not_active Abandoned
- 2003-07-25 WO PCT/EP2003/008230 patent/WO2004011449A2/de not_active Application Discontinuation
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7504425B2 (en) | 2002-05-29 | 2009-03-17 | Merck & Co., Inc. | Compounds useful in the treatment of anthrax and inhibiting lethal factor |
WO2004103984A1 (de) | 2003-05-26 | 2004-12-02 | Wilex Ag | Hydroxyamidin- und hydroxyguanidin-verbindungen als urokinase-hemmstoffe |
US7807681B2 (en) | 2003-05-26 | 2010-10-05 | Wilex Ag | Hydroxyamidine and hydroxyguanidine compounds as urokinase inhibitors |
US7579487B2 (en) | 2004-05-11 | 2009-08-25 | Merck & Co., Inc. | Process for making N-sulfonated-amino acid derivatives |
CN1993144B (zh) * | 2004-09-21 | 2012-05-30 | 威丽克斯股份公司 | 苯丙氨酸衍生物的稳定剂型 |
WO2006056448A1 (de) * | 2004-11-26 | 2006-06-01 | Wilex Ag | KRISTALLINE MODIFIKATIONEN VON N-α-(2,4,6-TRIISOPROPYLPHENYLSULFONYL)-3-HYDROXYAMIDINO-(L)-PHENYLALANIN-4-ETHOXYCARBONYLPIPERAZID UND/ODER SALZEN DAVON |
US7713980B2 (en) | 2004-11-26 | 2010-05-11 | Wilex Ag | Crystalline modifications of N-α-(2,4,6-triisopropyl-phenylsulfonyl)-3-hydroxyamidino-(L)- phenylalanine 4-ethoxycarbonylpiperazide and/or salts thereof |
US8492385B2 (en) | 2004-11-26 | 2013-07-23 | Wilex Ag | Crystalline modifications of N-alpha-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino- (L)- phenylalanine 4-ethoxycarbonylpiperazide and/or salts thereof |
Also Published As
Publication number | Publication date |
---|---|
US7247724B2 (en) | 2007-07-24 |
US20050245757A1 (en) | 2005-11-03 |
AU2003253326A1 (en) | 2004-02-16 |
WO2004011449A3 (de) | 2004-04-08 |
EP1525195A2 (de) | 2005-04-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0885204B1 (de) | Neue arylglycinamidderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende pharmazeutische zusammensetzungen | |
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 | |
DE68912811T2 (de) | Amide von Cyclomethylen-1,2 bicarbonsäure mit therapeutischer Wirkung, Verfahren zu deren Herstellung sowie diese enthaltende pharmazeutische Zusammensetzungen. | |
EP0094633B1 (de) | Spiro-2-aza-alkan-3-carbonitrile, Verfahren zu ihrer Herstellung und ihre Verwendung | |
DE60210696T2 (de) | Optisch aktive 4-(tert-Butoxycarbonyl)piperazin Derivate und Verfahren zu ihrer Herstellung | |
EP0217018B1 (de) | Verfahren zur Herstellung von 3-Aminoacrylsäureestern | |
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 | |
DE69427978T2 (de) | Zwischenprodukt zur verwendung in der synthese und verfahren zur herstellung eines aminopiperazinderivates | |
DE2725732C2 (de) | Bestatin-Analoga, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Präparate | |
DE69303333T2 (de) | Substituierte Benzoate-Derivate | |
EP1799665B1 (de) | Verfahren zur reinigung von 3-hydroxy-amidino-phenylalanin-derivaten durch ausfällung und umkristallisation eines salzes mit einer aromatischen sulfonsäure | |
DE69113365T2 (de) | Optisch aktives Morpholinooxobutansäure-Hydroxybinaphthalinderivat und seine Herstellung. | |
DE69902118T2 (de) | Verfahren zur Herstellung optisch aktiver 4-Hydroxy-2-pyrrolidone | |
DE68904546T2 (de) | Aminoacetonitril-derivate. | |
DE3882744T2 (de) | Methode zur Herstellung von Indan-Derivaten. | |
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 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2003771103 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10522218 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 2003771103 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |