USRE46424E1 - Method for producing 3-amidinophenylalanine derivatives - Google Patents
Method for producing 3-amidinophenylalanine derivatives Download PDFInfo
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- USRE46424E1 USRE46424E1 US14/145,892 US201314145892A USRE46424E US RE46424 E1 USRE46424 E1 US RE46424E1 US 201314145892 A US201314145892 A US 201314145892A US RE46424 E USRE46424 E US RE46424E
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- 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 title claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims abstract description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims abstract description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 5
- -1 2-thienylhydrazinocarbonyl Chemical group 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 16
- 230000009466 transformation Effects 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 230000001131 transforming effect Effects 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 2
- 230000002194 synthesizing effect Effects 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 6
- ZHUOMTMPTNZOJE-VIFPVBQESA-N (2s)-2-amino-3-(3-cyanophenyl)propanoic acid Chemical class OC(=O)[C@@H](N)CC1=CC=CC(C#N)=C1 ZHUOMTMPTNZOJE-VIFPVBQESA-N 0.000 abstract description 4
- 239000002797 plasminogen activator inhibitor Substances 0.000 abstract description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- 150000002825 nitriles Chemical group 0.000 description 15
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- 150000001411 amidrazones Chemical class 0.000 description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 0 [2*]C1CCN(C)C1 Chemical compound [2*]C1CCN(C)C1 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 229940093499 ethyl acetate Drugs 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000001409 amidines Chemical class 0.000 description 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 4
- 229920001429 chelating resin Polymers 0.000 description 4
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 4
- 230000036571 hydration Effects 0.000 description 4
- 238000006703 hydration reaction Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 3
- 239000003245 coal Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 125000002560 nitrile group Chemical group 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LVXNLGCFCOCULZ-UHFFFAOYSA-N CCOC(=O)N1CCN(C(=O)C(CC2=CC=CC(/C(N)=N\N)=C2)NS(=O)(=O)C2=C(C(C)C)C=C(C(C)C)C=C2C(C)C)CC1.CCOC(=O)N1CCN(C(=O)C(CC2=CC=CC(/C(N)=N\O)=C2)NS(=O)(=O)C2=C(C(C)C)C=C(C(C)C)C=C2C(C)C)CC1 Chemical compound CCOC(=O)N1CCN(C(=O)C(CC2=CC=CC(/C(N)=N\N)=C2)NS(=O)(=O)C2=C(C(C)C)C=C(C(C)C)C=C2C(C)C)CC1.CCOC(=O)N1CCN(C(=O)C(CC2=CC=CC(/C(N)=N\O)=C2)NS(=O)(=O)C2=C(C(C)C)C=C(C(C)C)C=C2C(C)C)CC1 LVXNLGCFCOCULZ-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- XKXHCNPAFAXVRZ-UHFFFAOYSA-N benzylazanium;chloride Chemical compound [Cl-].[NH3+]CC1=CC=CC=C1 XKXHCNPAFAXVRZ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention describes a method for the synthesis of enantiomerically pure 3-amidinophenylalanine derivatives, which are used as pharmaceutically effective urokinase inhibitors, by starting from 3-cyanophenylalanine derivatives. The methods of manufacture comprising only one synthesis step lead to new intermediates, namely 3-hydroxyamidino- and 3-amidrazonophenylalanine derivatives. These intermediates or their acetyl derivatives can be reduced into the desired 3-amidino-phenylalanine derivatives under gentle conditions (H2 or ammonium formiate formate, Pd/C (approx. 10%), ethanol/water, room temperature, normal pressure or also H2, Pd/C, AcOH or HCl/ethanol, 1-3 bar) in excellent yields and in an enantiomeric excess of up to 99.9%.
Description
This application is a broadening reissue application for U.S. Pat. No. 8,088,921 B2, which granted from U.S. application Ser. No. 12/905,769, filed Oct. 15, 2010 which is a divisional of U.S. application Ser. No. 11/699,228, filed Jan. 29, 2007, now U.S. Pat. No. 7,884,206, which is a divisional of U.S. application Ser. No. 10/506,256, filed Aug. 30, 2004, and afforded a 371(c) date of Mar. 18, 2005, now U.S. Pat. No. 7,211,670, which U.S. application Ser. No. 10/506,256 is the National Stage of International Application No. PCT/CH03/00147, filed Feb. 28, 2003, which claims the benefit of Swiss Application No. 0347/02, filed Feb. 28, 2002, the entire contents of all of which are incorporated by reference herein.
The present invention relates to a method for the synthesis of 3-amidinophenyl-alanine derivatives with an improved total chemical yield and an increased enantiomeric excess. These 3-amidinophenylalanine derivatives represent a class of highly efficient urokinase inhibitors (WO 00/17158).
The methods of synthesis described in WO 00/17158 for the preparation of urokinase inhibitors comprise a method for converting the cyano function of substituted 3-cyanophenylalanine derivatives into an amidino function. The disadvantages of the method are the insufficient yield produced by the multi-step transformation of the nitrile function into the amidino function, the use of carcinogenic reagents such as hydrogen sulphide and methyl iodide, as well as the release of methyl mercaptan in the form of a highly toxic gas as a by-product. The method requires a considerable quantity of devices and additional separation processes. Moreover, racemization and thus lower enantiomeric excess must be taken into account.
Transformation of a para-positioned nitrile group into an amidino function with hydroxylamine hydrochloride/triethylamine and subsequent Pd-catalytic hydration (10 bar/AcOH/50° C.) is described in Tetrahedron 51, 12047-68 (1995) (FIG. 3). However, the reaction conditions are so harsh that the chemical yield and the chemical purity are not satisfying. There is no indication about the enantiomeric excess.
In Tetrahedron Letters 40, 7067-71 (1999), a new gentle method for the preparation of aromatic amidines from nitriles is described which should be more advantageous than all other methods known. The reaction is performed with acetylcysteine and ammonia at temperatures of approximately 60° C. The disadvantage of this method lies in the fact that reasonable yields can only be obtained with π electron-poor (=πelectron-attracting) aromates.
Surprisingly, it has been found that transformation of the aromatic 3-cyano function of substituted phenylalanine derivatives of general formula (III) into the 3-amidino function of corresponding compounds of general formula (I) with hydroxylamine and subsequent reduction of the oxyamidine of general formula (IIa) with hydrogen over Pd—C (10%) or reduction of the corresponding acetyloxyamidine manufactured in situ with acetanhydride with ammonium formiate formate over Pd—C (10%) can be managed under gentle reaction conditions (see following FIG. 1 ). Here, reaction products with a high chemical yield and purity are obtained using only few devices and without racemization.
Moreover, EP 0 739 886 A2 describes a method for the synthesis of 4-amidrazono-phenylalanine derivatives from corresponding nitriles. Here, the nitrile is first converted into the corresponding thioamide which is activated over a thioimidoester derivative in such a way that it reacts with hydrazine to form hydrazonoamide (amidrazone).
A direct transformation of the nitrile group into an amidrazone is described in J. Heterocyclic Chem. 26, 1623 (1989). Here, π electron-deficient heteroaromates substituted with cyano (i.e. cyano groups favourable to a nucleophilic attack) have been heated with hydrazine for some hours, whereby amidrazone was obtained in moderate yields.
Moreover, it has been surprisingly found that also a non-activated nitrile that is not bound to an electron-attracting group can be transformed with hydrazine under similar conditions. Thus, compounds of formula (III) can be transformed into amidrazones of formula (IIb) in good yields (see FIG. 1 ).
Surprisingly, it has also been found that these amidrazones—analogously to the amidoximes of formula (IIa)—can be reduced to the amidines of formula (I) (see FIG. 1 ). The direct transformation of an unsubstituted amidrazone into an unsubstituted amidine has until now only been described, namely in the case of aza transfer reactions between arylamidrazones and aryldiazonium salts in Vestn. Slov. Kem. Drus. (1980), 27(3), 251-64.
Thus, the object of the present invention is a method for transforming 3-cyano-phenylalanine derivatives of general formula (III) into 3-amidino derivatives of general formula I, or salts thereof formed with acids, which are present either as L- or D-configurated compounds and wherein R1 represents (a) a group of formula
in which either p=1 and r=2 and R2 is benzyloxycarbonyl, benzylaminocarbonyl or 2-thienylhydrazinocarbonyl, or p=2 and r=1 and R2 is ethoxycarbonyl, 2-propyloxycarbonyl, 2-propylaminocarbonyl, methylaminocarbonyl or methyl; or (b) a group of formula
in which R3 is methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, dimethylaminocarbonyl, acetyl or propionyl;
using minimal equipment in high chemical yield and purity as well as without racemization.
In a first embodiment of the method of the present invention, transformation of the nitrile group into the amidino function occurs over the amidoxime intermediate of general formula (IIa) by means of hydroxylamine hydrochloride in the presence of sodium carbonate in alcoholic-aqueous solution at reflux temperature, advantageously by boiling for 2 to 20 hours, preferably 4 to 10 hours, a compound of formula (III) with a one to 5-fold excess of hydroxylamine hydrochloride/0.5-0.6 equiv. sodium carbonate in an alcoholic-aqueous, preferably ethanolic-aqueous solution. However, the transformation of nitrile (III) with hydroxylamine hydrochloride can also occur at room temperature in the presence of triethylamine in alcoholic solution, with or without addition of a further organic solvent, such as methylene chloride.
Subsequent reduction of the amidoxime function is performed either with hydrogen gas or with ammonium formiate formate (which is advantageously applied in an at least 4-fold excess) either by directly starting from unsubstituted amidoxime, or over the acetylated amidoxime manufactured in situ with acetanhydride in the presence of hydrochloric acid, advantageously at 20 to 60° C., in an alcoholic-aqueous solution, preferably in an ethanolic-aqueous solution, advantageously in the ratio of 1:1 to 20:1, preferably 3:1 to 10:1, ideally 5:1, in the presence of Pd/C, advantageously 1 to 50%, preferably 5 to 30% Pd/C (approx. 10%), advantageously at normal pressure and a temperature between 10 and 50° C., preferably between 20 and 30° C., ideally at room temperature. However, reduction can also occur by hydrogenation in the presence of Pd/C in an alcoholic, acetic acid-containing solution at a pressure of about 1-3 bar.
In a second embodiment of the method of the present invention, transformation of 3-cyanophenylalanine derivatives of general formula (III) into 3-amidinoderivatives of general formula I occurs over the amidrazone intermediate of general formula (IIb) by boiling, advantageously for 2 to 20 hours, preferably for 4 to 10 hours, a compound of formula (III) with an excess of hydrazine in alcoholic, preferably ethanolic solution. Reduction of the amidrazone intermediate (IIb) into the corresponding amidine (I) occurs under the same conditions as those starting from amidoxime (IIa).
Further objects of the present invention are compounds of general formula (II) as represented in FIG. 1 , in particular those of the following formulas (IV) and (V)
as (L)- or (D)-enantiomers, and as (E)- or (Z)-isomers or (E/Z)-mixtures, and as free bases or as salts thereof formed with acids.
The following examples further explain the improved methods of synthesis of the present invention and the synthesis of new intermediates, however without restricting the invention.
Analysis of the eluates and products obtained according to the examples was carried out with 1H-NMR, HPLC electrospray MS or elementary analysis. The enantiomeric excess was determined according to known methods using HPLC and chiral analytical columns. The starting compounds of general formula (III) and their manufacture are known (e.g. WO 00/17158).
75.4 g (0.126 mol) of N-α-2,4,6-triisopropylphenylsulfonyl-3-cyano-(L)-phenylalanine-4-ethoxycarbonyl piperazide was dissolved in 1.5 l of ethanol, the solution was mixed with 32.5 g (0.47 mol) of hydroxylamine hydrochloride and with a solution of 25.4 g (0.24 mol) of Na2CO3 in 0.5 l of water and refluxed for 6 hours (80° C.). The crude product obtained after evaporation of the solvent was taken up in 1.5 l of ethyl acetate and extracted with water (3×0.5 l), washed with saturated NaCl, dried over Na2SO4, filtered and the solvent was evaporated. Yield: 71.3 g (90%).
71.3 g (0.113 mol) of the N-α-2,4,6-triisopropylphenylsulfonyl-3-oxamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazide obtained under (A) was dissolved in 0.71 l of ethanol and the solution was mixed with a suspension of 14.2 g of 10% palladium coal in 140 ml of water. Injection of hydrogen until saturation was followed by hydration until complete transformation at normal pressure (approx. 5 hours). The suspension was filtered over Celite, washed with ethanol/water (9:1) and the solvent was evaporated. The crude product obtained was purified over silica gel 60 (ethyl acetate/2-propanol, 8:2) and finally transformed into the corresponding hydrochloride over Amberlite IRA-400 (Cl− form) in 2-propanol/water (8:2). Yield: 65.4 g (89%), ee-value: 99.9% of the (L) form.
71.3 g (0.113 mol) of the N-α-2,4,6-triisopropylphenylsulfonyl-3-oxamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazide was dissolved in 0.71 l of ethanol, the solution was mixed with 45.6 g (0.46 mol) of acetic anhydride and stirred for 10 min. at room temperature. Afterwards, 0.46 l of 1 N HCl was added and the thereby warm becoming solution was further stirred for 10 min. After cooling to room temperature, 29 g (0.46 mol) of ammonium formiate formate was added and the mixture was stirred for 5 min. After addition of a suspension of 14.2 g of 10% Pd/C in 140 ml of water, the mixture was stirred for 24 hours at room temperature. After HPLC check of the reaction completion, the suspension was filtered over Celite, washed with a 1:9 mixture of water/ethanol and the solvent was evaporated. The crude product was taken up in 1.5 l of EtOAc, washed with 3 portions of 0.5 l each of 1N HCl, water and saturated NaCl, and dried over Na2SO4. After chromatographic purification over silica gel 60 with ethylacetate/2-propanol (8:2) and subsequent ion exchange chromatography over Amberlite IRA-400 (Cl− form) in 2-propanol/water (8:2) for the conversion into the corresponding hydrochloride, 62.5 g (85%) of product was obtained. ee value: 99.9% of the (L) form.
2.3 g (3.6 mmol) of Nα-2,4,6-triisopropylphenylsulfonyl-(L)-3-cyanophenylalanyl-nipecotinic acid benzylamide was dissolved in 45 ml of ethanol and the solution was mixed with 0.94 g (13.6 mmol) of hydroxylamine hydrochloride followed by a solution of 0.74 g (7 mmol) of Na2CO3 in 15 ml of water and refluxed for 6 hours (80° C.). The crude product obtained after evaporation of the solvent was taken up in 100 ml of ethylacetate, extracted with water (3×30 ml), washed with saturated NaCl, dried over Na2SO4 and filtered, and the solvent was evaporated. Yield: 2.1 g (87%).
2.1 g (3.1 mmol) of the N-α-2,4,6-triisopropylphenylsulfonyl-(L)-3-oxamidino-phenylalanyl-nipecotinic acid benzylamide obtained under (A) was dissolved in 20 ml of ethanol and the solution was mixed with a suspension of 0.4 g of 10% palladium coal in 5 ml of water. Injection of hydrogen until saturation was followed by hydration at normal pressure until complete transformation (approx. 4 hours). The suspension was filtered over Celite, washed with ethanol/water (9:1) and the solvent was evaporated. The crude product obtained was purified over silica gel 60 (ethylacetate/2-propanol, 8:2) and finally converted into the corresponding hydrochloride over Amberlite IRA-400 (Cl− form) in 2-propanol/water (8:2). Yield: 1.74 g (85%), ee value: 99.7% of the (L) form.
75.4 g (0.126 mol) of N-α-2,4,6-triisopropylphenylsulfonyl-3-cyano-(L)-phenylalanine-4-ethoxycarbonyl piperazide was dissolved in 1.5 l of ethanol, the solution was mixed with 18.1 g (0.47 mol) of a 100% hydrazine hydrate solution and refluxed for 6 hours (80° C.). The crude product obtained after evaporation of the solvent was taken up in 1.5 l of ethylacetate, extracted with water (3×0.5 l), washed with saturated NaCl, dried over Na2SO4 and filtered, and the solvent was evaporated. Yield: 65.7 g (83%).
65.5 g (0.104 mol) of the N-α-2,4,6-triisopropylphenylsulfonyl-3-amidrazono-(L)-phenylalanine-4-ethoxycarbonyl piperazide obtained under (A) was dissolved in 0.66 l of ethanol and the solution was mixed with a suspension of 13.1 g of 10% palladium coal in 130 ml of water. Injection of hydrogen gas until saturation was followed by hydration at normal pressure until complete transformation (approx. 5 hours). The suspension was filtered over Celite and washed with ethanol/water (9:1), and the solvent was evaporated. The crude product obtained was purified over silica gel 60 (ethylacetate/2-propanol, 8:2) and finally converted into the corresponding hydrochloride over Amberlite IRA-400 (Cl− form) in 2-propanol/water (8:2). Yield: 54.1 g (80%), ee value: 99.8% of the (L) form.
Claims (9)
1. A method of synthesizing 3-amidino-phenylalanine derivatives of general formula (I)
or salts thereof formed with acids, which are present as either L- or D-configurated isomers and wherein R1 is selected from the group consisting of:
(a) a group of formula
wherein
(i) p=1 and r=2 and R2 is benzyloxycarbonyl, benyzlaminocarbonyl benzylaminocarbonyl or 2-thienylhydrazinocarbonyl or
(ii) p=2 and r=1 and R2 is ethoxycarbonyl, 2-propyloxycarbonyl, 2-propylcarbonyl, 2-propylaminocarbonyl, methylaminocarbonyl or methyl; and
(b) a group of formula
wherein R3 is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, dimethylaminocarbonyl, acetyl, and propionyl,
comprising the reduction of a compound of the general formula (IIa)
present as L- or D-enantiomers, as (E)- or (Z)-isomers or (E/Z)-mixtures, and wherein R1 is selected from the group consisting of:
(a) a group of formula
wherein
(i) p=1 and r=2 and R2 is benzyloxycarbonyl, benyzlaminocarbonyl benzylaminocarbonyl or 2-thienylhydrazinocarbonyl or
(ii) p=2 and r=1 and R2 is ethoxycarbonyl, 2-propyloxycarbonyl, 2-propylcarbonyl, 2-propylaminocarbonyl, methylaminocarbonyl or methyl; and
(b) a group of formula
wherein R3 is selected from the group consisting of methoxycarbonyk methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, dimethylaminocarbonyl, acetyl, and propionyl,
in the presence of Pd/C in an alcoholic-aqueous solution with hydrogen or ammonium formiate formate.
2. The method of claim 1 , wherein the compound of the general formula (IIa) is hydrogenated in the presence of Pd/C in an alcoholic, acetic acid- or hydrogen chloride-containing solution at a pressure of 1-3 bar.
3. The method of claim 1 , further comprising the step of transforming the compounds of general formula (IIa) into the corresponding acetoxyamidino derivatives with acetanhydride in the presence of hydrochloric acid and reducing the derivatives with hydrogen or ammonium formiate in the presence of Pd/C in an alcoholic-aqueous solution.
4. The method of claim 3 1, wherein the acetoxyamidino derivatives are hydrogenated in the presence of Pd/C in an alcoholic, acetic acid- or hydrogen chloride-containing solution at a pressure of 1-3 bar.
5. The method of claim 3 1, wherein the transformation of the compounds of formula (IIa) into the corresponding acetoxyamidino derivatives occurs at a temperature between 20 and 60° C.
6. The method of claim 1 , wherein the reduction occurs in an ethanolic-aqueous solution having a ratio of 1:1 to 20:1.
7. The method of claim 1 , wherein the reduction occurs in the presence of 1 to 50% Pd/C.
8. The method of claim 1 , wherein the reduction occurs at a temperature of 10 to 50° C.
9. The method of claim 1 , wherein the reduction occurs with an at least 4-fold excess of ammonium formiate formate.
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CH00347/02A CH695999A5 (en) | 2002-02-28 | 2002-02-28 | A process for preparing 3-amidinophenylalanine derivatives. |
CH0347/02 | 2002-02-28 | ||
PCT/CH2003/000147 WO2003072559A1 (en) | 2002-02-28 | 2003-02-28 | Method for producing 3-amidinophenylalanine derivatives |
US11/506,256 US20100284546A1 (en) | 2005-08-18 | 2006-08-18 | Active noise control algorithm that requires no secondary path identification based on the SPR property |
US11/699,228 US7884206B2 (en) | 2002-02-28 | 2007-01-29 | Method for producing 3-amidinophenylalanine derivatives |
US12/905,769 US8088921B2 (en) | 2002-02-28 | 2010-10-15 | Method for producing 3-amidinophenylalanine derivatives |
US14/145,892 USRE46424E1 (en) | 2002-02-28 | 2013-12-31 | Method for producing 3-amidinophenylalanine derivatives |
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US12/905,769 Reissue US8088921B2 (en) | 2002-02-28 | 2010-10-15 | Method for producing 3-amidinophenylalanine derivatives |
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US10/506,256 Expired - Lifetime US7211670B2 (en) | 2002-02-28 | 2003-02-28 | Method for producing 3-amidinophenylalanine derivatives |
US11/699,228 Active 2025-09-13 US7884206B2 (en) | 2002-02-28 | 2007-01-29 | Method for producing 3-amidinophenylalanine derivatives |
US12/905,769 Ceased US8088921B2 (en) | 2002-02-28 | 2010-10-15 | Method for producing 3-amidinophenylalanine derivatives |
US13/300,237 Expired - Lifetime US8642761B2 (en) | 2002-02-28 | 2011-11-18 | Method for producing 3-amidinophenylalanine derivatives |
US14/145,892 Expired - Fee Related USRE46424E1 (en) | 2002-02-28 | 2013-12-31 | Method for producing 3-amidinophenylalanine derivatives |
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US11/699,228 Active 2025-09-13 US7884206B2 (en) | 2002-02-28 | 2007-01-29 | Method for producing 3-amidinophenylalanine derivatives |
US12/905,769 Ceased US8088921B2 (en) | 2002-02-28 | 2010-10-15 | Method for producing 3-amidinophenylalanine derivatives |
US13/300,237 Expired - Lifetime US8642761B2 (en) | 2002-02-28 | 2011-11-18 | Method for producing 3-amidinophenylalanine derivatives |
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Cited By (2)
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US11045453B1 (en) | 2020-03-10 | 2021-06-29 | Redhill Biopharma Ltd. | Serine protease inhibitor for treating 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 |
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CH695999A5 (en) * | 2002-02-28 | 2006-11-15 | Wilex Ag | A process for preparing 3-amidinophenylalanine derivatives. |
DE10323898A1 (en) * | 2003-05-26 | 2004-12-23 | Wilex Ag | Hydroxyamidine and hydroxyguanidine compounds as urokinase inhibitors |
CA2583771C (en) * | 2004-10-14 | 2013-08-27 | Wilex Ag | Method for cleaning 3-hydroxyamidinophenylalanine derivatives by the precipitation and recrystallization of salt and an aromatic sulfonic acid |
DE102004057195A1 (en) * | 2004-11-26 | 2006-06-01 | Wilex Ag | Crystalline modifications of N-alpha (2,4,6-triisopropylphenylsulfonyl) -3-hydroxyamidino- (L) -phenylalanine-4-ethoxycarbonylpiperazide and / or salts thereof |
EP2832724A4 (en) * | 2012-03-29 | 2015-09-23 | Toray Industries | Nipecotic acid derivative and use thereof for medical purposes |
CN114105910B (en) * | 2021-11-02 | 2024-04-12 | 北京悦康科创医药科技股份有限公司 | Hydroxycarbamimidoyl phenylalanine derivative, pharmaceutical composition and application |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11045453B1 (en) | 2020-03-10 | 2021-06-29 | Redhill Biopharma Ltd. | Serine protease inhibitor for treating coronavirus infection |
US11052073B1 (en) | 2020-03-10 | 2021-07-06 | Redhill Biopharma Ltd. | Sphingosine kinase 2 inhibitor for treating coronavirus infection |
US11364227B2 (en) | 2020-03-10 | 2022-06-21 | Redhill Biopharma Ltd. | Sphingosine kinase 2 inhibitor for treating coronavirus infection |
US11918560B2 (en) | 2020-03-10 | 2024-03-05 | Redhill Biopharma Ltd. | Serine protease inhibitor for treating 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 |
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ES2282601T3 (en) | 2007-10-16 |
US20110087025A1 (en) | 2011-04-14 |
WO2003072559A1 (en) | 2003-09-04 |
DK1480963T3 (en) | 2007-09-10 |
ATE361285T1 (en) | 2007-05-15 |
CH695999A5 (en) | 2006-11-15 |
EP1480963A1 (en) | 2004-12-01 |
CN1639142A (en) | 2005-07-13 |
US8088921B2 (en) | 2012-01-03 |
DE50307171D1 (en) | 2007-06-14 |
JP2010265288A (en) | 2010-11-25 |
US7884206B2 (en) | 2011-02-08 |
AU2003205498A1 (en) | 2003-09-09 |
JP2005532270A (en) | 2005-10-27 |
US20050176962A1 (en) | 2005-08-11 |
CN100369906C (en) | 2008-02-20 |
US20070123706A1 (en) | 2007-05-31 |
US7211670B2 (en) | 2007-05-01 |
EP1480963B1 (en) | 2007-05-02 |
PT1480963E (en) | 2007-05-31 |
US8642761B2 (en) | 2014-02-04 |
US20120065398A1 (en) | 2012-03-15 |
JP5247970B2 (en) | 2013-07-24 |
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