AU692774B2 - Asymmetrically substituted diaminodicarboxylic acid derivatives and a process for their preparation - Google Patents
Asymmetrically substituted diaminodicarboxylic acid derivatives and a process for their preparation Download PDFInfo
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- AU692774B2 AU692774B2 AU68927/94A AU6892794A AU692774B2 AU 692774 B2 AU692774 B2 AU 692774B2 AU 68927/94 A AU68927/94 A AU 68927/94A AU 6892794 A AU6892794 A AU 6892794A AU 692774 B2 AU692774 B2 AU 692774B2
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- 238000000034 method Methods 0.000 title claims description 17
- 239000002253 acid Substances 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 10
- -1 9-fluorenylmethyl Chemical group 0.000 claims description 33
- 150000003254 radicals Chemical class 0.000 claims description 26
- 238000005868 electrolysis reaction Methods 0.000 claims description 14
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 238000006612 Kolbe reaction Methods 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229910052697 platinum Inorganic materials 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 3
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical compound [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- IVHKZGYFKJRXBD-UHFFFAOYSA-N amino carbamate Chemical class NOC(N)=O IVHKZGYFKJRXBD-UHFFFAOYSA-N 0.000 claims 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- SCEJQXRUWDSIBB-UHFFFAOYSA-N 2,2-diaminooctanedioic acid Chemical class OC(=O)C(N)(N)CCCCCC(O)=O SCEJQXRUWDSIBB-UHFFFAOYSA-N 0.000 description 1
- YQZHANAPVDIEHA-UHFFFAOYSA-N 2,7-bis(azaniumyl)octanedioate Chemical compound OC(=O)C(N)CCCCC(N)C(O)=O YQZHANAPVDIEHA-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- PQGAHNJECSVDEI-UHFFFAOYSA-N [CH2]CCCCC Chemical compound [CH2]CCCCC PQGAHNJECSVDEI-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000002946 cyanobenzyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 125000006285 dibromobenzyl group Chemical group 0.000 description 1
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 125000006286 dichlorobenzyl group Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- GMKMEZVLHJARHF-SYDPRGILSA-N meso-2,6-diaminopimelic acid Chemical class [O-]C(=O)[C@@H]([NH3+])CCC[C@@H]([NH3+])C([O-])=O GMKMEZVLHJARHF-SYDPRGILSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 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
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
- C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/20—Processes
- C25B3/29—Coupling reactions
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Electrochemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)
Description
6.L{AY, 19%8 14:47 SPRUSON FERGUSON 61 2 92615486 H. 2311 P. 4 1 Asymnmetrically Substituted Diaminodicarboxyiic Acid Derivatives and a Process For Their Preparation The invention relates to novel asynunetrically substituted diaxninodlcarboxylic acid derivatives and a process for their preparation.
6 Asymmetrically substituted diaminodicarboxylic acid derivatives are useful intermediates for the synthesis of peptides, In J. Org. Chem. 1980, 45, 3078-3080, asymmetrically substituted diaminosuberic acid derivatives are described which were prepared by mixed Kolbe synthesis. Separation of the symmetrical by-products was unsuccessful there. The preparation of asymmnetrically substituted diaminopimelic acid derivatives by a complicated 9-stage enantioselective synthesis is also known from Tetrahedron Lett. 30, 1982, 33, 4727-4730.
Unexpectedly, it has been possible to find novel asymmetrically substituted diaminodicarboxylic acid derivatives which are useful intermediates for the synthesis of petie an opud*otiiguntrlaioais pesdeadcmone otiiguntrlamn cd.sbttte imndcroyi .00. is ~The invention therefore relates to an asymmetricallysutite amndcroyc acid derivative of the formula: 0 0() -NH NH 0 E F wherein represents methyl or phenyl, E and F in each case represent an optionally halogenated straight chain, branched or cyclic alkyl radical having 1 to 10 C aorns or' 0 0 Wor0 where W represents 9-fluorenyirnethyl, benzyl which is optionally mono-, poly- or mixed substituted by halogen, -NO 2 alkoxy or CN,, or W represents a straight chain 26 or branched alkyl radical having 1 to 4 C atoms, and n represents an integer from 2 to tNAUW003Q029:S&F 6.l MAY, 1998 14:47 SPRUSON FERGUSON 61 292615486 NO 2311 P. 2 The invention also relates to a process for the preparation by mixed Kolbe synthesis of asymmuetrically substituted diarninodicarboxylic acid derivatives of the formula-, 0 0 0(1
CH
2 aC H-c 2 )n-CH-C -0 (CH 2 1 -13 NH 0 wherein B3 represents methyl or phenyl, E and F in each case represent an optionally halogenated straight chain, branched or cyclic alkyl radical having I to 10 C atoms or: 0 0 000 or where W represents 9-tluorenylmethyl, benzyl which is optionally mono-, poly- or o mixed substituted by halogen, -NO 2 alkoxy or CN; or W represents a straight chain or branched alky) radical having 1 to 4 C atoms, and ni represents an integer from 2 to which process is characterized in that a protected amino acid derivative of the formula: 00 K) CH 2 -O-C -CH-(CH2)k-COOH E- NH .0.
:00 is in which E is as defined above and k denotes an integer, is subjected to electrolysis on platinum wire-gauze electrodes with an amino acid derivative of the formula: 0 0 HOC-CH)1-CH -C -0-(CH 2 2 -S -B in which D and P are as defined above and I denotes an integer, where k and I together make the number n.
The invention further relates to a process for the preparation of asymmetrically substituted diatninodicarboxylic acid derivatives, of the formula: INALUMxOgS&P 6.MAY. 1998 14:48 SPRUSON FERGUSON 81 2 92615486 NO, 2311 F. 6 3 0 0 Ak-C -CH-(CH 2 )n-CjH-C by mixed Kolbe synthesis, which Is characterized in that a protected amino acid derivative of the formula: 0 11 A-C--CH H2)k -COOH E- NH s in which A and E are as defined below and k denotes an Integer, is subjected to electrolysis on platinum wire-gauze electrodes with an amino acid derivative of the formula: .9 4 0 HOC-(C H 2 1 -CH -C -B F- NH in which B and P are as defined below and I denotes an integer, where k and 1 together In ak the noue A and B in each case denote the radical -OR, where R denotes an optionally mono- or polyhalcogenated straight-chain or branched or cyclic alkyl radical *having 1-10 C atoms, for example an optionally halogenated methyl, ethyl, i-propyl, n-butyl, i-butyl, t-butyl radical and the like, a cyclohexyl, cyclopcntyl or cyclobutyl :is1 radical or phenyl.
R can additionally denote the radical -CI- 2 where X denotes the radicals 9-fluorenyl-, phenyl-, -OCH 3
-CI
2
SO
2
CH
3
-CH
2
SO
2 CAI{, -CCd 3 -CfI 2 with Y denoting halogen, -p-tosyl, a phenyl or phenacyl radical which is optionally mono- or polysubstituted by halogen, -NO 2 or alkoxy, for example p-broniophenacyl, p-chlorophenacyl and the like, diphenylrnethyl, triphenylrnethyl, 2-pyridyl, or a radical -SIRIPR 2
R
3 where the radicals
R
1
R
2 and R 3 in each case independently of one another can denote a straight-chain or branched alkyl radical having 1-4 C atoms or phenyl.
0NLh]O2;S 4 Preferably A and B denote a radical -OR, where R denotes a 9-fluorenylmethyl or a substituted or unsubstituted phenyl, benzyl or phenacyl radical or an optionally halogenated straight-chain or branched alkyl radical having 1-4 C atoms.
The radicals E and F in each case denote an optionally halogenated straight-chain, branched or cyclic alkyl radical having 1-10 C atoms, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl or hexyl radical and the like, which can optionally be mono- or polyhalogenated.
The radicals E and F can additionally denote a radical or o01 where W denotes a 9-fluorenylmethyl radical or a benzyl radical which is optionally mono- or polysubstituted by halogen, NO 2 alkoxy or -CN or mixed radicals therefrom, for example a bromobenzyl, dibromobenzyl, chlorobenzyl, O t dichlorobenzyl, nitrobenzyl, methoxybenzyl or cyanobenzyl S 20 radical and the like.
a. The substituents E and F, if the hydrogen atom is omitted, can additionally form one of the ring systems indicated.
The radicals E and F preferably in each case denote a radical o o AW r Ao
W
where W denotes a 9-fluorenylmethyl radical, an optionally substituted benzyl radical or a straight-chain or branched alkyl radical having 1-4 C atoms.
If the radicals A and B are different, the substituents on the amino function of the dicarboxylic acid can be identical or different. If the radicals A and B are identical, the substituents on the amino function i I I of the dicarboxylic acid must be different.
The centers of chirality of the dicarboxylic acids are determined by the choice of the starting materials used. They can either both have the D configuration or both have the L or D,L or L,D configuration respectively, for example 2,7-diaminosuberic acid mono-A ester mono-B ester when using N-E-D-glutamic acid A ester and N-F-L-glutamic acid B ester.
The asymmetrically substituted dicarboxylic acid derivatives according to the invention can be prepared by mixed Kolbe synthesis.
In this process, appropriately protected amino acid derivatives are subjected to electrolysis on platinum S 15 wire-gauze electrodes.
S. The starting compounds are known from the literature or can be prepared by methods familiar to the person skilled in the art.
The amino acid derivatives are dissolved in a solvent which is inert under the reaction conditions.
Suitable solvents are, for example, lower aliphatic alcohols, for example methanol, ethanol, propanol or i-propanol or a heterocyclic solvent such as, for example, pyridine, or dimethylformamide, acetonitrile, nitromethane or mixtures of such solvents.
In the electrolysis cell the solution of a base is added, for example alkali metal in alcoholic solution, for example sodium methoxide in methanol, or potassium ethoxide in ethanol.
Electrolysis is then carried out on platinum wire-gauze electrodes with cooling, the temperature preferably being kept at 18-25 0 C. The current strength during the electrolysis is about 5-15 A at 60-120 V applied voltage and is otherwise independent of the geometry of the electrodes used.
The electrolysis process is complete as soon as starting material can no longer be determined in the electrolysis solution.
The electrolysis solution is then optionally concentrated
-I
6 under low pressure, the residue is taken up in a suitable solvent, for example ethyl acetate, and this solution is washed successively with dilute acid, for example dilute hydrochloric acid, a saturated salt solution, tor example a saturated sodium hydrogen carbonate solution, and saturated sodium chloride solution.
The solution is then dried with a suitable drying agent, for example sodium sulfate or magnesium sulfate, filtered and concentrated again, optionally under low pressure.
The residue is purified by chromatography, for example on silica gel, it being possible to separate the symmetrically substituted by-products. The reaction proceeds in a good yield of 10-15 of theory to give the desired asymmetrically substituted final product.
15 Example 1: 29.41 g (96 mmol) of o-t-butyl N-t-butoxycarbonylglutamate and 35.63 g (96 mmol) of a-benzyl Nbenzyloxycarbonylglutamate were dissolved in 240 ml of MeOH and 80 ml of pyridine by swirling. The reaction 20 solution was transferred to the electrolysis cell having cylindrically arranged platinum wire-gauze electrodes. It 'was rinsed with MeOH and the electrolysis cell filled *with MeOH until both electrodes were completely immersed.
0.8 ml of NaOCH 3 (30 in MeOH) was then added, and the electrolysis cell was well cooled. When the reaction solution has cooled to 15 0 C, the wire-gauze apparatus is switched on. The reaction temperature was kept between +180 and +24 0 C by temperature control or by control of the current strength or current potential (5-15 A, 1;20 V).
The reaction course was checked by means of TLC.
After complete reaction the reaction solution was concentrated in a rotary evaporator at 40 0
C.
The residue from the Kolbe synthesis was dissolved in 500 ml of ethyl acetate, and washed first with dilute HCl solution (25 ml of conc. HC1 made up to 250 ml with H 2 then with 250 ml of sat. NaHCO3 and -7 finally with 250 ml each of sat. NaCi up to neutrality of the aqueous phase.
The organic phase was dried with Na 2
SO
4 filtered off and evaporated.
Evaporation residue: 58.17 g.
The evaporation residue was filtered through silica gel and then separated by means of HPLC.
YA. 4.5 g of pure monobenzyl mono-t-butyl N' -benzyloxycarbonyl-N' -t-butoxycarbonyl-2, 7-dianiinosuberate (10 of theory), m.p. 51-560C, [aJn -21.50.
The following compounds were prepared in an 0 0 see* 00.
0* 6 **be analogous manner: N. A B E Fn 2 0-benzyl 0-methyl t-butoxycarbonyl t-butoxycarbonyl 4 3 O-benzyl O-benzyl t-butoxycarbonyl benzyloxycarbonyl 4 4 0-benzyl 0-2-tosylethyl t-butoxycarbonyl benzyloxycarbonyl 4 5 0-benzyl 0-2-tonylethyl t-butoxycarbonyl t-butoxycarboiyl 4 6 O-benzyl 0.2-tonylethyl t-butoxycarbonyl benzyloxycarbonyl 3 7 0-benzyl 0-2-tocylethyl t-butoxycarbonyl benzyloxycarbonyl 2 20 8 0-berizyl 0-methyl t-butoxycarbonyl benzyloxycarbonyl 3 9 0-benzyl 0-phenacy3. t-butoxycarbonyl benzyloxycarbenyl 3 10 0-benzyl 0-2-trimethyl- t-butoxycarbonyl benzyloxycarbonyl 3 silylethyl 11 0-benzyl 0-berizyl t-butoxycarbonyl benzyloxycarbonyl 3 12 0-benzyl 0-2,2,2-tri- t-butoxycarbonyl benzyloxycarbonyl 2 chioroethyl 13 O-bcrzyl 0-benzyl t-butoxycurbonyl borizyloxycarbonyl 2 14 0-benzyl 0-2-tonylethyl t-butoxycorbonyl benzyloyaboy in Examples 5 and 14 the corresponding D- and Lamino acid derivatives were employed in mixed form.
Chemical data of the abovementioned compounds, where the abbreviations used have the following meaning: 8- 0..
a.
4* a 00@ 06009 Abbreviation Meaning OBn 0-benzyl OMe 0-methyl OEtzTos 0-ethyltosyl OtBu 0- tert-butyl Boc t -butozycarbonyl z benzyloxycarbonyl SUB n=4 PIM n=3 ADI n=2 Example 1: Boc-Z-StTB-OtBu-OBn 1 3 C-NMR(CDC1 3 100 MHz): 24.80(CH 2 24,82(CH 2 28.02(0-t- Bu-CH 3 28.34(Boo-CH 3 32.52(CH 2 32.72(CH 2 53.82(CH), 67.00 and 67.12(benzyl-CH 2 79.62((CH 3 of Boa), 15 81.57((CH 3 3 Cof OtBu), 128.09-128.633(aromatic 135.36, 136.30, 155.34 and 155.87(carbamate CO), 171.86 and 172.22 (CO).
Mp. 51-56-C [u]D -21.5 Exam~le 2: Di-Boc-SUB-OBn-O~e 3 C-NMR(CDC1 3 100MHZ): 24. 82 (2CH 2 1 2 8. 3 1(CHO 3 C),1 32.49 (CHO), 32.54 (CHO), 52. IS(ocHO), 53.38 (br a, 2CH) 66.99(benzyl-CH 2 128.31, 128.42, 128.59, 135.46, and 155.32(2 carbamate-CO), 172.57 and 172.20(ester CO).
M.p. 55-59-C [013D= -24.9 (1 in DMF) Excample-3: Boc-Z-SUB-Di-OBn "C-NMR (CDC1 3 10HZ): 24. 6 8(CH 2 24. 81 (CH 2 28.32(2 (CH 3 32.47 (2CH 2 53.37(CH), 53.83(Cu), 6 6. 9 9(benzyl -CH2) 67.13 (benzyl-CH 2 1 79.90 ((CHO) 3 C) 1 128.10-128.63 (aromatic C) 135.33, 135.46, 136.28, 155.30 -9and 155.83(carbamate CO), 172.17 and 172.56(ester CO) M.p. 65-67 0
C
[cl, -1.4 (5 in CHC1,) Example 4: Boc-Z-SUB-OBn-OEtTos C-NMR (CDC1 3 100MZz): 21. 65 (toly CH), 24.65 (CH), 24. 81 (CH 2 28. 32 (CH) 3 C) 3 2. 0 6 (CH 2 3 2. 3 8 (CH), 53 .12 53.80 (CH) 54.94 (OCR 2
CH
2
SO
2
C
7
H
7 58.27 (OCH 2 Cr 2
SO
2
C
7
R
7 67.01 (benzyl-cR 2 67.17 (benzyl-CH 2 80.05((CH) 3 128.12-128.65 (aromatic 130.08, 135.32, 136.27, 145.23, 155.26 and 155.90(carbamate CO), 172.15(2 ester CO) Oil 4 [aeD= +3.45 (5 in CHC1 3 Example 5: Di-Boc-D,L-SUB-OBn-OtTos 1 3 C-NMR(CDC1 3 100MHz): 21.63(tolyl-CH 3 24.79 (CHO), 24. 84 (CH) 2 8. 3 (2 (CH)3C) 3 2 13 (CH 2 32 52(CH), 53.23 (br S, 2CH), 54.99 (OCH 2
CH
2
SO
2
C
7
R
7 58.28(OCH 2
CH
2
SO
2
C
7
H
7 67.01(benzyl-CH 2 79.98(2(CH) 3
C)
128.13-128.61 (aromatic 135.45, 136.35, 145.21, 155.30 and 155.83(carbamate CO), 172.11(2 ester CO) xainple 6: Boc-Z-PIM-OBn-OEtTos 13 C-NMR (CDC1 3 1OMHz): 21. 10 (CH 2 2 1. 6 0 (tolyl CH 3 fff28.31( (CHO 3 C) 31.62(CHE), 31.90(CH 2 52.85(C), 53.55(CR), 54. 93 (OCH 2
CH
2
SO
2
C
7 58.32 (OCJI 2
CHSO,
2
CH),
67.05 and 67.22(benzyl-CH 2 80. 08((CH) 3 C) 128.11- 128.66(aromatic 130.05, 135.31, 136.25, 145.21, 155.45 and 155.83(carbaEmate CO), 171.97 and 172.08 (enter
CO)
Example 7: Boc-'Z--ADI-OBn-OtTou 1"C-NM (CDC1 3 100MHz): 21.60(tolyL-CH 3 28.17((CH 3 3
C),
28.29(CH 2 52.79(CH), 53.61(CH), 54.87(OC 2
CH
2
S
2
CR
7 58.29 (OCH 2
CH
2
S
2
C
7
H
7 1 67.04 and 67.31 (benzyl-CH 2 80.18((CH 3 3 C),128.05-128.67 (aromatic C) 130.09, 135.24, 136.20, 136.26, 145.27 and 156.00(2 carbamate CO), 171.59 and 171.75(ester CO) 10 Example 8: Boc-Z-PIM-OBn-OMe 1 3 C -NMR (CDC1 3 10OMHZ) 20.82 (CH) 1 21 16 (CH), 28.31((H 3 3 C) 31.97(CH), 3 2.17(CH, 52.23(OMe), 52.93(CH), 53.61(CH), 67.07(benzyl-CH 2 80.O1((CH 3 3
C),
128.17-128.64 (aromatic 135.29, 136.23, 155.55 and 156,06(carbamate CO), 172.12 and 173.06(ester CO) Examn1e 9: Boc -Z-PIM-On-OC136COCjH 3 C-NMR(CDC1 3 10IMHz): 20.82(2CH 2 28.33((CH) 3
C),
31.86(CHO), 32.16(CH), 53.08(CH), 53.69(CH), 66.35(OCH 2 COCH.), 66.97(benzyl-CH 2 67.13(benzyl CEI 2 80.05((CH) 3 127.77-128.89 (aromatic 133.99, 135.43, 136.36, 155.51 and 156.17(carbamate CO), 172.16(2 ester CO), 191.61(OCH 2
COCH
5 ExAMPle 0: Boc-Z-PIM-OBn-OCH 2
CH
2 Si (C 3 3 13 C-NMR(d 6 -DMSO, 100MHz) -1.54( (CH 3 3
S)
17 42(OCH 2
CH
2 Si (CHO 3 21.22(CH), 22.20(CH), 28.32((CH)3C), 31.91(CH 2 32.34(CH 2 53.01(CH), 53.73(CH), 63.74 (OcH 2
CH
2 Si (CH 3 67.05(benzyl-CH) 67.17 (benzyl-CH 2 79.89((CH 3 3 C) 128.14, 128.26, 128.50, 128.64, 135.32, 136.25, 155.58 and 156.06(carbamate CO), 172.17 and 172.68(2 ester CO) ExaMple 11: Boc-Z-PIM-Di-OBn lC.NMR (CDC, 10 04MHz): 21. 14 (CH 2 28 .30 (CH) 3
C),
31.92(CH 2 32.16(CH), 53.07(CH), 53.64(CH), 67.06(2 benzvl-CH 2 67.18(benzyl-Cu 2 79.98((CH 3 3 128.16, 128.29, 128.44, 128.50, 128.61, 128.63, 135.30, 135.40, 136.24, 155.53 and 156.04(carbamate CO), 172.09 and 172.41(2 ester CO).
Exampl e 12: Doc -Z -ADI:-OBn-OaH 2 CC1 3 3 C-NMR(CDC1 3 100MHz): 28.60 (CH) 3 C) 29.25 (CH, 00 (CH 2 I 53.34(CH), 53.78(CH), 74.67(OCH 2 CC1 3 67.47 (benzyl-CH 2 1 67.72 (benzyl 2 74.67 (OCH 2 CC1 3 80.69((CH 3 3 94.79(OCHCC1 3 128.42, 128.54, 128.74, 128.87, 128.96, 129.02, 135.43, 136.46, 155.53 and 56.17(carxbamate CO), 171.09 and 171.96(2 CO) 11 Example 13: Boc-Z-ADI-Di-OBf 1 3 C-_MR (cDC1 3 100MHz): 21. 2 2 (CH6), 22.20 (CH 2 28.32((C 3 3 31.91(CH 2 32.34 53 .01(CH), 53.73(CH), 63.74 (OCH 2
CH
2 Si(CH 3 67.05(benzyl- CHOI 67.17 (benzyl-CH), 79.89((CH 3 3 128.14, 128.26, 128.50, 128.64, 135.32, 136.25, 155.58 and 156.06(carbamate CO), 172.17 and 172.68(2 ester CO).
Example 14: Boc-Z-D,L-PIM-On-OEtTos 23C-NMR(CDC1 3 10 MHz): 20.98(CHOI 21.5B(tolyl-CH.), 28.29((CH) 3 C) 31.77(CH 2 31.93(CH), 52.98(CH), 53.73 54.94 (OCH 2
CH
2 So 2 C7H 7 1 58.25 (OCH 2
CH
2
SO
2
C
7
H
7 67.00 and 67.15(benzyl-Cal,), 80 .10(((CH) 3 128.09- 128.64(aromatic 130.05, 135.31, 136.32, 145.19, 155.28 and 156.02(carbamate CO), 171.87 and 171.94(ester
CC).
Claims (4)
- 4. a* #.1 a 10 where W represents 9-fluorenylmethyl, benzyl which is optionally mono-, poly- or mixed substituted by halogen, -NO 2 alkoxy or CN; or W represents a straight chain or branched alkcyl radical having i to 4 C atoms, and n represents an integer from 2 to 2. An asymmetrically substituted diaminodicarboxylic acid derivative of the i formula I according to claim 1, .44..0 wherein E and F in each case represent., sea 4 0 0 or where W represents 9-fluorenylmethyl, bernzyl which is optionally mono-, poly. or mixed subistituted by halogen, -NO 2 alkoxy or -CN; or W represents a straight chain or brancked alkyl radical having 1 to 4 C atoms, 3. Process for the preparation by miged Kolbe synthesis of asymmetrically substituted diaminodicarboxylic acid derivatives of the formula I as claimed in claim 1, which process is characterized in that a, protected amino acid derivative of the formula: 0 E- NH (i 2s in which B is as defined in claim 1 and k denotes an integer, is subjected to electrolysis on platinum wire-gauze electrodes with an amino acid derivative of the formula: [MN)MbaOOO9UL
- 6. MAY, 998 14:48 SPRUSON FERGUSON 61 29215486 NO, 2311 P, 8 0 0 HOIOC H 2 1 -CH -C (CH 2 2 -S -B F-NH 0 onl) in which B3 and F are as defined in claim 1 and I denotes an integer, where k and 1 together make the number n. 4. A process for the preparation by mixed Kolbe synthesis of asymmnetrically substituted diaminodic-arboxylic acid derivatlies as claimed in claim 2, which process is characterised in that a protected amino acid derivative of the forrnala: 0 CH 2 -0-C--CH----CH2)k-COOH In which E is as defined above in claim 2 and k denotes an integer, is subjected to 10electrolysis on platinum wire-gauze electrodes with an amino acid derivative of the lo: formula: 0 0 HOOC-(CH 2 1 -CH-C -0-(CH1) 2 -S -13 (I 4. in which B3 and F are as defined above In claim 2 and I denotes an integer, where k and I together make the number n. A process according to claim 3 or claimn 4, characterised in that the temperature in the electrolysis is kept between 18-251C by cooling. 6, A process for the preparation of asyimmetrically substituted diaminodicarboxylic, acid derivatives substantially as hercinbefore described with reference to any one of the Examples.
- 7. The product of the process of any one of claims 3 to 6.
- 8. Asymmetrically substituted diaminodicarboxcylic acid derivatives substantially as hereinbefore described with reference to any one of the Examples. Dated 6 May, 1998 Hafslund Nycomed Pharma Aktiengesellschaft Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON tNA~L~baJO19:80~S& I Asymmetrically Substituted Diaminocarboxylic Acid Derivatives and a Process for their Preparation Abstract The invention relates to asymmetrically substituted diaminocarboxylic acid I derivatives of the formula 0 0 A (C H2)C B H E I F H in which A and B independently of one another in each case denote a radical -OR where R denotes an optionally :,iono or polyhalogenated straight-chain, branched or cyclic alkyl radical having 1-10 C-atoms, phenyl or the radical -CH 2 where X denotes the radicals 10 9-fluorenyl, phenyl -OCH 3 -CH2SO 2 CH 3 -CH 2 SO 2 C 6 H 5 -CC13, -CH2-Y, with Y denoting halogen, -p-tosyl, a phenyl or phenacyl radical which is optionally mono- or polysubstituted by halogen, -NO 2 or alkoxy, diphenylmethyl, triphenylmethyl, 2-pyridyl or a radical SiRIR 2 R 3 where tho radicals RI, R 2 and R 3 in each case independently of one another can denote a straight-chain or branched alkyl radical having 1-4 C atoms or phenyl, E and F in each case denote an optionally halogenated straight-chain, branched or cyclic 0 0 W A, W alkyl radical having 1-10 C atoms or a radical or where W can denote 4 a 9-fluorenylmethyl radical or benzyl radical which is optionally mono- or polysubstituted by halogen, -N02, alkoxy or -CN or mixed radicals therefrom, or the substituents E and if the hydrogen atom is omitted, together with the nitrogen atom form one of the O 0 Si N following ring systems S, i or where, if the radicals A and B are different, E and F can be different or identical, on the other hand if the radicals A and B are identical, E and F must be different, and n denotes an integer from 2 to where the centres of chirality in the molecules are determined by the starting materials used and both can have the L configuration or both can have the D or D,L or L,D configuration respectively. ILibUl0446JOC I
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HUT68091A (en) | 1995-05-29 |
CN1107463A (en) | 1995-08-30 |
HRP940472A2 (en) | 1997-04-30 |
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NO304941B1 (en) | 1999-03-08 |
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SK98594A3 (en) | 1995-07-11 |
IL110706A (en) | 1999-11-30 |
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ZA946323B (en) | 1995-03-23 |
NZ264002A (en) | 1995-08-28 |
RU2142450C1 (en) | 1999-12-10 |
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