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 PDF

Info

Publication number
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
Authority
AU
Australia
Prior art keywords
radical
denotes
benzyl
integer
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU68927/94A
Other versions
AU6892794A (en
Inventor
Johann Hiebl
Franz Rovenszky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hafslund Nycomed Pharma AG
Original Assignee
Hafslund Nycomed Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hafslund Nycomed Pharma AG filed Critical Hafslund Nycomed Pharma AG
Publication of AU6892794A publication Critical patent/AU6892794A/en
Application granted granted Critical
Publication of AU692774B2 publication Critical patent/AU692774B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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

Landscapes

  • 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)

  1. 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
  2. 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.
  3. 7. The product of the process of any one of claims 3 to 6.
  4. 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
AU68927/94A 1993-08-20 1994-08-05 Asymmetrically substituted diaminodicarboxylic acid derivatives and a process for their preparation Ceased AU692774B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT1683/93 1993-08-20
AT0168393A AT401517B (en) 1993-08-20 1993-08-20 ASYMMETRICALLY SUBSTITUTED DIAMINODICARBOXYLIC DERIVATIVES AND A METHOD FOR THE PRODUCTION THEREOF

Publications (2)

Publication Number Publication Date
AU6892794A AU6892794A (en) 1995-03-02
AU692774B2 true AU692774B2 (en) 1998-06-18

Family

ID=3518736

Family Applications (1)

Application Number Title Priority Date Filing Date
AU68927/94A Ceased AU692774B2 (en) 1993-08-20 1994-08-05 Asymmetrically substituted diaminodicarboxylic acid derivatives and a process for their preparation

Country Status (17)

Country Link
EP (1) EP0639560A1 (en)
JP (1) JPH07173118A (en)
CN (1) CN1107463A (en)
AT (1) AT401517B (en)
AU (1) AU692774B2 (en)
CA (1) CA2127938A1 (en)
CZ (1) CZ199894A3 (en)
FI (1) FI943811A (en)
HR (1) HRP940472A2 (en)
HU (1) HUT68091A (en)
IL (1) IL110706A (en)
NO (1) NO304941B1 (en)
NZ (1) NZ264002A (en)
RU (1) RU2142450C1 (en)
SK (1) SK98594A3 (en)
YU (1) YU51494A (en)
ZA (1) ZA946323B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4161521A (en) * 1975-08-08 1979-07-17 Merck & Co., Inc. Somatostatin analogs

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR77929B (en) * 1981-01-29 1984-09-25 Fujisawa Pharmaceutical Co
JPS6327499A (en) * 1986-07-21 1988-02-05 Asahi Chem Ind Co Ltd Alpha,alpha'-diaminosuberic acid derivative

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4161521A (en) * 1975-08-08 1979-07-17 Merck & Co., Inc. Somatostatin analogs

Also Published As

Publication number Publication date
FI943811A0 (en) 1994-08-19
CZ199894A3 (en) 1995-03-15
AU6892794A (en) 1995-03-02
CA2127938A1 (en) 1995-02-21
NO943062L (en) 1995-02-21
RU94030731A (en) 1996-08-20
FI943811A (en) 1995-02-21
HUT68091A (en) 1995-05-29
CN1107463A (en) 1995-08-30
HRP940472A2 (en) 1997-04-30
HU9402413D0 (en) 1994-11-28
NO304941B1 (en) 1999-03-08
EP0639560A1 (en) 1995-02-22
JPH07173118A (en) 1995-07-11
SK98594A3 (en) 1995-07-11
IL110706A (en) 1999-11-30
AT401517B (en) 1996-09-25
ZA946323B (en) 1995-03-23
NZ264002A (en) 1995-08-28
RU2142450C1 (en) 1999-12-10
NO943062D0 (en) 1994-08-19
ATA168393A (en) 1996-02-15
IL110706A0 (en) 1994-11-11
YU51494A (en) 1997-09-30

Similar Documents

Publication Publication Date Title
JPH05247039A (en) Novel tetraoxo-diazabicyclo-(3,3,1)-nonane compound and preparation thereof
Nutt et al. Useful intermediates for synthesis of dicarba analogs of cystine peptides: selectively protected. alpha.-aminosuberic acid and. alpha.,. alpha.'-diaminosuberic acid of defined stereochemistry
WO2014094354A1 (en) Preparation of maytansinoid esters
US6201118B1 (en) Process for forming an N-acylated, N,N-containing bicyclic ring from piperazic acid or an ester thereof especially useful as an intermediate in the manufacture of a caspase inhibitor
Kohn et al. Syntheses and spectral properties of substituted imidazolidones and imidazolines
GB2066812A (en) 5'-acyl-uridine derivatives and processes for the preparation thereof
Miyoshi Peptide Synthesis via N-Acylated Aziridinone. II. The Reaction of N-Acylated Aziridinone and Its Use in Peptide Synthesis
US11708336B2 (en) Anodic oxidation of 5-aminouracil
Napoli et al. Synthesis of [1-15N]-labeled 2'-deoxyinosine and 2'-deoxyadenosine
AU692774B2 (en) Asymmetrically substituted diaminodicarboxylic acid derivatives and a process for their preparation
Kardassis et al. Electrogenerated chiral cationic glycine equivalents—Part 2: Chiral 3-methoxy-2, 5-morpholinediones from (S)-α-hydroxy acids and dimethyl aminomalonate
Bradshaw et al. The preparation of new chiral diphenyl‐substituted macrocyclic polyether‐diester compounds and their enantiomeric recognition of chiral organic ammonium salts
JP2000502661A (en) Method for synthesizing 2-chloro-5-chloromethylthiazole
HIGUCHI et al. Chemistry of Succinimido Esters. IV. A Facile Preparation of N-Succinimidyl Carboxylates Using N, N'-Disuccinimidyl Carbonate
US5627302A (en) Asymmetrically substituted diaminodicarboxylic acid derivatives
Guirado et al. A new synthetic route to 2-oxazolines. The electrochemical reduction of N-(2, 2-dichloroethyl) amides as a key step
AU700928B2 (en) Process for the preparation of substituted diaminodicarboxylic acid derivatives
JP3459270B2 (en) Preparation of N-tert-butoxycarbonyl-maleimide
Prasitpan et al. 5-Bromo-DL-tryptophan and protected intermediates for peptide synthesis
MAKI Reduction of the Amidine C= N Bond of 7-Aminofurazano (3, 4-d)-pyrimidines with Sodium Borohydride
Di Gregorio et al. Mono-and polyanhydride formation by reaction of 2, 2, 4, 4, 6, 6-hexachlorotriazatriphosphorine with carboxylic acid salts under mild conditions
US3658793A (en) 6-amino-5-aza- and -5 7-diaza-azulenes and process for the production thereof
HU190527B (en) Process for preparing thiazole derivatives
EP0158843B1 (en) A n-(6-substituted pyridine-2-carbonyl)-3-substituted histidine derivative, a method of preparing the same and its use as an anti-tumor agent
CA1187834A (en) Method for the preparation of narwedine-type dienones and their derivatives

Legal Events

Date Code Title Description
MK14 Patent ceased section 143(a) (annual fees not paid) or expired