CA2127938A1 - Asymmetrically substituted diaminodicarboxylic acid derivatives and a process for their preparation - Google Patents
Asymmetrically substituted diaminodicarboxylic acid derivatives and a process for their preparationInfo
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- CA2127938A1 CA2127938A1 CA002127938A CA2127938A CA2127938A1 CA 2127938 A1 CA2127938 A1 CA 2127938A1 CA 002127938 A CA002127938 A CA 002127938A CA 2127938 A CA2127938 A CA 2127938A CA 2127938 A1 CA2127938 A1 CA 2127938A1
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- denotes
- benzyl
- phenyl
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- 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
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- 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
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- 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
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- 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 System
- 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
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- 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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- 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)
- Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
Abstract
Abstract The invention relates to novel asymmetrically substituted diaminodicarboxylic acid derivatives of the formula
Description
~ i~ 7 ~
Asymmetrically sub~tituted diaminodicarboxylic acid - f -~
derivativQs and a process for th~ir preparation.
The invention relates to novel asymmetrically substituted diaminodicarboxylic acid derivati~e~ a~d a process for their preparation.
A~ymmetrically Rub~tituted diaminodicarboxylic acid derivative~ are useful interm~diate~ for the syntheRi~ of peptid~.
In J. Org. Chem. 1980, 45, 3078-3080, a~ymmetrically substltuted diaminosuberic acid deriva-ti~ are describ9d which were prepared by mixed Rolbe synthe~i~. Separation of the symmetrical by-product~ was unsucce~f~l thsre. The preparation of a~ymmetrically ~ub~tituted diaminopimelic acid deri~ati~e~ by a compli-cated 9-stage enantio~elective synthe3is iB al~o known from Tetrahedro~ Lott. 30, 1982, 33, 4727-4730.
~nexp~ctedly, it ha~ been po~sibl~ to find ~ovel ~ -a~ymmetrically substituted diaminodicarboxylic acid derivativec which are u~ful i~tQrmcd~ate~ for the ~ynthe~is of peptide~ a~d co~pou~ds containing un~atural ~mino acid~.
The in~ention thereore relate~ to a~y~metrically sub~tituted diaminodicarboxylic acid deri~ativ~a of the formula O O
Il 11 A - C - CH - (C~2 )n ~ CF.' - C - }~ (I) ....
E-NH F-NH
25 in which A and B i~d~pende~tly oi o~e a~otker i~ each,ca~e denote a radical -OR where R de~otes an optionally mono-or polyhalogenated ~traight-chain, bra~ched or cyclic alkyl radical having 1-10 C-a~o~s, phe~yl ox the radical -CH2-X, where X de~otea the radicals 9-~luoren~l, phenyl, -OC~3~ -C~2SO2C$3, ~C~2So2C6~s~ -CC13~ C~2-Y, with Y
denoting halogen, -p-to~yl, a phenyl or phenacyl radical 't~ r~g which ia op~ion~lly mono- or poly~ub~tituted by halogen, N2 or alkoxy, diph~ylmethyl, triphenylmethyl, 2-pyridyl or a radical SiR1R2R3, where the radicals R1, R2 and R3 in each ca~e independently of o~e another can denote a ~traight-chain or branched alkyrl radical having 1-4 C atom~ or phenyl, E and F in each ca~ denote an optionally halogenated ~traight-chain, branched or cyclic alkyl radical havin~ 1-10 C atom~ or a radical 0~ o,W
wh~re W can d~note a 9-fluoreny~meth~l radical or a benzyl radical which i~ optionally mono- or poly~ub~tituted by halogen, -~0~, alkoxy or -CN or mlxed radiaals there~rom, or the ~ubntituent~ E a~d F, i~ th~
hydrog~n atom i~ omitted, togeShQ~ with th~ nitrogen atom form one of the foll~wing ri~g ~yst~m~
~N Csl ~N
where, lf the radicals A and B are diff~rent, ~ and F can be different or identical, on the oth~r hand if ~he radicals A and B ar~ ident~al, E a~d F ~u~t be dif4erent, and n denote~ an integer ~rom 2 to 10, wh~re the center~
of chirality in the moleaule~ are dekermined by the ~tarting material~ u~ed and both c~n have th~ L
co~iguration or both can hava the D or D,L or L,D
configuzation resp0cti~ely.
The invention further relate~ to a proceR~ for the prepara~ion o~ such asymmatrically ~ub~titut~d diaminodicarboxylic acid derivativa~ by mixed g~lbe l - :
~ynthe~i~, which i8 characterized in that a protected amino acid deri~ati~e o~ the ~ormula O
A - C - C~ - (CH2)k - COOH (Il) E-NH
in whlch A and E have the abov~tioned m~aning and k denote~ a~ integer, i8 ~ub; octed to electrolysi~ on plati~u~ wire-gauzo elec~rode~ with an d ~o acid derivative o~ the formula ~ ~
O : . .-.:
E~OOC - (C~2)1 - C~ - C - B ( 111 ) F-~ :
in which B and F haYe the abov~m0ntio~ed meaning a~d 1 ~:
denote~ an integor, where k and 1 together make the number ~.
In the ~ormulae I, II a~d III, A and ~ in each ca~e denote the radical -OR, where R denotes ~n optio~ally mono- ox polyhalogenated ~traig~t-cha~n or branched or cyclic al~yl r~dical having 1-10 C atom~, for example an optionally halogenated methyl, sthyl, 15 i-propyl, n-butyl, i-butyl, t-butyl radical a~d the like, : ::
a cyclohexyl, cyclopentyl or cyclobutyl radi~al Qr phe~1.
R can additionally denote the radical -C~-X, where X denote~ the radical~ 9-~l~orenyl-, phenyl-, -OC~I3~ -CH2SOlC~3~ C~aS02CCHs~ -CC~3~ -C~2-Y, llqith Y
denoting halogen, -p-to~yl, a ~henyl or phenacyl radical which i~ optionally mono- or poly~ub~tituted by halogen, -NO2 or alkoxy, or exampl~ p-bro~ophenacyl, p-chlorop~e~acyl a~d the like, diphenylmethyl, triphenylmethyl, 2-pyridyl, or a radical -SiR~R2~, wh~re the radical~ Rl, R2 and R3 in ~aah ca~e indepe~dently of one another can denote a ~traight-ch~in or branched al~yl radical haYing 1-~ C atom~ or phenyl.
,~. .. ,~ . :,:
, . .,. . ., . " ,:
i;,: ~ . . . . ; :
~,.j, ., ~ ~ , ,": : .
: . : , , 3 ~ 3 Preferably A and B d~note a radical -OR, where R
denote3 a 9-fluorenylmsthyl or a sub~tituted or unsub~ti-tuted phenyl, be~z~l or phanaeyl radieal or an optionally h~logenated ~t~aight-ehain or branehed al~yl radieal ha~ing 1-4 C a om~.
The radieals ~ and F in eaah ca~e denotQ an optio~ally halogenated straight-ehain, branehed or eyclic alkyl radieal having 1-10 C atom~, ~or example a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, p~ntyl or hexyl radieal and the like, which ean optio-nally be mono- or polyhalog~uated.
The xadieals E and F ean additionally denote a radieal o o ~ or ~ O,w where W denotes a 9-fluoronyl~thyl radieal or a b~nzyl radieal whieh i~ optionally mo~o- or ~olysubstituted by halogen, ~2~ alXoxy or -C~ or mixed radieal~ therefrom, for example a bromobenzyl, dlbromobenzyl~ chlorobenzyl, diehlorobenzyl, nitrobenzyl, methoxyben~yl or eyanobenzyl 20 radical aud the liks. ~.
The ~ub~titue~t~ E and F, i~ the hydrogen ato~ i8 omitted, can additionally form one of the ring ~y~tems indicatsd.
The radical~ E and F preferably in each case denote a radical o o ~ w or ~ O,~
where W denotes a 9-fluorenylmethyl radical, an op~io-~ally sub~tituted benzyl radical or a ~traight-chai~ or branehed alkyl radical ha~ing 1-4 C ato~.
If the radical~ A a~d ~ are difierent, the ~ub~tituent~ on the amino functio~ of the dicarboxylic acid can be identical or differsnt. I the radlcals A and B ars identical, the sub~tituents on the amino function . . ., ~ -:. , . :
3 ~
of the dicarboxyllc a~id mu~t b~ di~fer~nt.
The cent~r~ o chirality o~ the dicarboxylic acids are determin~d by the ahoice o the starting materials used. They c~n either both have the D aonfigu-ration or both have the L or D,L or ~,D configurationrespectively, for axample N'-E-N''-F~ D,L-2,7-diaminosuberic acid mono-A e~ter mo~o-B e~ter when u~ing N-~-D-glutamic acid A ester and N-F-~-glut~mic acid B ~ster.
The a~ymmetrically ~ubHtituted dicarboxylic aaid dQr~vati~s according to the in~ention can be prepared by mixed ~olbe syn~h0~
In this proc~a~, appropri~taly protectQd amino aci.d derivati~s~ are ~ubjected to elactroly~is on platinu~
wire-gauze elect~odes.
The ~tarting compow~d~ are known from the literature or can be prepared by ~ethods ~amlliar to the per~o~ ~killed - -i~ the art.
The amino acid d~rivative~ are di~olved in a 20 801ve~t which i~ inert under the reaction condi~lo~u.
Suitable ~olvents are, for example, lower aliphatic alcohols, for example methanol, ethanol, propanol or i-propanol er a heterocyclic ~olvant such a~, for exam~le, pyridine, or dimethylformEmide, aceto~itril~, nitromethans or ~ixtures of such ~olv~t~.
In the electroly~ ell the ~olution o~ a ba~e i~ added, 40r e~mplQ alkali metal in alcoholic ~olution~ -for ~xample ~odium methoxide in methanol~ or pot~sium ethoxide i~ ethanol.
Electrolysi~ is then carried out on platinum wire-gauze electrode~ with cooling, the t~mperature preferably being kept at 18-25C. The current stre~gth during th~ electroly~is is about 5-15 A at 60-120 V
applied ~oltage a~d i~ otherwi~e independ~nt of the geometry of the Qlectrode~ used.
The electrolysis proce~s i~ compl~e as ~oon as ~tarti~g material can no longer be de~er~ined in the electroly~is solution .
The electroly~i~ solution i8 th~n option~lly concen ~ated .:.:, :: - ~ ,, - , ' , ' ~, . :- . , . :: , f,J 7 ~
under low pre~ure, the residue i~ taken up ln a suitable ~olvent, for example ethyl acetate, and thi~ solution iB
wa~hed succe~nlvely with dllute acid, for exa~ple dilute hydrochloric-acid, a saturated ~alt ~olution, for example a ~aturated ~odium hydrogen carbonate ~olutio~, a~d saturatsd ~odium chlorida nolution.
The ~olution i~ then dried with a ~uitable drying agent, for example ~odium nul~ate or magnesium uul~ate, filtered and concentrated agai~, optioually under low prea~ure.
The redidue i~ purif ted by chromatography, for example on silica gel, it being po~sible to separate the ~ymmetrically cub~t~tuted by-product~. The reaction proceed~ in a good yield of 10-15 % of theory to give the de~ired a~ymmetrically ~ub~tituted ~inal product.
15 ~xample 1: :~
29.41 g (96 mmol) o~ ~-t-butyl N-t-butoxy~
carbonylgluta~ate and 35.63 g ~95 ~ol) of ~-benzyl N-benzyloxyaarbonylglutamate were dis~ol~ed i~ 240 ml of ~ -MeOH and 80 ml of pyridin~ by ~wirli~g. The reaction 20 ~olutio~ wa~ tran~ferred to the electroly~i~ cell haviug ~ ~:
cylindrically arranged plati~um wire~gauze electrode~. It was rinsed with MeO~ and the electrolysi~ cell filled with MeOH until both el~ctrode3 wer~ compl~tely i~mersed.
o.a ml of NaOC~3 (30 % in MeO~) wa~ then added, and the 25 electroly~i~ c911 wa~ well cooled. When the reaction :
801utlon ha~ cooled to 15C, ths wire-gauze apparatu~ i~
~witched on. The reaction temperature wa~ kept b~tween ~18 and +24C by temperature contro~ or by con~rol o~
the current strength or curre~t potantial (5-15 A, 60- -120 V).
The ~eaction cour~e wan checked by ~eans of T~C.
After complete reaction the reaction ~ol~tio~ wa~ ao~c~n ;:
trated in a rotary evapor3tor at 40C.
The res~duQ ~rom the Kolbe ~ynthesi~ was dis~olved in 500 ml of ethyl a~etate, and wa~hed ~ t with dilute ~Cl ~olutlon (25 ~1 o~ conc. ~Cl made up ~o 250 ml with H20), the~ with 250 ml o~ ~at. NaHCO3 and ,.,. , . , . " .. , - ~ . . . ~ -: ::;: . , : , .
, . ~ , ,, . .: . , - , :
, .. , .,, - . . . .
: , . . .
Y~ 3 finally with 250 ml e~ch of ~at. NaCl up to neutrality of ~ ;:
the aqueous pha~e.
The organic phase wac dried with Na2SO~, fi~tered off and evaporated~
~vaporation re idue: 58.17 g.
The evaporatio~ re~idue wa~ ~iltered through silica gel and then ~eparated by ~eianc of ~PLC.
Yield: 4.5 g of pure mo~obenzyl mono-t-butyl N'-benzyloxycarbonyl-N''~t-butoxycarbo~yl-2,7-diamino-suberate (10 ~ of theory), m.p. 51-56C, 1~]D = -21.5.
The following compoundR were prepared in a~ ~ ~-analogou~ ~anner:
i ~ - ~ =
No _ ~3 F n 2 0-benzyl 0-methylt-butoxycarbonyl t-butoxycarbonyl 4 1 5 3 0-benzyl 0-benzylt-butoxycarbonyl b~nzyloxyearbonyl 4 , ~ _ 4 0-benzyl 0-2-tosylethylt-butoxyearbonyl benzyloxyearbonyl 4 : :
_ . . "::
0-benzyl 0-2 to~ylethylt-butoxyearbonyl t-butoxyaarbonyl 4 l _ 6 0-benzyl 0-2-to~ylethylt-butoxyearbonyl benzyloxyearbonyl 3 I_ __ _ ' ' :~:
7 0-benzyl 0-2-to~ylet~ylt-butoxyearbonyl benzyloxyearbonyl 2 I _ _ ~ ~ ' ~
2 0 8 0-benzyl 0-methylt-butoxyearbonyl benzyloxycarbonyl 3 . ~
l_ _ _ : ' : ' 9 0-benzyl 0-phenaeylt-butoxycarbonyl benzyloxycarbonyl 3 ~ :~
I_ . _ . _ , ~, , 0-benzyl 0-2-trimethyl-t-butoxycarbonyl benzyloxycarbonyl 3 isilylethyl l _ 11 0-benzyl 0-benzylt-butoxyci~rbonyl benzyloxyearbonyl 3 _ _ 12 0-benzyl 0-2,2,2-trl- t-butoxycarbonyl benzyloxycarbonyl 2 chloroethyl _ 2 5 13 0-benzyl 0-benzyl t-bu~oxycarbonyl benzyloxycarbonyl 2 I _ _ _ _ _ 14 0-benzyl 0-2-tosylethyl t-butoxycarbonyl benzyloxycarbonyl 3 I _ _ . _ _ _ In ~xample~ S a~d 14 the corre~ponding D- and L-amino acid deri~ati~e~ were employed in mixed ~orm.
Chemical data of the abo~ementioned compound~, where the abbreviation~ u~ed havs the following meaning:
...... - , ....... .. . . . .
,., . , . , ,. . .: ..................... .::. :
, : . , - ~ :- ~ ::: . : , 3 i~
.
Abbrsviation ~eaning _ _ OBn O-benzyl I _ O~e O-methyl I _ _ OEtTo~ O-ethyltosyl I _ OtBu O-tert-butyl I _ .
Boc t-butoxycarbonyl _ _ .
Z benzyloxycarbonyl ~ .
SlJ~3 r~=4 l : :
¦PIM n=3 ADI n=2 I _ _ Examl~le_1: Boc-Z-Sl~B-OtBu-OBn ~ 6 13C-NMR(CDCl3, 100 M~z): 24.80~C~2), 24.82(C~Hl~, 28.02(0-t-l3u-CEI33, 28.34SBoc-C~I3), 32.52(C~a), 32.72(CEl2), 53~82(C~I)o 67.00 and 67.12(benzyl-l~I2), 79.62( (C}I3) 3C~ of Boc), 15 81.57( ~CH3)3C of OtBu), 128.09-128.63(aromatic C), 135.36, 136.30, 155.34 and 155.87(carbamate CO), 171.86 and ~ ~ -172.22 (CO) O
Mp. 51-56C
= -21.S
: .
20 Example 2: Di-Boc-S~-OBn-O~e ~3C-NMR(s~DC13~ lOOMH~): 24.82 (2CH2) ~ 28.31 (CH3)3C), 32.49(CE2), 32.54(CH2), 52.18(0CH3), 53.38(br ~3, 2CE~), -66.99(benzyl-CH2), 128.31, 128.42, 128.59, 135.46, and 155.32(2 carbamate-CO), 172.57 and 172.20(euter CO).
M.p. 55-59C
~a:lD= -24.9 (1 % in DMF) Exa~pl~ 3: Boc-Z-SlJB-Di-OBn ~3C-NMR(CDCl3, lOOMHz): 24.68(CH2),24.81(CH2), 28.32(2 (CEI3)3C), 32.4712C~I2), 53.37(C~I), 53.83(C~), 66.99(benzyl-CH2), 67.13(be~3Yl-C~2)~ 79.90((C~I3)3C), 128.10-128.63 (aro~atic C), 135.33, 135.46, 136.28, 155.30 ., .. ~ ., , , . ., ~ , . . .
. . .: . :. : : : - . . . : . . ~ . . , ,.. ~ .. ,, . ., " , . . , : . . , ~' ,'' ,'' '' . '' "' ` ~ ' ` ' : ., '' . ' '1, ' : ,'' ' ~ . . ~ ' ' ' ' '' '' ' ' ~',: ' ' ' ' ' ' ~'.' ' ,~, ' '' ' ' ' : ". . :
".' ,'' ' ' , .'i ' ' ~ ' .' , and 155.83(Carbamat~ CO), 172.17 and 172.56(e~ter CO) M.p. 65-67C
[~] D = 1 . 4 (5 % i~ C~ICl3) EXamP1~ 4: BO~-Z-S~B-OBn- OE tTOB
l3C-N~R(C~Cl3, 1001~Iz): 21.65(tolyl-CH3), 24.65(CH2)~
24.81(CEI2), 28.32((~I3)3C)~ 32.06 (C1E~2) ~ 32.38(CH2), 53 .12 (CH), 53. 80 (CEE), 54.94 (OCEIlC~2SO2C.~E7), 58. 27 (OC~I2CHaSO2C7H7), 67.01 (beIlzyl-cH2), 67~17(benzyl-C~2), 80.05((C~I3)3C), 128.12~128.65(arOma'CiC C), 130.08, 135.32, 10 136.27, 145.23, 155.26 a~d 155.90 (carbamate CO), 172O15(2 ~8ter CO) Oil [a~] D +3.45 (5 % in ~}ICl3) Example 5: Di-Boc-D,I.-SllB-OBn-OEtTo~
lS l3C_NMR(CDCl3~ 100MEIz): 21.63~tolyl-C~I3), 24.79(C~
24.84 (C~1:2), 28,31(2 (C~3)3C) ~ ~2.13 (C~EI2), 32.5~(C~2), 53.23(br ~, 2C~), 54-99(C~2C~a92C7H7)~
5828(C~ 2S2C7}I7), 6701 (benzyl-CH2), 79.98(2(CE3) 3C), 128.13-128.61(arOmatiC C), 135.45, 136.35, 145.21, 155.30 20 and 155.83(carbamate CO), 1'72.11(2 e~ter CO) Exam~le 6: B~C-Z-PIN-OBn-O~tTOB
3C-NMR~COCl3, lOOMElz): 2~L.lO(C~2), 21.60(tolyl-CEI3), 28.31((CH3)3C), 31-62(CH2)~ 31.90(CH2), 52 85(CH)~
53.55(C~), 54.93(O~H2C~2SO2C7~7), 58~32(OC~2G~2SO2C7~7), 25 67.05 and 67.22(benzYl-CH2)~ 80-08((CE~3)3C)~ 128-11-128.66(arOmatiC C), 130.05, 135.31, 136.25, 145.21, 155.45 and 155.83(carbamate CO), 171.97 and 172.08 (e~ter CO) EXamP1e 7: BOC-Z-~DI-OBn-OB~TO~;
30 13C_NMR$CDC13, 100M~Z): 21.60(tO1Y1-CH3)~ 28.17((CH3)3C~, 28.29(C~2), 52.795CH), 53.61(CH), 54.87(OC~3CH2~O2C7~7), 58-29(CH2C~S2C7~7)~ 67.04 ;3nd 67~31~benZY1-C~2)~
80.18((CH3)3C1,128.05-128.67(arOmatiC C), 130.09, 135.24, 136.20, 136.26, 145.27 a~d 156.00(2 Ca~bamate CO), 171.59 and 171.75(e~t~r CO) ,1 cJ ~
Exam~e 8: Boc-Z-PIPq-OBn-OP~3 3C~ CDCl3~ 100MHz): 20.82(CH2), 21.16~C~2)~
28.31((CH3) 3C) ~ 31.97(CHl), 32.17 (C~2) ~ 52.23(0~
52.93(C~), 53.61(C~I), 67.07(benzyl-CH2), 80.01((C~I3)3C), 128.17-128.64(aromatic C~, 135.29, 136.23, 155.55 and 156.06(carbamate CO), 172.12 and 173.06(e~ter CO) Exam~le 9: Boc-Z-PIP~-OBn~ IaCOC~5 R(cDcl3~ 100P~z) 20.82(2CH~), 28.33((~3)3C), 31.86(CH2), 32.16(CH2), 53~08(CH), 53.69(C~
66.35(O~I2COC6~Is), 66.97(benzyl-CEIa), 67.13(be~zyl ~EIa3, 80.05~ 13~3C), 127.77-128.89(axomatic: C), 133.99, 135.43, 136.36, 15S.Sl and 156.17lcarbamate CO), 172.16(2 e~ter CO)~ 191.61(OC}I2~:OC6E~5) E:xample 10_ Boc-Z-PI~ t)BY~ ~Si~C~3)3 s3C-NMR(d6-DMSO~ 100MHz): -1.54 ( (C~3)3Si), 17.42 (OC~,CE~2Si (C~I3)3), 21 ~22 (C~2) ~ 22 o2S) (CE~2) 28 ~ 32 ((~}I3)3C~, 31.91(C~,), 32.34(C~Ia), 53.01(C~
53.73(C~I), 63.74(0~I2C~Si ~C~EI3) 3), 67.05~be~lzYl-(~2)~
67.17tbenzyl-C~2), 79~89((CHI)3C)~ 128~14~ 128~26~ 128~50 128~64~ 135.32, 136.25, 155.58 alld 155.06(carbamate CO), 172~17 and 172~68 (2 ester CO) ;
Exam~l~ 11: Boc-Z-PI~-Di-OBn 3C_NMR(CDCl3~ 100MEIz): 21.14(CH2), 28.30((~II)3C), 31. 92 (CHa), 32.16(CH2), 53.07(ClI)~ 53 ~ 64(CH), 67 ~ 06 (2 benzyl-C }Ia), 67.18(benzyl-CEI2), 79.98((C}I3)3C), 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).
Exam~le 12: ~oc-Z-BDI-OBII-OOElaCCl3 ~3C-N~R~CDC13, 1001~EIz): 28.60((C~3)3C), 29.25~C~2)J
30.00(CH2), 53.34(C~I), 53.78(C~1), 74.67(O~I2CCl3), 67.47(beDzYl-c~2)~ 67.72(b~nzyl-CH2), 74.67(0C:HlCCl3), 80.69((C~I3)3C), 94.79~0C~I2~Cl3), 128.4~, 128.54, 128.74, 128.87, 128.96, 129.02, 135.43, 136.46, 155.53 z~nd 156.17(carbamate CO), 171.09 and 171.96(2 CO) : . ~ . ~ . . . . . ~
:, ~ ~ : , ., . . , , .,:
h'$ ~ 79~S
~xample 13: ~oc-Z-ADI-Di-OB~
R(cDcl3~ 100M~z~: 21.22( OEl)~22.20(CH23, 28.32( (C~3) 3C), 31.91(CH2), 32.34(CH2~, 53.01(CH), 53.73(CH), 63.74(OCH2CH2Si (CH3) 3), 67.05(b~nzyl-C~2), 67.17(benzyl- ~ ), 79.89((CH3)3C), 128.14, 128.26, 128.50, 128.64, 135.32, 136.25, 155.58 and 156.06(carba~ate CO), 172.17 and 172.68(2 e~ter CO).
ExamDle 14: Boc-Z-D,~-PI~2-O~n-OEtTo~
~C-~MR(CDCl3, 100N~z)s 20.98(CH2), 21.58(tolyl-CH3), 28.29(CH3)3C), 31.77(C~), 31.93(CK2)~ 520g~(C~
53.73(C~), 54.94(OCK2~2SQ2~E~), 58.25(OC~C~2SO2C7~7), 67.00 a~ 67.15(~enzyl-~23, 80.10((C~333C), 128.09-128.64(aromatic C), 130.05, 135.31, 136.32, 145.19, 155.28 and 156.02(carba~ate CO), 171.87 and 171.94(Q~t~r CO~
Asymmetrically sub~tituted diaminodicarboxylic acid - f -~
derivativQs and a process for th~ir preparation.
The invention relates to novel asymmetrically substituted diaminodicarboxylic acid derivati~e~ a~d a process for their preparation.
A~ymmetrically Rub~tituted diaminodicarboxylic acid derivative~ are useful interm~diate~ for the syntheRi~ of peptid~.
In J. Org. Chem. 1980, 45, 3078-3080, a~ymmetrically substltuted diaminosuberic acid deriva-ti~ are describ9d which were prepared by mixed Rolbe synthe~i~. Separation of the symmetrical by-product~ was unsucce~f~l thsre. The preparation of a~ymmetrically ~ub~tituted diaminopimelic acid deri~ati~e~ by a compli-cated 9-stage enantio~elective synthe3is iB al~o known from Tetrahedro~ Lott. 30, 1982, 33, 4727-4730.
~nexp~ctedly, it ha~ been po~sibl~ to find ~ovel ~ -a~ymmetrically substituted diaminodicarboxylic acid derivativec which are u~ful i~tQrmcd~ate~ for the ~ynthe~is of peptide~ a~d co~pou~ds containing un~atural ~mino acid~.
The in~ention thereore relate~ to a~y~metrically sub~tituted diaminodicarboxylic acid deri~ativ~a of the formula O O
Il 11 A - C - CH - (C~2 )n ~ CF.' - C - }~ (I) ....
E-NH F-NH
25 in which A and B i~d~pende~tly oi o~e a~otker i~ each,ca~e denote a radical -OR where R de~otes an optionally mono-or polyhalogenated ~traight-chain, bra~ched or cyclic alkyl radical having 1-10 C-a~o~s, phe~yl ox the radical -CH2-X, where X de~otea the radicals 9-~luoren~l, phenyl, -OC~3~ -C~2SO2C$3, ~C~2So2C6~s~ -CC13~ C~2-Y, with Y
denoting halogen, -p-to~yl, a phenyl or phenacyl radical 't~ r~g which ia op~ion~lly mono- or poly~ub~tituted by halogen, N2 or alkoxy, diph~ylmethyl, triphenylmethyl, 2-pyridyl or a radical SiR1R2R3, where the radicals R1, R2 and R3 in each ca~e independently of o~e another can denote a ~traight-chain or branched alkyrl radical having 1-4 C atom~ or phenyl, E and F in each ca~ denote an optionally halogenated ~traight-chain, branched or cyclic alkyl radical havin~ 1-10 C atom~ or a radical 0~ o,W
wh~re W can d~note a 9-fluoreny~meth~l radical or a benzyl radical which i~ optionally mono- or poly~ub~tituted by halogen, -~0~, alkoxy or -CN or mlxed radiaals there~rom, or the ~ubntituent~ E a~d F, i~ th~
hydrog~n atom i~ omitted, togeShQ~ with th~ nitrogen atom form one of the foll~wing ri~g ~yst~m~
~N Csl ~N
where, lf the radicals A and B are diff~rent, ~ and F can be different or identical, on the oth~r hand if ~he radicals A and B ar~ ident~al, E a~d F ~u~t be dif4erent, and n denote~ an integer ~rom 2 to 10, wh~re the center~
of chirality in the moleaule~ are dekermined by the ~tarting material~ u~ed and both c~n have th~ L
co~iguration or both can hava the D or D,L or L,D
configuzation resp0cti~ely.
The invention further relate~ to a proceR~ for the prepara~ion o~ such asymmatrically ~ub~titut~d diaminodicarboxylic acid derivativa~ by mixed g~lbe l - :
~ynthe~i~, which i8 characterized in that a protected amino acid deri~ati~e o~ the ~ormula O
A - C - C~ - (CH2)k - COOH (Il) E-NH
in whlch A and E have the abov~tioned m~aning and k denote~ a~ integer, i8 ~ub; octed to electrolysi~ on plati~u~ wire-gauzo elec~rode~ with an d ~o acid derivative o~ the formula ~ ~
O : . .-.:
E~OOC - (C~2)1 - C~ - C - B ( 111 ) F-~ :
in which B and F haYe the abov~m0ntio~ed meaning a~d 1 ~:
denote~ an integor, where k and 1 together make the number ~.
In the ~ormulae I, II a~d III, A and ~ in each ca~e denote the radical -OR, where R denotes ~n optio~ally mono- ox polyhalogenated ~traig~t-cha~n or branched or cyclic al~yl r~dical having 1-10 C atom~, for example an optionally halogenated methyl, sthyl, 15 i-propyl, n-butyl, i-butyl, t-butyl radical a~d the like, : ::
a cyclohexyl, cyclopentyl or cyclobutyl radi~al Qr phe~1.
R can additionally denote the radical -C~-X, where X denote~ the radical~ 9-~l~orenyl-, phenyl-, -OC~I3~ -CH2SOlC~3~ C~aS02CCHs~ -CC~3~ -C~2-Y, llqith Y
denoting halogen, -p-to~yl, a ~henyl or phenacyl radical which i~ optionally mono- or poly~ub~tituted by halogen, -NO2 or alkoxy, or exampl~ p-bro~ophenacyl, p-chlorop~e~acyl a~d the like, diphenylmethyl, triphenylmethyl, 2-pyridyl, or a radical -SiR~R2~, wh~re the radical~ Rl, R2 and R3 in ~aah ca~e indepe~dently of one another can denote a ~traight-ch~in or branched al~yl radical haYing 1-~ C atom~ or phenyl.
,~. .. ,~ . :,:
, . .,. . ., . " ,:
i;,: ~ . . . . ; :
~,.j, ., ~ ~ , ,": : .
: . : , , 3 ~ 3 Preferably A and B d~note a radical -OR, where R
denote3 a 9-fluorenylmsthyl or a sub~tituted or unsub~ti-tuted phenyl, be~z~l or phanaeyl radieal or an optionally h~logenated ~t~aight-ehain or branehed al~yl radieal ha~ing 1-4 C a om~.
The radieals ~ and F in eaah ca~e denotQ an optio~ally halogenated straight-ehain, branehed or eyclic alkyl radieal having 1-10 C atom~, ~or example a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, p~ntyl or hexyl radieal and the like, which ean optio-nally be mono- or polyhalog~uated.
The xadieals E and F ean additionally denote a radieal o o ~ or ~ O,w where W denotes a 9-fluoronyl~thyl radieal or a b~nzyl radieal whieh i~ optionally mo~o- or ~olysubstituted by halogen, ~2~ alXoxy or -C~ or mixed radieal~ therefrom, for example a bromobenzyl, dlbromobenzyl~ chlorobenzyl, diehlorobenzyl, nitrobenzyl, methoxyben~yl or eyanobenzyl 20 radical aud the liks. ~.
The ~ub~titue~t~ E and F, i~ the hydrogen ato~ i8 omitted, can additionally form one of the ring ~y~tems indicatsd.
The radical~ E and F preferably in each case denote a radical o o ~ w or ~ O,~
where W denotes a 9-fluorenylmethyl radical, an op~io-~ally sub~tituted benzyl radical or a ~traight-chai~ or branehed alkyl radical ha~ing 1-4 C ato~.
If the radical~ A a~d ~ are difierent, the ~ub~tituent~ on the amino functio~ of the dicarboxylic acid can be identical or differsnt. I the radlcals A and B ars identical, the sub~tituents on the amino function . . ., ~ -:. , . :
3 ~
of the dicarboxyllc a~id mu~t b~ di~fer~nt.
The cent~r~ o chirality o~ the dicarboxylic acids are determin~d by the ahoice o the starting materials used. They c~n either both have the D aonfigu-ration or both have the L or D,L or ~,D configurationrespectively, for axample N'-E-N''-F~ D,L-2,7-diaminosuberic acid mono-A e~ter mo~o-B e~ter when u~ing N-~-D-glutamic acid A ester and N-F-~-glut~mic acid B ~ster.
The a~ymmetrically ~ubHtituted dicarboxylic aaid dQr~vati~s according to the in~ention can be prepared by mixed ~olbe syn~h0~
In this proc~a~, appropri~taly protectQd amino aci.d derivati~s~ are ~ubjected to elactroly~is on platinu~
wire-gauze elect~odes.
The ~tarting compow~d~ are known from the literature or can be prepared by ~ethods ~amlliar to the per~o~ ~killed - -i~ the art.
The amino acid d~rivative~ are di~olved in a 20 801ve~t which i~ inert under the reaction condi~lo~u.
Suitable ~olvents are, for example, lower aliphatic alcohols, for example methanol, ethanol, propanol or i-propanol er a heterocyclic ~olvant such a~, for exam~le, pyridine, or dimethylformEmide, aceto~itril~, nitromethans or ~ixtures of such ~olv~t~.
In the electroly~ ell the ~olution o~ a ba~e i~ added, 40r e~mplQ alkali metal in alcoholic ~olution~ -for ~xample ~odium methoxide in methanol~ or pot~sium ethoxide i~ ethanol.
Electrolysi~ is then carried out on platinum wire-gauze electrode~ with cooling, the t~mperature preferably being kept at 18-25C. The current stre~gth during th~ electroly~is is about 5-15 A at 60-120 V
applied ~oltage a~d i~ otherwi~e independ~nt of the geometry of the Qlectrode~ used.
The electrolysis proce~s i~ compl~e as ~oon as ~tarti~g material can no longer be de~er~ined in the electroly~is solution .
The electroly~i~ solution i8 th~n option~lly concen ~ated .:.:, :: - ~ ,, - , ' , ' ~, . :- . , . :: , f,J 7 ~
under low pre~ure, the residue i~ taken up ln a suitable ~olvent, for example ethyl acetate, and thi~ solution iB
wa~hed succe~nlvely with dllute acid, for exa~ple dilute hydrochloric-acid, a saturated ~alt ~olution, for example a ~aturated ~odium hydrogen carbonate ~olutio~, a~d saturatsd ~odium chlorida nolution.
The ~olution i~ then dried with a ~uitable drying agent, for example ~odium nul~ate or magnesium uul~ate, filtered and concentrated agai~, optioually under low prea~ure.
The redidue i~ purif ted by chromatography, for example on silica gel, it being po~sible to separate the ~ymmetrically cub~t~tuted by-product~. The reaction proceed~ in a good yield of 10-15 % of theory to give the de~ired a~ymmetrically ~ub~tituted ~inal product.
15 ~xample 1: :~
29.41 g (96 mmol) o~ ~-t-butyl N-t-butoxy~
carbonylgluta~ate and 35.63 g ~95 ~ol) of ~-benzyl N-benzyloxyaarbonylglutamate were dis~ol~ed i~ 240 ml of ~ -MeOH and 80 ml of pyridin~ by ~wirli~g. The reaction 20 ~olutio~ wa~ tran~ferred to the electroly~i~ cell haviug ~ ~:
cylindrically arranged plati~um wire~gauze electrode~. It was rinsed with MeO~ and the electrolysi~ cell filled with MeOH until both el~ctrode3 wer~ compl~tely i~mersed.
o.a ml of NaOC~3 (30 % in MeO~) wa~ then added, and the 25 electroly~i~ c911 wa~ well cooled. When the reaction :
801utlon ha~ cooled to 15C, ths wire-gauze apparatu~ i~
~witched on. The reaction temperature wa~ kept b~tween ~18 and +24C by temperature contro~ or by con~rol o~
the current strength or curre~t potantial (5-15 A, 60- -120 V).
The ~eaction cour~e wan checked by ~eans of T~C.
After complete reaction the reaction ~ol~tio~ wa~ ao~c~n ;:
trated in a rotary evapor3tor at 40C.
The res~duQ ~rom the Kolbe ~ynthesi~ was dis~olved in 500 ml of ethyl a~etate, and wa~hed ~ t with dilute ~Cl ~olutlon (25 ~1 o~ conc. ~Cl made up ~o 250 ml with H20), the~ with 250 ml o~ ~at. NaHCO3 and ,.,. , . , . " .. , - ~ . . . ~ -: ::;: . , : , .
, . ~ , ,, . .: . , - , :
, .. , .,, - . . . .
: , . . .
Y~ 3 finally with 250 ml e~ch of ~at. NaCl up to neutrality of ~ ;:
the aqueous pha~e.
The organic phase wac dried with Na2SO~, fi~tered off and evaporated~
~vaporation re idue: 58.17 g.
The evaporatio~ re~idue wa~ ~iltered through silica gel and then ~eparated by ~eianc of ~PLC.
Yield: 4.5 g of pure mo~obenzyl mono-t-butyl N'-benzyloxycarbonyl-N''~t-butoxycarbo~yl-2,7-diamino-suberate (10 ~ of theory), m.p. 51-56C, 1~]D = -21.5.
The following compoundR were prepared in a~ ~ ~-analogou~ ~anner:
i ~ - ~ =
No _ ~3 F n 2 0-benzyl 0-methylt-butoxycarbonyl t-butoxycarbonyl 4 1 5 3 0-benzyl 0-benzylt-butoxycarbonyl b~nzyloxyearbonyl 4 , ~ _ 4 0-benzyl 0-2-tosylethylt-butoxyearbonyl benzyloxyearbonyl 4 : :
_ . . "::
0-benzyl 0-2 to~ylethylt-butoxyearbonyl t-butoxyaarbonyl 4 l _ 6 0-benzyl 0-2-to~ylethylt-butoxyearbonyl benzyloxyearbonyl 3 I_ __ _ ' ' :~:
7 0-benzyl 0-2-to~ylet~ylt-butoxyearbonyl benzyloxyearbonyl 2 I _ _ ~ ~ ' ~
2 0 8 0-benzyl 0-methylt-butoxyearbonyl benzyloxycarbonyl 3 . ~
l_ _ _ : ' : ' 9 0-benzyl 0-phenaeylt-butoxycarbonyl benzyloxycarbonyl 3 ~ :~
I_ . _ . _ , ~, , 0-benzyl 0-2-trimethyl-t-butoxycarbonyl benzyloxycarbonyl 3 isilylethyl l _ 11 0-benzyl 0-benzylt-butoxyci~rbonyl benzyloxyearbonyl 3 _ _ 12 0-benzyl 0-2,2,2-trl- t-butoxycarbonyl benzyloxycarbonyl 2 chloroethyl _ 2 5 13 0-benzyl 0-benzyl t-bu~oxycarbonyl benzyloxycarbonyl 2 I _ _ _ _ _ 14 0-benzyl 0-2-tosylethyl t-butoxycarbonyl benzyloxycarbonyl 3 I _ _ . _ _ _ In ~xample~ S a~d 14 the corre~ponding D- and L-amino acid deri~ati~e~ were employed in mixed ~orm.
Chemical data of the abo~ementioned compound~, where the abbreviation~ u~ed havs the following meaning:
...... - , ....... .. . . . .
,., . , . , ,. . .: ..................... .::. :
, : . , - ~ :- ~ ::: . : , 3 i~
.
Abbrsviation ~eaning _ _ OBn O-benzyl I _ O~e O-methyl I _ _ OEtTo~ O-ethyltosyl I _ OtBu O-tert-butyl I _ .
Boc t-butoxycarbonyl _ _ .
Z benzyloxycarbonyl ~ .
SlJ~3 r~=4 l : :
¦PIM n=3 ADI n=2 I _ _ Examl~le_1: Boc-Z-Sl~B-OtBu-OBn ~ 6 13C-NMR(CDCl3, 100 M~z): 24.80~C~2), 24.82(C~Hl~, 28.02(0-t-l3u-CEI33, 28.34SBoc-C~I3), 32.52(C~a), 32.72(CEl2), 53~82(C~I)o 67.00 and 67.12(benzyl-l~I2), 79.62( (C}I3) 3C~ of Boc), 15 81.57( ~CH3)3C of OtBu), 128.09-128.63(aromatic C), 135.36, 136.30, 155.34 and 155.87(carbamate CO), 171.86 and ~ ~ -172.22 (CO) O
Mp. 51-56C
= -21.S
: .
20 Example 2: Di-Boc-S~-OBn-O~e ~3C-NMR(s~DC13~ lOOMH~): 24.82 (2CH2) ~ 28.31 (CH3)3C), 32.49(CE2), 32.54(CH2), 52.18(0CH3), 53.38(br ~3, 2CE~), -66.99(benzyl-CH2), 128.31, 128.42, 128.59, 135.46, and 155.32(2 carbamate-CO), 172.57 and 172.20(euter CO).
M.p. 55-59C
~a:lD= -24.9 (1 % in DMF) Exa~pl~ 3: Boc-Z-SlJB-Di-OBn ~3C-NMR(CDCl3, lOOMHz): 24.68(CH2),24.81(CH2), 28.32(2 (CEI3)3C), 32.4712C~I2), 53.37(C~I), 53.83(C~), 66.99(benzyl-CH2), 67.13(be~3Yl-C~2)~ 79.90((C~I3)3C), 128.10-128.63 (aro~atic C), 135.33, 135.46, 136.28, 155.30 ., .. ~ ., , , . ., ~ , . . .
. . .: . :. : : : - . . . : . . ~ . . , ,.. ~ .. ,, . ., " , . . , : . . , ~' ,'' ,'' '' . '' "' ` ~ ' ` ' : ., '' . ' '1, ' : ,'' ' ~ . . ~ ' ' ' ' '' '' ' ' ~',: ' ' ' ' ' ' ~'.' ' ,~, ' '' ' ' ' : ". . :
".' ,'' ' ' , .'i ' ' ~ ' .' , and 155.83(Carbamat~ CO), 172.17 and 172.56(e~ter CO) M.p. 65-67C
[~] D = 1 . 4 (5 % i~ C~ICl3) EXamP1~ 4: BO~-Z-S~B-OBn- OE tTOB
l3C-N~R(C~Cl3, 1001~Iz): 21.65(tolyl-CH3), 24.65(CH2)~
24.81(CEI2), 28.32((~I3)3C)~ 32.06 (C1E~2) ~ 32.38(CH2), 53 .12 (CH), 53. 80 (CEE), 54.94 (OCEIlC~2SO2C.~E7), 58. 27 (OC~I2CHaSO2C7H7), 67.01 (beIlzyl-cH2), 67~17(benzyl-C~2), 80.05((C~I3)3C), 128.12~128.65(arOma'CiC C), 130.08, 135.32, 10 136.27, 145.23, 155.26 a~d 155.90 (carbamate CO), 172O15(2 ~8ter CO) Oil [a~] D +3.45 (5 % in ~}ICl3) Example 5: Di-Boc-D,I.-SllB-OBn-OEtTo~
lS l3C_NMR(CDCl3~ 100MEIz): 21.63~tolyl-C~I3), 24.79(C~
24.84 (C~1:2), 28,31(2 (C~3)3C) ~ ~2.13 (C~EI2), 32.5~(C~2), 53.23(br ~, 2C~), 54-99(C~2C~a92C7H7)~
5828(C~ 2S2C7}I7), 6701 (benzyl-CH2), 79.98(2(CE3) 3C), 128.13-128.61(arOmatiC C), 135.45, 136.35, 145.21, 155.30 20 and 155.83(carbamate CO), 1'72.11(2 e~ter CO) Exam~le 6: B~C-Z-PIN-OBn-O~tTOB
3C-NMR~COCl3, lOOMElz): 2~L.lO(C~2), 21.60(tolyl-CEI3), 28.31((CH3)3C), 31-62(CH2)~ 31.90(CH2), 52 85(CH)~
53.55(C~), 54.93(O~H2C~2SO2C7~7), 58~32(OC~2G~2SO2C7~7), 25 67.05 and 67.22(benzYl-CH2)~ 80-08((CE~3)3C)~ 128-11-128.66(arOmatiC C), 130.05, 135.31, 136.25, 145.21, 155.45 and 155.83(carbamate CO), 171.97 and 172.08 (e~ter CO) EXamP1e 7: BOC-Z-~DI-OBn-OB~TO~;
30 13C_NMR$CDC13, 100M~Z): 21.60(tO1Y1-CH3)~ 28.17((CH3)3C~, 28.29(C~2), 52.795CH), 53.61(CH), 54.87(OC~3CH2~O2C7~7), 58-29(CH2C~S2C7~7)~ 67.04 ;3nd 67~31~benZY1-C~2)~
80.18((CH3)3C1,128.05-128.67(arOmatiC C), 130.09, 135.24, 136.20, 136.26, 145.27 a~d 156.00(2 Ca~bamate CO), 171.59 and 171.75(e~t~r CO) ,1 cJ ~
Exam~e 8: Boc-Z-PIPq-OBn-OP~3 3C~ CDCl3~ 100MHz): 20.82(CH2), 21.16~C~2)~
28.31((CH3) 3C) ~ 31.97(CHl), 32.17 (C~2) ~ 52.23(0~
52.93(C~), 53.61(C~I), 67.07(benzyl-CH2), 80.01((C~I3)3C), 128.17-128.64(aromatic C~, 135.29, 136.23, 155.55 and 156.06(carbamate CO), 172.12 and 173.06(e~ter CO) Exam~le 9: Boc-Z-PIP~-OBn~ IaCOC~5 R(cDcl3~ 100P~z) 20.82(2CH~), 28.33((~3)3C), 31.86(CH2), 32.16(CH2), 53~08(CH), 53.69(C~
66.35(O~I2COC6~Is), 66.97(benzyl-CEIa), 67.13(be~zyl ~EIa3, 80.05~ 13~3C), 127.77-128.89(axomatic: C), 133.99, 135.43, 136.36, 15S.Sl and 156.17lcarbamate CO), 172.16(2 e~ter CO)~ 191.61(OC}I2~:OC6E~5) E:xample 10_ Boc-Z-PI~ t)BY~ ~Si~C~3)3 s3C-NMR(d6-DMSO~ 100MHz): -1.54 ( (C~3)3Si), 17.42 (OC~,CE~2Si (C~I3)3), 21 ~22 (C~2) ~ 22 o2S) (CE~2) 28 ~ 32 ((~}I3)3C~, 31.91(C~,), 32.34(C~Ia), 53.01(C~
53.73(C~I), 63.74(0~I2C~Si ~C~EI3) 3), 67.05~be~lzYl-(~2)~
67.17tbenzyl-C~2), 79~89((CHI)3C)~ 128~14~ 128~26~ 128~50 128~64~ 135.32, 136.25, 155.58 alld 155.06(carbamate CO), 172~17 and 172~68 (2 ester CO) ;
Exam~l~ 11: Boc-Z-PI~-Di-OBn 3C_NMR(CDCl3~ 100MEIz): 21.14(CH2), 28.30((~II)3C), 31. 92 (CHa), 32.16(CH2), 53.07(ClI)~ 53 ~ 64(CH), 67 ~ 06 (2 benzyl-C }Ia), 67.18(benzyl-CEI2), 79.98((C}I3)3C), 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).
Exam~le 12: ~oc-Z-BDI-OBII-OOElaCCl3 ~3C-N~R~CDC13, 1001~EIz): 28.60((C~3)3C), 29.25~C~2)J
30.00(CH2), 53.34(C~I), 53.78(C~1), 74.67(O~I2CCl3), 67.47(beDzYl-c~2)~ 67.72(b~nzyl-CH2), 74.67(0C:HlCCl3), 80.69((C~I3)3C), 94.79~0C~I2~Cl3), 128.4~, 128.54, 128.74, 128.87, 128.96, 129.02, 135.43, 136.46, 155.53 z~nd 156.17(carbamate CO), 171.09 and 171.96(2 CO) : . ~ . ~ . . . . . ~
:, ~ ~ : , ., . . , , .,:
h'$ ~ 79~S
~xample 13: ~oc-Z-ADI-Di-OB~
R(cDcl3~ 100M~z~: 21.22( OEl)~22.20(CH23, 28.32( (C~3) 3C), 31.91(CH2), 32.34(CH2~, 53.01(CH), 53.73(CH), 63.74(OCH2CH2Si (CH3) 3), 67.05(b~nzyl-C~2), 67.17(benzyl- ~ ), 79.89((CH3)3C), 128.14, 128.26, 128.50, 128.64, 135.32, 136.25, 155.58 and 156.06(carba~ate CO), 172.17 and 172.68(2 e~ter CO).
ExamDle 14: Boc-Z-D,~-PI~2-O~n-OEtTo~
~C-~MR(CDCl3, 100N~z)s 20.98(CH2), 21.58(tolyl-CH3), 28.29(CH3)3C), 31.77(C~), 31.93(CK2)~ 520g~(C~
53.73(C~), 54.94(OCK2~2SQ2~E~), 58.25(OC~C~2SO2C7~7), 67.00 a~ 67.15(~enzyl-~23, 80.10((C~333C), 128.09-128.64(aromatic C), 130.05, 135.31, 136.32, 145.19, 155.28 and 156.02(carba~ate CO), 171.87 and 171.94(Q~t~r CO~
Claims (4)
1. Asymmetrically substituted diaminodicarboxylic acid derivatives of the formula (I) in which A and B independently of one another in each case denote a radical -OR where R denotes an optionally mono-or polyhalogenated straight-chain, branched or cyclic alkyl radical having 1-10 C-atoms, phenyl or the radical -CH2-X, where X denotes the radicals 9-fluoroenyl, phenyl, -OCH3, -CH2SO2CH3, -CH2SO2C6H5, -CCl3, -CH2-Y, with Y
denoting halogen , -p-tosyl, a phenyl or phenacyl radical which is optionally mono- or polysubstituted by halogen, -NO2 or alkoxy, disphenylmethyl, triphenylmethyl,
denoting halogen , -p-tosyl, a phenyl or phenacyl radical which is optionally mono- or polysubstituted by halogen, -NO2 or alkoxy, disphenylmethyl, triphenylmethyl,
2-pyridyl or a radical SiR1R2R3, where the radicals R2, R2 and R3 in each case independently of one another can denotes 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 alkyl radical having 1-10 C atoms or a radical or where W can denote a 9-fluorenylmethyl radical or a benzyl radical which is optionally mono- or polysubstituted by halogen, -NO2, alkoxy or -CN or mixed radicals therefrom, or the substitutents E and F, if the hydrogen atom is omitted, together with the nitrogen atom form one of the following ring systems 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 10, where the centers 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.
2. Asymmetrically substituted diaminodicarboxylic acid derivatives of the formula I according to Claim 1, according to which A and B denote a radical -OR, where R
denotes a 9-fluorentylmethyl or a substituted or unsubsti-tuted phenyl, benzyl or phenacyl radical, a 2-(2-pyridyl)ethyl radical, a 2-p-tosylethyl radical or an optionally halogenated straight-chain or branched alkyl radical having 1-4 C atoms, E and F in each case denote a radical or where W denotes a 9-fluorenylmethyl radical, an optio-nally substituted benzyl radical or a straight-chain or branched alkyl radical having 1-4 C atoms and n denotes an integer from 2 to 10.
configuration or both can have the D or D,L or L,D
configuration respectively.
2. Asymmetrically substituted diaminodicarboxylic acid derivatives of the formula I according to Claim 1, according to which A and B denote a radical -OR, where R
denotes a 9-fluorentylmethyl or a substituted or unsubsti-tuted phenyl, benzyl or phenacyl radical, a 2-(2-pyridyl)ethyl radical, a 2-p-tosylethyl radical or an optionally halogenated straight-chain or branched alkyl radical having 1-4 C atoms, E and F in each case denote a radical or where W denotes a 9-fluorenylmethyl radical, an optio-nally substituted benzyl radical or a straight-chain or branched alkyl radical having 1-4 C atoms and n denotes an integer from 2 to 10.
3. Process for the preparation of such asymmetrically substituted diaminodicarboxylic acid derivatives by mixed Kolbe synthesis, which is characte-rized in that a protected amino acid derivative of the formula (II) in which A and E have the abovementioned meaning and k denotes an integer, is subjected to electrolysis on platinum wire-gauze electrodes with an amino acid derivative of the formula (III) in which B and F have the abovementioned meaning and 1 denotes an integer, where k and l together make the number n.
4. A process according to Claim 3, characterized in that the temperature in the electrolysis is kept between 18-25°C by cooling.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0168393A AT401517B (en) | 1993-08-20 | 1993-08-20 | ASYMMETRICALLY SUBSTITUTED DIAMINODICARBOXYLIC DERIVATIVES AND A METHOD FOR THE PRODUCTION THEREOF |
| ATA1683/93 | 1993-08-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2127938A1 true CA2127938A1 (en) | 1995-02-21 |
Family
ID=3518736
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002127938A Abandoned CA2127938A1 (en) | 1993-08-20 | 1994-07-13 | 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) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4161521A (en) * | 1975-08-08 | 1979-07-17 | Merck & Co., Inc. | Somatostatin analogs |
| 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 |
-
1993
- 1993-08-20 AT AT0168393A patent/AT401517B/en not_active IP Right Cessation
-
1994
- 1994-07-13 CA CA002127938A patent/CA2127938A1/en not_active Abandoned
- 1994-07-14 NZ NZ264002A patent/NZ264002A/en unknown
- 1994-08-04 EP EP94112178A patent/EP0639560A1/en not_active Withdrawn
- 1994-08-05 AU AU68927/94A patent/AU692774B2/en not_active Ceased
- 1994-08-16 YU YU51494A patent/YU51494A/en unknown
- 1994-08-18 SK SK985-94A patent/SK98594A3/en unknown
- 1994-08-18 IL IL11070694A patent/IL110706A/en not_active IP Right Cessation
- 1994-08-19 JP JP6195542A patent/JPH07173118A/en not_active Withdrawn
- 1994-08-19 NO NO943062A patent/NO304941B1/en not_active IP Right Cessation
- 1994-08-19 RU RU94030731A patent/RU2142450C1/en active
- 1994-08-19 HU HU9402413A patent/HUT68091A/en active IP Right Revival
- 1994-08-19 FI FI943811A patent/FI943811A/en unknown
- 1994-08-19 HR HRA1683/93A patent/HRP940472A2/en not_active Application Discontinuation
- 1994-08-19 ZA ZA946323A patent/ZA946323B/en unknown
- 1994-08-19 CZ CZ941998A patent/CZ199894A3/en unknown
- 1994-08-20 CN CN94116814A patent/CN1107463A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| YU51494A (en) | 1997-09-30 |
| NO304941B1 (en) | 1999-03-08 |
| EP0639560A1 (en) | 1995-02-22 |
| AT401517B (en) | 1996-09-25 |
| SK98594A3 (en) | 1995-07-11 |
| ZA946323B (en) | 1995-03-23 |
| HUT68091A (en) | 1995-05-29 |
| AU692774B2 (en) | 1998-06-18 |
| CZ199894A3 (en) | 1995-03-15 |
| NO943062L (en) | 1995-02-21 |
| FI943811A0 (en) | 1994-08-19 |
| FI943811A (en) | 1995-02-21 |
| AU6892794A (en) | 1995-03-02 |
| NZ264002A (en) | 1995-08-28 |
| CN1107463A (en) | 1995-08-30 |
| IL110706A (en) | 1999-11-30 |
| RU94030731A (en) | 1996-08-20 |
| NO943062D0 (en) | 1994-08-19 |
| HU9402413D0 (en) | 1994-11-28 |
| HRP940472A2 (en) | 1997-04-30 |
| ATA168393A (en) | 1996-02-15 |
| JPH07173118A (en) | 1995-07-11 |
| IL110706A0 (en) | 1994-11-11 |
| RU2142450C1 (en) | 1999-12-10 |
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