CA2077002A1 - Substituted 2,3-diamino acids, processes for their preparation and their use as intermediates for peptide active substances - Google Patents
Substituted 2,3-diamino acids, processes for their preparation and their use as intermediates for peptide active substancesInfo
- Publication number
- CA2077002A1 CA2077002A1 CA 2077002 CA2077002A CA2077002A1 CA 2077002 A1 CA2077002 A1 CA 2077002A1 CA 2077002 CA2077002 CA 2077002 CA 2077002 A CA2077002 A CA 2077002A CA 2077002 A1 CA2077002 A1 CA 2077002A1
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- Canada
- Prior art keywords
- compounds
- meaning given
- general formula
- preparation
- atoms
- 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.)
- Abandoned
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002253 acid Substances 0.000 title claims abstract description 9
- 150000007513 acids Chemical class 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims abstract description 8
- 239000013543 active substance Substances 0.000 title claims abstract description 6
- 239000000543 intermediate Substances 0.000 title claims abstract description 6
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- FCFWEOGTZZPCTO-QMMMGPOBSA-N (2s)-3,6-dimethoxy-2-propan-2-yl-2,5-dihydropyrazine Chemical group COC1=N[C@@H](C(C)C)C(OC)=NC1 FCFWEOGTZZPCTO-QMMMGPOBSA-N 0.000 claims description 2
- QPLJYAKLSCXZSF-UHFFFAOYSA-N 2,2,2-trichloroethyl carbamate Chemical compound NC(=O)OCC(Cl)(Cl)Cl QPLJYAKLSCXZSF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000004030 hiv protease inhibitor Substances 0.000 abstract description 2
- 239000002461 renin inhibitor Substances 0.000 abstract description 2
- 229940086526 renin-inhibitors Drugs 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910001868 water Inorganic materials 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- -1 bislactim ether halides Chemical class 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- 101000654316 Centruroides limpidus Beta-toxin Cll2 Proteins 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 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
- 230000000903 blocking effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- CEMZBWPSKYISTN-YFKPBYRVSA-N methyl (2s)-2-amino-3-methylbutanoate Chemical compound COC(=O)[C@@H](N)C(C)C CEMZBWPSKYISTN-YFKPBYRVSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Novel substituted 2,3-diamino acids, processes for their preparation and their use as intermediates for peptide active substances Abstract The invention relates to novel substituted 2,3-diamino acids, processes for their enantioselective preparation and their use as intermediates for the synthesis ofpeptide active substances, in particular for renin inhibitors and HIV-protease inhibitors.
Le A 28 551
Le A 28 551
Description
~77~
The invention relates to novel substituted 2,3-diamino acids, processes for their enantioselective preparation and their use as intermediates for the synthesis of pep~ide active substances, in particular for renin inhibitors and HIV-protease inhibitors.
There are diamino acids already known, cf. German Offenlegungsschrift 3 810 973 or Japanese Application 52 021 327 or Rapoport et al. J. Org. Chem. (1990) 5017 ff., but which differ significantly in their ~hemi-cal structure from the 2,3-diamino acids according to the invention.
The invention relates to novel substituted 2,3-diamino acids of the general formula (I) R4 ~3 N (I) R~ ~
in which R1 represents alkyl having 1 to 10 C atoms~ alkenyl having up to 4 C atoms, phenyl, benzyl or phenethyl, Le A 28 551 - 1 ~77~
R2 represents hydrogen, benzyl or alkyl having 1 to 6 C atoms, R3 and R4 are identical or different and each represent hydrogen or a protecting group such as BOC (tert-butyloxycarbonyl), acetyl, benzoyl, benzyloxycar-bonyl, fluorenyl-methyloxycarbonyl, formyl, tri-fluoroacetyl, 2,2,2-trichloroethylcarbamate, 2-haloethylcarbamate, 2-trimethylsilylcarbamate and R5 and R6 are identical or different and each have the meaning given for R3 and R4, and their salts.
Compounds of the general formula (I) are of particular intereqt, in which R1 represents alkyl or alkenyl having up to 4 C atoms, benzyl or phenyl and R2 to R6 have the meaning given above.
The preparation of the compounds according to the inven-tion in each of the enantiomeric forms is carried out by reducing enantiomerically pure azido compounds of the general formula (II) Le A 28 551 - 2 -,. , ~ ' , ~.
.' ' .
', ' ' ?
, R~" N o -R2 R80 ~ N CH2N3 (II) in which R1 and R2 have the meaning given above, R7 represents methyl, isopropyl or tert-butyl, and Ra has the meaning given for R1 and is identical to or different from R1, according to conventional methods to give the correspond-ing amino compounds, blocking these amino groups using a conventional protectinq group and subsequently opening the bislactim ether rings and, if xequired, substituting the resulting primary amino group (R3 and R4 = H3 by conventional protecting groups.
The bislactim ether halides used as starting compounds are known or can be prepared according to known methods ~cf. German Offenlegungsschrift 2 934 252).
The process according to the invention can be illustrated by the following reaction scheme as an exampleO
Le A 28 551 - 3 -': ~ ''` ', ' : ' `
7 ~
X ~`'"""`
H3CO N CH2_B
NaN3 ~ `R
DMSO H3CO N CH2~ N
nuc leophil ic substitution:
reduction ~"", ~ N ~, OCH3 PPh3, H20 H3CO~NlCH2 O
PhCH20CCI J"", N~OCH3 CH2Cl2 H3CO ~ CH~ COCH2Ph iPr2NEt Le A 28 551 - 4 -~,' - ' ' 7 ~7~2 HCI H2N ~ C02CH3 " CH
NH- COCH2Ph o BOC-H~ C02CH3 (BOC)~O,NEt3 \v~
CH2CI2 Rl CH2 NH-COCH2Ph o H2~C BOC-HN CO2CH3 P ~
Rl CH2 hydrogenolytic removal of protecting groups The possibility of substituting the 2,3-diamino acids according to the invention of the general formula (I) by differentiable amino-protecting groups makes possible their incorporation into pep$ide active ~ubstances via the 2- or the 3-amino function according to choice. This thu~ enables those skilled in the art to syn~hPsise new peptide active substances in a sLmple manner.
Le A 28 551 - 5 -., , The invsntion also relates to int~rmediates of the general formula ~II) R7 ~ o _R2 ~ Rl (II) R8 ~ N CH2-.~3 in which R1, R2, R7 and R8 havs the meaning given above, and also their use for the preparation of a compound of the general formula (I).
The halogeno- or bromo compounds usable or the prepara-tion of compounds of the general formula (II) are known or can be prepared by known methods (cf.: Synthesis 1983, 37 and Angew. Chem. 1989 ~Q~, 633).
The following exemplary embodiments illustrate the invention. The Example6 1 and 2 support the preparation of the intermediate of the general formula (II). The Examples Nos. 3 to 6 illustrate the reduction of the azido group to give the corresponding amino compounds, which are already partially subs~itu~ed by protecting groups. The Examples 7 to 10 illustrate the opening of the ring to give the compounds according to the invention Le A 28 551 - 6 -of the formula (I).
Exemplary em~odiments Experimental Examples The preparation of the starting compound 1 was carried out according to Ref. 2 and 5 of the publication (Synthesis 1983, 37; Angew. Chem. 1989, 101, 633).
Example 1 J "", N OCH3 (l!
To a solution of 3.70 g (12.7 mmol) of the compound J"", N OCH3 ~ CH3 in 35 ml of DMSO 3.39 g ( 52.1 mmol) of sodium azide are added and is heated to 70C for 48 h.
After addition of 50 ml of water, the mixture is Le A 28 551 - 7 -, .
, , ' ' ~ ' ~; " . ' .
, ,: ' ~7~
extracted three tLmes each with 50 ml of petroleum ether and the combined organic phases are dried over sodium sulphate, filtered and concen~rated in vacuo. The residue is chromatographed on silica gel.
Yield: 3.22 g (100 ~5) C11H1gN5O2 (253.3) RF = 0.58 (ether: petroleum ether - 1:5) Example 2 The compound X~ ~" cll2~r~
CH2-~;
was prepared analogously to Example 1.
Yield: 100 %
C17H23N5O2 (329 3) RF = 35 (toluene~
Le A 28 551 - 8 -,. " : , ~, ~
, ~ ; ', .
The invention relates to novel substituted 2,3-diamino acids, processes for their enantioselective preparation and their use as intermediates for the synthesis of pep~ide active substances, in particular for renin inhibitors and HIV-protease inhibitors.
There are diamino acids already known, cf. German Offenlegungsschrift 3 810 973 or Japanese Application 52 021 327 or Rapoport et al. J. Org. Chem. (1990) 5017 ff., but which differ significantly in their ~hemi-cal structure from the 2,3-diamino acids according to the invention.
The invention relates to novel substituted 2,3-diamino acids of the general formula (I) R4 ~3 N (I) R~ ~
in which R1 represents alkyl having 1 to 10 C atoms~ alkenyl having up to 4 C atoms, phenyl, benzyl or phenethyl, Le A 28 551 - 1 ~77~
R2 represents hydrogen, benzyl or alkyl having 1 to 6 C atoms, R3 and R4 are identical or different and each represent hydrogen or a protecting group such as BOC (tert-butyloxycarbonyl), acetyl, benzoyl, benzyloxycar-bonyl, fluorenyl-methyloxycarbonyl, formyl, tri-fluoroacetyl, 2,2,2-trichloroethylcarbamate, 2-haloethylcarbamate, 2-trimethylsilylcarbamate and R5 and R6 are identical or different and each have the meaning given for R3 and R4, and their salts.
Compounds of the general formula (I) are of particular intereqt, in which R1 represents alkyl or alkenyl having up to 4 C atoms, benzyl or phenyl and R2 to R6 have the meaning given above.
The preparation of the compounds according to the inven-tion in each of the enantiomeric forms is carried out by reducing enantiomerically pure azido compounds of the general formula (II) Le A 28 551 - 2 -,. , ~ ' , ~.
.' ' .
', ' ' ?
, R~" N o -R2 R80 ~ N CH2N3 (II) in which R1 and R2 have the meaning given above, R7 represents methyl, isopropyl or tert-butyl, and Ra has the meaning given for R1 and is identical to or different from R1, according to conventional methods to give the correspond-ing amino compounds, blocking these amino groups using a conventional protectinq group and subsequently opening the bislactim ether rings and, if xequired, substituting the resulting primary amino group (R3 and R4 = H3 by conventional protecting groups.
The bislactim ether halides used as starting compounds are known or can be prepared according to known methods ~cf. German Offenlegungsschrift 2 934 252).
The process according to the invention can be illustrated by the following reaction scheme as an exampleO
Le A 28 551 - 3 -': ~ ''` ', ' : ' `
7 ~
X ~`'"""`
H3CO N CH2_B
NaN3 ~ `R
DMSO H3CO N CH2~ N
nuc leophil ic substitution:
reduction ~"", ~ N ~, OCH3 PPh3, H20 H3CO~NlCH2 O
PhCH20CCI J"", N~OCH3 CH2Cl2 H3CO ~ CH~ COCH2Ph iPr2NEt Le A 28 551 - 4 -~,' - ' ' 7 ~7~2 HCI H2N ~ C02CH3 " CH
NH- COCH2Ph o BOC-H~ C02CH3 (BOC)~O,NEt3 \v~
CH2CI2 Rl CH2 NH-COCH2Ph o H2~C BOC-HN CO2CH3 P ~
Rl CH2 hydrogenolytic removal of protecting groups The possibility of substituting the 2,3-diamino acids according to the invention of the general formula (I) by differentiable amino-protecting groups makes possible their incorporation into pep$ide active ~ubstances via the 2- or the 3-amino function according to choice. This thu~ enables those skilled in the art to syn~hPsise new peptide active substances in a sLmple manner.
Le A 28 551 - 5 -., , The invsntion also relates to int~rmediates of the general formula ~II) R7 ~ o _R2 ~ Rl (II) R8 ~ N CH2-.~3 in which R1, R2, R7 and R8 havs the meaning given above, and also their use for the preparation of a compound of the general formula (I).
The halogeno- or bromo compounds usable or the prepara-tion of compounds of the general formula (II) are known or can be prepared by known methods (cf.: Synthesis 1983, 37 and Angew. Chem. 1989 ~Q~, 633).
The following exemplary embodiments illustrate the invention. The Example6 1 and 2 support the preparation of the intermediate of the general formula (II). The Examples Nos. 3 to 6 illustrate the reduction of the azido group to give the corresponding amino compounds, which are already partially subs~itu~ed by protecting groups. The Examples 7 to 10 illustrate the opening of the ring to give the compounds according to the invention Le A 28 551 - 6 -of the formula (I).
Exemplary em~odiments Experimental Examples The preparation of the starting compound 1 was carried out according to Ref. 2 and 5 of the publication (Synthesis 1983, 37; Angew. Chem. 1989, 101, 633).
Example 1 J "", N OCH3 (l!
To a solution of 3.70 g (12.7 mmol) of the compound J"", N OCH3 ~ CH3 in 35 ml of DMSO 3.39 g ( 52.1 mmol) of sodium azide are added and is heated to 70C for 48 h.
After addition of 50 ml of water, the mixture is Le A 28 551 - 7 -, .
, , ' ' ~ ' ~; " . ' .
, ,: ' ~7~
extracted three tLmes each with 50 ml of petroleum ether and the combined organic phases are dried over sodium sulphate, filtered and concen~rated in vacuo. The residue is chromatographed on silica gel.
Yield: 3.22 g (100 ~5) C11H1gN5O2 (253.3) RF = 0.58 (ether: petroleum ether - 1:5) Example 2 The compound X~ ~" cll2~r~
CH2-~;
was prepared analogously to Example 1.
Yield: 100 %
C17H23N5O2 (329 3) RF = 35 (toluene~
Le A 28 551 - 8 -,. " : , ~, ~
, ~ ; ', .
2~7 ~OD2 ~xample_3 J ~ ~ OCH3 CH2-NH~
A solution of 0.25 g (1.0 mmol) l~, 0.26 g (1.0 mmol) of triphenylphosphine and 0.027 g (1.5 mmol) of H20 in 10 ml of THF is stirred for 48 h. The solvent is removed in vacuo and the residue is taken up in 5 ml of ether/-petrol~um ether (l:1). Triphenylphosphine oxide is filtered off, the solvent is removed in vacuo and the residue is chromatographed on silica gel (ether:aceto-nitrile:concentrated aqueous NH3 solution = 10:1:0.1).
Yield: 0.17 g (75 ~) C1~H2lN3O2 (227.3) RF: 0.26 (ether:AcCN:conc. NH3 = 10:1:0.1) Le A 28 551 - 9 -..
- ' ' :
2~7 ~0 Example 4 The compound H~CO N
¢~L
was prepared from 1~ analogously to Ex~mple 3.
Yield: 55 ~
C17Hz5N3O2 (303-4) RF: 0.31 (ethersAcCN:conc. NH3 = 10:1:0.1) Example 5 ~"" ~ N
CH2NH C--OCH2~
To a solution of 0.23 g (1.0 mmol) ~3) and 0.39 g ~3.0 mmol) of ethyl diisopropylamin~ in 5 ml of Le A 28 551 - 10 -.
~7~
dichloromethane 0.17 g (1.0 mmol) of benzyl chloroformate i~ added dropwise. The mixture i~ stirred for 3 h at room temperature, subsequently washed with water, 1 % hydro-chloric acid and saturated aqueous NaHCO3 solution and dried over Na2SO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (ether:petroleum ether = l:1).
Yield: 0.31 g (86 %) C1gH27N3O4 (361.4) R~ = 0.49 (ether:petroleum ether = 1:1) Exam~le 6 The compound CH2~
CH2NH2- C-OCH2Ph o (6! ., was prepared analogously to Example 5.
Yield: 75 %
C25H31N3O4 (437-5) M.p.: 70C
Le A 28 551 , , : , , . ~ ~ . , , Example 7 H2N CO2CH3 o H3C ~ CH2NH - C-OCH
(7) A solution of 4.10 g (11.3 mmol) (5) in 227 ml (22.7 mmol~ of 0.1 N HCl and 20 ml of acetonitrile is stirred for 5 h at room temperature. The acetonitrile is removed in vacuo, the aqueous phase is extracted 2 x each with 50 ml o ether, the ether phases are discarded and the aqueous phase is concentrated to a volume of approxi-mately 30 ml in vacuo. A layer of 50 ml of ether is ~dded, and concentrated NH3 solution is added to the mixture at pH 9-lOo The phas~s are separated and the aqueous phase is extracted a fur~her 2 x each with 50 ml of ether. The combined ether phases are dried over Na25O4 and filtered, and the solvent is removed in vacuo. Valine methyl ester is distilled off in a bulb tube at 0.1 mm Hg/60C, and the residue is chromatographed on silica gel (ether:acetonitrile:concentrated NH3 10:1-0.1~
Yield: 1.78 g (59 ~) C13H18NzO4 (266-3) RF: 0-33 (ether:acetonitrile:conc. NH3 = 10:1'0.1) Le A 28 551 - 12 -.... ~
: ~:
.
Example 8 BOC-~N CO2CH3 O
H3C ~ CH2NH - C-OCH
(8!
A solution of 0.25 g (1.0 mmol) l~, 0.26 g (1.0 mmol) of triphenylphosphine and 0.027 g (1.5 mmol) of H20 in 10 ml of THF is stirred for 48 h. The solvent is removed in vacuo and the residue is taken up in 5 ml of ether/-petrol~um ether (l:1). Triphenylphosphine oxide is filtered off, the solvent is removed in vacuo and the residue is chromatographed on silica gel (ether:aceto-nitrile:concentrated aqueous NH3 solution = 10:1:0.1).
Yield: 0.17 g (75 ~) C1~H2lN3O2 (227.3) RF: 0.26 (ether:AcCN:conc. NH3 = 10:1:0.1) Le A 28 551 - 9 -..
- ' ' :
2~7 ~0 Example 4 The compound H~CO N
¢~L
was prepared from 1~ analogously to Ex~mple 3.
Yield: 55 ~
C17Hz5N3O2 (303-4) RF: 0.31 (ethersAcCN:conc. NH3 = 10:1:0.1) Example 5 ~"" ~ N
CH2NH C--OCH2~
To a solution of 0.23 g (1.0 mmol) ~3) and 0.39 g ~3.0 mmol) of ethyl diisopropylamin~ in 5 ml of Le A 28 551 - 10 -.
~7~
dichloromethane 0.17 g (1.0 mmol) of benzyl chloroformate i~ added dropwise. The mixture i~ stirred for 3 h at room temperature, subsequently washed with water, 1 % hydro-chloric acid and saturated aqueous NaHCO3 solution and dried over Na2SO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (ether:petroleum ether = l:1).
Yield: 0.31 g (86 %) C1gH27N3O4 (361.4) R~ = 0.49 (ether:petroleum ether = 1:1) Exam~le 6 The compound CH2~
CH2NH2- C-OCH2Ph o (6! ., was prepared analogously to Example 5.
Yield: 75 %
C25H31N3O4 (437-5) M.p.: 70C
Le A 28 551 , , : , , . ~ ~ . , , Example 7 H2N CO2CH3 o H3C ~ CH2NH - C-OCH
(7) A solution of 4.10 g (11.3 mmol) (5) in 227 ml (22.7 mmol~ of 0.1 N HCl and 20 ml of acetonitrile is stirred for 5 h at room temperature. The acetonitrile is removed in vacuo, the aqueous phase is extracted 2 x each with 50 ml o ether, the ether phases are discarded and the aqueous phase is concentrated to a volume of approxi-mately 30 ml in vacuo. A layer of 50 ml of ether is ~dded, and concentrated NH3 solution is added to the mixture at pH 9-lOo The phas~s are separated and the aqueous phase is extracted a fur~her 2 x each with 50 ml of ether. The combined ether phases are dried over Na25O4 and filtered, and the solvent is removed in vacuo. Valine methyl ester is distilled off in a bulb tube at 0.1 mm Hg/60C, and the residue is chromatographed on silica gel (ether:acetonitrile:concentrated NH3 10:1-0.1~
Yield: 1.78 g (59 ~) C13H18NzO4 (266-3) RF: 0-33 (ether:acetonitrile:conc. NH3 = 10:1'0.1) Le A 28 551 - 12 -.... ~
: ~:
.
Example 8 BOC-~N CO2CH3 O
H3C ~ CH2NH - C-OCH
(8!
3.70 g (16.95 mmol) of di-tert-butyl dicarbonate are added to a solution of 1.78 g (6.68 mmol) of l~L and 2.29 g (22.6 mmol) of triethylamine in 50 ml of dichloro-methane and the mixture is stirred for 12 h at room temperature. ~ ::
The solution is wa~hed twice each with 50 ml of H2O, dried over Na2SO4 and concentrated in ~acuo. The residue is chromatographed on silica gel (toluene:ethyl acetate = 3:1).
Yield: 2.20 g (90 ~) C18H26N2O6 (366.41) RF: 0.41 (toluene:ethyl acetate = 3 Le A 28 551 - 13 -, ., , . ~ , . ~
.
, 2~7r~2 Example 9 C -~'H ~ CO,CH3 H3C CH2~2 (9) 100 mg of palladium (10 % on activated charcoal) are added to a solution of 1.74 g (4.91 mmol) (8) in 70 ml of ethanol, and the mixture i~ hydrogenated with H2 for 8 h at room temperature and 3 bar. The solution is filtered and concentrated in vacuo. The residue is chromatographed on silica gel ~ether:acetonitrile:concentrated NH3 = .
10:1:0.1).
Yield: 1.00 g (87 %) C1oH20Nzo4 (232-80) RF: 0.24 (ether: acetonitrile:conc. NH3 = 10:1:0.1) Example 10 H2-~' CO2H
\~ xHCl (10) Le A 28 551 14 -.
' .: , ~, : ,. -;
A solution of 0.440 g (1.89 mmol) l~L in 10 ml of 3 M HCl is refluxed for 3 h. The solution is concentrated in vacuo, the residue is dried for 3 h at 0.1 mm Hg/60C and then 7 ml of ethanol and 1.4 ml of propene oxide are S added. The solution is refluxed for 3 h. The mixture is allowed to cool to room temperature: precipitated product is filtered off with suction and washed with ethanol and ether.
Yield: 0.220 g (75 %) C4HloN2O2 x HCl (118.1 x 36.5) [ ~20 = _3.47 (c = 0-7~ H2O) Le A 28 ~51 - 15 -" ~
:;
The solution is wa~hed twice each with 50 ml of H2O, dried over Na2SO4 and concentrated in ~acuo. The residue is chromatographed on silica gel (toluene:ethyl acetate = 3:1).
Yield: 2.20 g (90 ~) C18H26N2O6 (366.41) RF: 0.41 (toluene:ethyl acetate = 3 Le A 28 551 - 13 -, ., , . ~ , . ~
.
, 2~7r~2 Example 9 C -~'H ~ CO,CH3 H3C CH2~2 (9) 100 mg of palladium (10 % on activated charcoal) are added to a solution of 1.74 g (4.91 mmol) (8) in 70 ml of ethanol, and the mixture i~ hydrogenated with H2 for 8 h at room temperature and 3 bar. The solution is filtered and concentrated in vacuo. The residue is chromatographed on silica gel ~ether:acetonitrile:concentrated NH3 = .
10:1:0.1).
Yield: 1.00 g (87 %) C1oH20Nzo4 (232-80) RF: 0.24 (ether: acetonitrile:conc. NH3 = 10:1:0.1) Example 10 H2-~' CO2H
\~ xHCl (10) Le A 28 551 14 -.
' .: , ~, : ,. -;
A solution of 0.440 g (1.89 mmol) l~L in 10 ml of 3 M HCl is refluxed for 3 h. The solution is concentrated in vacuo, the residue is dried for 3 h at 0.1 mm Hg/60C and then 7 ml of ethanol and 1.4 ml of propene oxide are S added. The solution is refluxed for 3 h. The mixture is allowed to cool to room temperature: precipitated product is filtered off with suction and washed with ethanol and ether.
Yield: 0.220 g (75 %) C4HloN2O2 x HCl (118.1 x 36.5) [ ~20 = _3.47 (c = 0-7~ H2O) Le A 28 ~51 - 15 -" ~
:;
Claims (5)
1. 2,3-Diamino acids of the general formula (I) (I) in which R1 represents alkyl having 1 to 10 C atoms, alkenyl having up to 4 C atoms, phenyl, benzyl or phenethyl, R2 represents hydrogen, benzyl or alkyl having 1 to 6 C atoms, R3 and R4 are identical or different and each represent hydrogen or a protecting group such as BOC (tert-butyloxycarbonyl), acetyl, benzoyl, benzyloxycar-bonyl, fluorenyl-methyloxycarbonyl, formyl, tri-fluoroacetyl, 2,2,2-trichloroethylcarbamate, 2-haloethylcarbamate, 2-trimethylsilylcarbamate and R5 and R6 are identical or diffrent and each have the meaning given for R3 and R4, and their salts.
Le A 28 551 - 16 -
Le A 28 551 - 16 -
2. Compounds of the general formula (I) according to Claim 1, in which R1 represents alkyl or alkenyl having up to 4 C atoms, benzyl or phenyl and R2 to R6 have the meaning given in Claim 1.
3. Process for the preparation of compounds of the general formula (I) according to Claim 1, characterised in that enantiomerically pure azido compounds of the general formula (II) (II) in which R1 and R2 have the meaning given above, R7 represents methyl, isopropyl or tert-butyl, and R8 has the meaning given for R1 and is identical to or different from R1, are reduced according to conventional methods to give the Le A 28 551 - 17 -corresponding amino compounds, these amino groups are blocked using a conventional protecting group and subse-quently the bislactim ether rings are opened and, if re-quired, the resulting primary amino group (R3 and R4 = H) are substituted by conventional protecting groups.
4. Compounds of the general formula (II) (II) in which R1 and R2 have the meaning given in Claim 1, R7 represents methyl, isopropyl or tert-butyl, and R8 has the meaning given for R1 and is identical to or different from R1.
5. Use of compounds of the general formulae (I) and (II) as intermediates in the preparation of peptide active substances.
Le A 28 551 - 18 -
Le A 28 551 - 18 -
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4128790.8 | 1991-08-30 | ||
| DE19914128790 DE4128790A1 (en) | 1991-08-30 | 1991-08-30 | NEW SUBSTITUTED 2,3-DIAMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS INTERMEDIATE STAGES FOR PEPTIDIC ACTIVE SUBSTANCES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2077002A1 true CA2077002A1 (en) | 1993-03-01 |
Family
ID=6439461
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2077002 Abandoned CA2077002A1 (en) | 1991-08-30 | 1992-08-27 | Substituted 2,3-diamino acids, processes for their preparation and their use as intermediates for peptide active substances |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0529469A2 (en) |
| JP (1) | JPH05213839A (en) |
| CA (1) | CA2077002A1 (en) |
| DE (1) | DE4128790A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5679688A (en) | 1992-03-11 | 1997-10-21 | Narhex Limited | Quinaldoyl-amine derivatives of oxo-and hydroxy-substituted hydrocarbons |
| US5888992A (en) | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
| US6071895A (en) | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
| US6258806B1 (en) | 1992-03-11 | 2001-07-10 | Narhex Limited | Amine derivatives of oxo- and hydroxy- substituted hydrocarbons |
-
1991
- 1991-08-30 DE DE19914128790 patent/DE4128790A1/en not_active Withdrawn
-
1992
- 1992-08-18 EP EP19920114033 patent/EP0529469A2/en not_active Withdrawn
- 1992-08-27 CA CA 2077002 patent/CA2077002A1/en not_active Abandoned
- 1992-08-28 JP JP4253817A patent/JPH05213839A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5679688A (en) | 1992-03-11 | 1997-10-21 | Narhex Limited | Quinaldoyl-amine derivatives of oxo-and hydroxy-substituted hydrocarbons |
| US5888992A (en) | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
| US5942504A (en) | 1992-03-11 | 1999-08-24 | Narhex Limited | Amine derivatives of oxo- and hydroxy- substituted hydrocarbons |
| US6071895A (en) | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
| US6258806B1 (en) | 1992-03-11 | 2001-07-10 | Narhex Limited | Amine derivatives of oxo- and hydroxy- substituted hydrocarbons |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0529469A2 (en) | 1993-03-03 |
| JPH05213839A (en) | 1993-08-24 |
| DE4128790A1 (en) | 1993-03-04 |
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