PL215841B1 - Enantiomer of gem-dimethylcyclopropane delta-amino acid and process for the preparation thereof - Google Patents
Enantiomer of gem-dimethylcyclopropane delta-amino acid and process for the preparation thereofInfo
- Publication number
- PL215841B1 PL215841B1 PL390968A PL39096810A PL215841B1 PL 215841 B1 PL215841 B1 PL 215841B1 PL 390968 A PL390968 A PL 390968A PL 39096810 A PL39096810 A PL 39096810A PL 215841 B1 PL215841 B1 PL 215841B1
- Authority
- PL
- Poland
- Prior art keywords
- dimethylcyclopropane
- gem
- amino acid
- enantiomer
- dimethylcyclopropyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- PBIJFSCPEFQXBB-UHFFFAOYSA-N 1,1-dimethylcyclopropane Chemical compound CC1(C)CC1 PBIJFSCPEFQXBB-UHFFFAOYSA-N 0.000 title claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000004809 thin layer chromatography Methods 0.000 claims description 4
- RGEQGOBYSKPHNM-NTSWFWBYSA-N 2-[(1s,3r)-3-(aminomethyl)-2,2-dimethylcyclopropyl]acetic acid Chemical compound CC1(C)[C@H](CN)[C@@H]1CC(O)=O RGEQGOBYSKPHNM-NTSWFWBYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- KKUHCAMYDDZIAF-QWHCGFSZSA-N OC(=O)C[C@@H]1C(C)(C)[C@@H]1CNC(=O)OCC1=CC=CC=C1 Chemical compound OC(=O)C[C@@H]1C(C)(C)[C@@H]1CNC(=O)OCC1=CC=CC=C1 KKUHCAMYDDZIAF-QWHCGFSZSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 239000007809 chemical reaction catalyst Substances 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Przedmiotem wynalazku jest (+)-enancjomer δ-aminokwasu gem-dimetylocyklopropanu oraz sposób wytwarzania (+)-enancjomeru δ-aminokwasu gem-dimetylocyklopropanu, mającego zastosowanie w projektowaniu peptydomimetyków oraz analogów neuroprzekaźników stosowanych w leczeniu chorób neurodegeneracyjnych, jak choroba Parkinsona, Alzheimera, schizofrenia czy epilepsja.The subject of the invention is the (+) - δ-amino acid enantiomer of gem-dimethylcyclopropane and a method for the preparation of the (+) - δ-amino acid enantiomer of gem-dimethylcyclopropane, applicable in the design of peptidomimetics and neurotransmitter analogs used in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzophrenia, or epilepsy.
(+)-Enancjomer δ-aminokwasu gem-dimetylocyklopropanu, będący kwasem (+)-[(1 S,3R)-3-(aminometylo)-2,2-dimetyloyklopropylo]octowym, o wzorze 1, ma określoną, jednoznaczną budowę przestrzenną(+) - The δ-amino acid enantiomer of gem-dimethylcyclopropane, which is the (+) - [(1S, 3R) -3- (aminomethyl) -2,2-dimethylyclopropyl] acetic acid, with the formula 1, has a specific, unique spatial structure
Związek należy do grupy niebiałkowych usztywnionych aminokwasów. Struktura związku jest usztywniona przez obecność ugrupowania gem-dimetylocyklopropanowego, będącego zarazem cennym źródłem chiralności związku.The compound belongs to the group of non-protein stiffened amino acids. The structure of the compound is stiffened by the presence of the gem-dimethylcyclopropane moiety, which is also a valuable source of the compound's chirality.
Sposób wytwarzania (+)-enancjomeru δ-aminokwasu gem-dimetylocyklopropanu, będącego kwasem (+)-[(1S,3R)-3-(aminometylo)-2,2-dimetylocyklopropylojoctowym, o wzorze 1, polega na tym, że kwas (+)-[(1 S,3R)-3-({(benzyloksy)karbonyloamino}metylo)-2,2-dimetylocyklopropylo]-octowy poddaje się reakcji hydrogenolizy, przy czym reakcję prowadzi się w obecności katalizatora w postaci metanolowego roztworu wobec palladu na węglu aktywnym, przez który barbotuje się gazowy wodór, aż do momentu całkowitego przereagowania substratu, co stwierdza się za pomocą chromatografii cienkowarstwowej.The preparation of the (+) - δ-amino acid enantiomer of gem-dimethylcyclopropane, which is (+) - [(1S, 3R) -3- (aminomethyl) -2,2-dimethylcyclopropyl] acetic acid, formula 1, consists in the fact that the acid ( +) - [(1S, 3R) -3 - ({(benzyloxy) carbonylamino} methyl) -2,2-dimethylcyclopropyl] acetic acid is subjected to a hydrogenolysis reaction, the reaction being carried out in the presence of a catalyst in the form of a methanolic solution against palladium on activated carbon through which hydrogen gas is bubbled until the substrate has reacted completely, as determined by thin layer chromatography.
Korzystnie jako układ eluujący stosuje się mieszaninę heksan:aceton w stosunku 2:1.Preferably, a 2: 1 mixture of hexane: acetone is used as the eluting system.
Korzystnie obecność surowego produktu potwierdza się próbą ninhydrynową.Preferably the presence of the crude product is confirmed by the ninhydrin test.
Korzystnie po zakończeniu procesu odsącza się katalizator reakcji i odparowuje się rozpuszczalnik pod zmniejszonym ciśnieniem.Preferably, after the end of the process, the reaction catalyst is filtered off and the solvent is evaporated off under reduced pressure.
Sposób według wynalazku jest przedstawiony w poniższym przykładzie wykonania.The method according to the invention is illustrated in the following embodiment.
Przez roztwór 0,10 g (0,34 mmola) kwasu (+)-[(1S,3R)-3-({(benzyloksy)karbonyloamino}-metylo)-2,2-dimetylocyklopropylo]octowego w 10,00 ml metanolu wobec 35,00 mg palladu na węglu aktywnym, będącego katalizatorem reakcji, barbotuje się gazowy wodór. Całość poddaje się dodatkowo delikatnemu mieszaniu na mieszadle magnetycznym. Reakcję prowadzi się do momentu, kiedy kontrola chromatografii cienkowarstwowej, z użyciem mieszaniny eluującej heksan:aceton 2:1, wykaże całkowite przereagowanie substratu tj. po około 3 godzinach. Jednocześnie potwierdza się obecność produktu, δ-aminokwasu wykonując próbę ninhydrynową na płytce TLC, gdzie płytkę eluuje się metanolem, a następnie wywołuje się ją roztworem ninhydryny w butanolu. Pozytywna próba ninhydrynowa daje kolor purpurowy. Następnie odsącza się katalizator, a metanol usuwa się na wyparce obrotowej pod zmniejszonym ciśnieniem i otrzymuje się 0,03 g δ-aminokwasu.By a solution of 0.10 g (0.34 mmol) of (+) - [(1S, 3R) -3 - ({(benzyloxy) carbonylamino} -methyl) -2,2-dimethylcyclopropyl] acetic acid in 10.00 ml of methanol Hydrogen gas is bubbled through in the presence of 35.00 mg of palladium on activated charcoal catalyst of the reaction. The whole is additionally subjected to gentle mixing on a magnetic stirrer. The reaction is carried out until the control of thin layer chromatography with a mixture eluting with hexane: acetone 2: 1 shows complete conversion of the substrate, ie after about 3 hours. Simultaneously, the presence of the product, a δ-amino acid, is confirmed by performing a ninhydrin test on a TLC plate, where the plate is eluted with methanol and then developed with a solution of ninhydrin in butanol. A positive ninhydrin test produces a purple color. The catalyst is then filtered off and the methanol is removed on a rotary evaporator under reduced pressure to give 0.03 g of a δ-amino acid.
Otrzymany według przykładu związek charakteryzuje się następującymi stałymi fizycznymi i spektralnymi:The compound obtained in the example is characterized by the following physical and spectral constants:
= + 34.10 (c 2.00, MeOH); Ttop= 154-160°C= + 34.10 (c 2.00, MeOH); Ttop = 154-160 ° C
IR (KBr, cm-1): 3424 (s), 2943 (m), 1563 (vs), 1396 (s), 741 (w);IR (KBr, cm -1 ): 3424 (s), 2943 (m), 1563 (vs), 1396 (s), 741 (w);
1H NMR (D2O, δ, ppm): 0.71-0.80 (m, 2H przy C-3 i C-5); 0.82 i 0.91 (2s, 6H przy C-1 i C-8); 1.96 (dd, J=15.6, 10.0 Hz, 1H przy C-2); 2.22 (dd, J=15.4, 5.3 Hz, 1H przy C-2); 2.83 (dd, J=13.4, 9.5 Hz, 1H przy C-6); 3.02 (dd, J=13.4, 6.2 Hz, 1H przy C-6); 1 H NMR (D 2 O, δ, ppm): 0.71-0.80 (m, 2 H at C-3 and C-5); 0.82 and 0.91 (2s, 6H at C-1 and C-8); 1.96 (dd, J = 15.6, 10.0 Hz, 1H at C-2); 2.22 (dd, J = 15.4, 5.3 Hz, 1H at C-2); 2.83 (dd, J = 13.4, 9.5 Hz, 1H at C-6); 3.02 (dd, J = 13.4, 6.2Hz, 1H at C-6);
13C NMR (D2O, δ, ppm): 14.00 i 27.70 (C-7 i C-8), 18.00 (C-4), 22.33(C-3), 24.59 (C-5), 32.70 (C-2), 37.87 (C-6), 182.09 (C-1). 13 C NMR (D2O, δ, ppm): 14.00 and 27.70 (C-7 and C-8), 18.00 (C-4), 22.33 (C-3), 24.59 (C-5), 32.70 (C-2 ), 37.87 (C-6), 182.09 (C-1).
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL390968A PL215841B1 (en) | 2010-04-13 | 2010-04-13 | Enantiomer of gem-dimethylcyclopropane delta-amino acid and process for the preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL390968A PL215841B1 (en) | 2010-04-13 | 2010-04-13 | Enantiomer of gem-dimethylcyclopropane delta-amino acid and process for the preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL390968A1 PL390968A1 (en) | 2011-10-24 |
| PL215841B1 true PL215841B1 (en) | 2014-02-28 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL390968A PL215841B1 (en) | 2010-04-13 | 2010-04-13 | Enantiomer of gem-dimethylcyclopropane delta-amino acid and process for the preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| PL (1) | PL215841B1 (en) |
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2010
- 2010-04-13 PL PL390968A patent/PL215841B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PL390968A1 (en) | 2011-10-24 |
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| Date | Code | Title | Description |
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| LAPS | Decisions on the lapse of the protection rights |
Effective date: 20130413 |