NO172894B - PROCEDURE FOR THE PREPARATION OF L-ALANYL-L-PROLINE DERIVATIVES - Google Patents
PROCEDURE FOR THE PREPARATION OF L-ALANYL-L-PROLINE DERIVATIVES Download PDFInfo
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- NO172894B NO172894B NO892813A NO892813A NO172894B NO 172894 B NO172894 B NO 172894B NO 892813 A NO892813 A NO 892813A NO 892813 A NO892813 A NO 892813A NO 172894 B NO172894 B NO 172894B
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- proline
- formula
- alanyl
- preparation
- ethoxycarbonyl
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- 238000000034 method Methods 0.000 title claims description 9
- WPWUFUBLGADILS-WDSKDSINSA-N Ala-Pro Chemical class C[C@H](N)C(=O)N1CCC[C@H]1C(O)=O WPWUFUBLGADILS-WDSKDSINSA-N 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 9
- 229960002429 proline Drugs 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- CEIWXEQZZZHLDM-AAEUAGOBSA-N (2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoic acid Chemical class CCOC(=O)[C@@H](N[C@@H](C)C(O)=O)CCC1=CC=CC=C1 CEIWXEQZZZHLDM-AAEUAGOBSA-N 0.000 claims description 5
- 229910052739 hydrogen Chemical group 0.000 claims description 5
- 239000001257 hydrogen Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003495 polar organic solvent Substances 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 101800000734 Angiotensin-1 Proteins 0.000 description 3
- 102400000344 Angiotensin-1 Human genes 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- 229930182821 L-proline Natural products 0.000 description 3
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 108010058865 angiotensinase Proteins 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- 102000004881 Angiotensinogen Human genes 0.000 description 1
- 108090001067 Angiotensinogen Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 108010087924 alanylproline Proteins 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- OYFJQPXVCSSHAI-QFPUQLAESA-N enalapril maleate Chemical compound OC(=O)\C=C/C(O)=O.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 OYFJQPXVCSSHAI-QFPUQLAESA-N 0.000 description 1
- LZFZMUMEGBBDTC-QEJZJMRPSA-N enalaprilat (anhydrous) Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 LZFZMUMEGBBDTC-QEJZJMRPSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
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- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Description
Den foreliggende oppfinnelse vedrører området kjemi om peptider og vedrører en fremgangsmåte til fremstilling av L-alanyl-L-prolinderivater med formelen The present invention relates to the area of chemistry about peptides and relates to a method for the preparation of L-alanyl-L-proline derivatives with the formula
hvor R er etyl eller hydrogen, samt farmasøytisk akseptable salter derav. where R is ethyl or hydrogen, as well as pharmaceutically acceptable salts thereof.
Forbindelsen med formelen I inhiberer omdannelsen av dekapeptidet angiotensin I til angiotensin II, som virker som blodtrykksregulator. Enzymet renin, som utskilles av nyren, The compound with formula I inhibits the conversion of the decapeptide angiotensin I to angiotensin II, which acts as a blood pressure regulator. The enzyme renin, which is secreted by the kidney,
virker på det ene av plasmapeptidene, dvs. på reninsubstratet angiotensinogen. Det sistnevnte utskilles av leveren, og fra dette substrat utvinnes dekapeptidet angiotensin I. Angiotensin I omdannes til angiotensin II ved hjelp av enzymet angiotensinase. Forbindelsen med den generelle formel I inhiberer imidlertid enzymet angiotensinase og er egnet for behandling av kardio-vaskulære sykdommer, særlig for høyt blodtrykk. acts on one of the plasma peptides, i.e. on the renin substrate angiotensinogen. The latter is secreted by the liver, and from this substrate the decapeptide angiotensin I is extracted. Angiotensin I is converted to angiotensin II with the help of the enzyme angiotensinase. However, the compound of the general formula I inhibits the enzyme angiotensinase and is suitable for the treatment of cardiovascular diseases, in particular for high blood pressure.
Det forelå et behov for å finne en ny fremgangsmåte til fremstilling av L-alanyl-L-prolinderivater med formelen I, som ville være teknologisk og økonomisk mer gunstig enn kjente fremgangsmåter. There was a need to find a new method for the preparation of L-alanyl-L-proline derivatives of the formula I, which would be technologically and economically more favorable than known methods.
Ved kjente fremgangsmåter fremstilles L-alanyl-L-prolinderivater med formelen I ved kondensasjon av etyl-4-fenyl-2-oksy-butanoat med L-alanyl-L-prolin og ved hydrogenering By known methods, L-alanyl-L-proline derivatives with the formula I are prepared by condensation of ethyl 4-phenyl-2-oxy-butanoate with L-alanyl-L-proline and by hydrogenation
(US-patentskrift 4.374.829) eller ved kondensasjon av N-karboksy-anhydrid-N-[1(S)-etoksykarbonyl-3-fenylpropyl]-L-alanin med et salt av L-prolin (EP A 215.335). (US Patent 4,374,829) or by condensation of N-carboxy anhydride-N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine with a salt of L-proline (EP A 215,335).
Fremgangsmåten ifølge den foreliggende oppfinnelse til fremstilling av L-alanyl-L-prolinderivater med den generelle formel I The method according to the present invention for the preparation of L-alanyl-L-proline derivatives with the general formula I
hvor R er etyl eller hydrogen, og av farmasøytisk akseptable salter derav, kjennetegnes ved at N,0-bistrimetylsilyl'-L-prolin med formelen II omsettes med N-[1(S)-etoksykarbonyl-3-fenylpropyl]-L-alanin-derivatet med den generelle formel III where R is ethyl or hydrogen, and of pharmaceutically acceptable salts thereof, characterized in that N,0-bistrimethylsilyl'-L-proline of the formula II is reacted with N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine -the derivative with the general formula III
hvor Het er et imidazol-1- eller et 2-tiobenztiazolradikal, where Het is an imidazole-1- or a 2-thiobenzthiazole radical,
i upolare organiske løsningsmidler, såsom dioksan, tetrahydrofuran, metylenklorid, fortrinnsvis tetrahydrofuran, ved en temperatur i området fra -10 til +20°C, og at den oppnådde forbindelse med formelen (I), hvor R er etyl, dersom det er ønskelig, hydroliseres til en forbindelse med formelen I, hvor R er hydrogen. in non-polar organic solvents, such as dioxane, tetrahydrofuran, methylene chloride, preferably tetrahydrofuran, at a temperature in the range from -10 to +20°C, and that the obtained compound of formula (I), where R is ethyl, if desired, is hydrolysed to a compound of the formula I, where R is hydrogen.
Fremgangsmåten ifølge oppfinnelsen avviker fra kjente fremgangsmåter ved at det anvendes N,0-bistrimetylsilyl-L-prolin med formelen II, som kondenseres med et amid eller en tioester med formelen III. Den er fordelaktig ved at kondensasjonstiden er kortere og at reaksjonen er kvantitativ. The method according to the invention differs from known methods in that N,0-bistrimethylsilyl-L-proline of the formula II is used, which is condensed with an amide or a thioester of the formula III. It is advantageous in that the condensation time is shorter and that the reaction is quantitative.
Utgangsforbindelsene med formlene II og III er kommersielt tilgjengelige eller kan fremstilles på kjent måte. The starting compounds of the formulas II and III are commercially available or can be prepared in a known manner.
Oppfinnelsen vil bli nærmere belyst mer detaljert i de etterfølgende eksempler. The invention will be further elucidated in more detail in the following examples.
Eksempel 1 Example 1
N-[l(S)-etoksykarbonyl-3-fenylpropyl]-L-alanyl-L-prolin-maleinsyresalt. N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline-maleic acid salt.
Til en løsning av 2,8 g N-[1(S)-etoksykarbonyl-3-fenyl-propyl ]-L-alanin i 40 ml metylenklorid ble det etter at løsningen var avkjølt til -5°C tilsatt 2,44 g N,N'-karbonyldiimidazol, og løsningen ble omrørt i 3 timer ved en temperatur på fra 0 til To a solution of 2.8 g of N-[1(S)-ethoxycarbonyl-3-phenyl-propyl]-L-alanine in 40 ml of methylene chloride, after the solution had been cooled to -5°C, 2.44 g of N ,N'-carbonyldiimidazole, and the solution was stirred for 3 hours at a temperature of from 0 to
-5°C. I mellomtiden ble N,0-bistrimetylsilyl-L-prolin fremstilt ved å tilsette 4,2 ml trietylamin og 3,8 ml trimetylklorsilan til en suspensjon av 1,72 g L-prolin i 40 ml metylenklorid og ved å omrøre i en halv time ved 4 0°C og 2 timer ved romtemperatur. Fra det således fremstilte og avkjølte N,0-bistrimetylsilyl-L-Drolin ble det dannete trietylaminhydroklorid avfiltrert og filtratet ble helt i N-[1(S)-etoksykarbonyl-3-fenylpropyl]-L-alanylimidazol. Omrøringen ble fortsatt ved en temperatur på fra 0 til -5°C. Etter at fravær av utgangsforbindelsen var bekreftet ved væskekromatografi ble metylenklorid avdampet. 40 ml vann og 15 ml etylacetat ble tilsatt til resten, og pH ble regulert til 8,7 med 2 N NaOH. Det vandige sjikt ble én gang til vasket med 10 ml etylacetat, og NaCl ble tilsatt inntil løsningen var mettet, og 15 ml etylacetat ble tilsatt. pH ble regulert til 4,2 med 1:1 HC1, sjiktene ble adskilt og det vandige sjikt ekstrahert med 7 x 8 ml etylacetat. Etylacetatsjiktene ble tørket med Na2S04 og N- [1(S)-etoksykarbonyl-3-fenylpropyl]-L-alanyl-L-prolin ble utfelt med 1,2 g maleinsyre. Bunnfallet ble avfiltrert og tørket i en vakuumtørker ved 40°C. 4,1 g (83%) av tittelforbindelsen ble oppnådd, smp. 143-147°C. -5°C. Meanwhile, N,0-bistrimethylsilyl-L-proline was prepared by adding 4.2 ml of triethylamine and 3.8 ml of trimethylchlorosilane to a suspension of 1.72 g of L-proline in 40 ml of methylene chloride and stirring for half an hour at 40°C and 2 hours at room temperature. From the thus prepared and cooled N,0-bistrimethylsilyl-L-Droline, the formed triethylamine hydrochloride was filtered off and the filtrate was poured into N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanylimidazole. Stirring was continued at a temperature of from 0 to -5°C. After the absence of the starting compound was confirmed by liquid chromatography, the methylene chloride was evaporated. 40 ml of water and 15 ml of ethyl acetate were added to the residue, and the pH was adjusted to 8.7 with 2 N NaOH. The aqueous layer was washed once more with 10 ml of ethyl acetate, and NaCl was added until the solution was saturated, and 15 ml of ethyl acetate was added. The pH was adjusted to 4.2 with 1:1 HCl, the layers were separated and the aqueous layer was extracted with 7 x 8 mL of ethyl acetate. The ethyl acetate layers were dried with Na 2 SO 4 and N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline was precipitated with 1.2 g of maleic acid. The precipitate was filtered off and dried in a vacuum dryer at 40°C. 4.1 g (83%) of the title compound was obtained, m.p. 143-147°C.
Eksempel 2 Example 2
Til en løsning av 1,4 g N-[1(S)-etoksykarbonyl-3-fenyl-propyl ] -L-alanin i 40 ml tetrahydrofuran ble det tilsatt 0,85 g 2-merkaptobenztiazol, og den resulterende blanding ble avkjølt til 0°C. Deretter ble 1,2 g N,N<*->dicykloheksylkarbodiimid tilsatt, og den resulterende blanding ble omrørt ved en temperatur på fra -5°C til 0°C i 3 timer. Dicykloheksylurea som ble utskilt, ble avfiltrert, og den således fremstilte ester av 2-merkaptobenzotiazol og N-[1(S)-etoksykarbonyl-3-fenylpropyl]-L-alanin ble tilsatt dråpevis til avkjølt (0°C) N,0-bistrimetyl-silyl-L-prolin, som på forhånd var fremstilt ved tilsetning av 2,8 ml trietylamin og 2,6 ml trimetylklorsilan til en suspensjon av 1,1 g L-prolin i 40 ml tetrahydrofuran og omrøring ved romtemperatur i 3 timer. Omrøringen ble fortsatt inntil fravær av utgangsforbindelsen ble påvist ved væskekromatografi. Tetrahydrofuran ble avdampet, 20 ml vann og 10 ml metylenklorid ble tilsatt til resten, pH ble regulert med 2 N natriumhydroksid til 8,7, og sjiktene ble adskilt. Natriumklorid ble tilsatt til det vandige sjikt inntil løsningen var mettet, det vandige sjikt ble dekket med 15 ml etylacetat og regulert til pH 4,2 med saltsyre. Sjiktene ble adskilt og det vandige sjikt ekstrahert med 4 x 8 ml etylacetat. De kombinerte etylacetatsjikt ble tørket med natriumsulfat, og N-[l(S)-etoksykarbonyl-3-fenylpropyl] -L-alanyl-L-prolin ble utfelt med 0,6 g maleinsyre. Bunnfallet ble avfiltrert og tørket i vakuum ved 40°C. 1,5 g (61%) av tittelforbindelsen ble derved oppnådd. To a solution of 1.4 g of N-[1(S)-ethoxycarbonyl-3-phenyl-propyl]-L-alanine in 40 ml of tetrahydrofuran was added 0.85 g of 2-mercaptobenzthiazole, and the resulting mixture was cooled to 0°C. Then 1.2 g of N,N<*->dicyclohexylcarbodiimide was added, and the resulting mixture was stirred at a temperature of from -5°C to 0°C for 3 hours. The dicyclohexylurea that was separated was filtered off, and the thus prepared ester of 2-mercaptobenzothiazole and N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine was added dropwise to cooled (0°C) N,0- bistrimethyl-silyl-L-proline, which was previously prepared by adding 2.8 ml of triethylamine and 2.6 ml of trimethylchlorosilane to a suspension of 1.1 g of L-proline in 40 ml of tetrahydrofuran and stirring at room temperature for 3 hours. Stirring was continued until the absence of the starting compound was detected by liquid chromatography. Tetrahydrofuran was evaporated, 20 mL of water and 10 mL of methylene chloride were added to the residue, the pH was adjusted with 2 N sodium hydroxide to 8.7, and the layers were separated. Sodium chloride was added to the aqueous layer until the solution was saturated, the aqueous layer was covered with 15 ml of ethyl acetate and adjusted to pH 4.2 with hydrochloric acid. The layers were separated and the aqueous layer extracted with 4 x 8 ml of ethyl acetate. The combined ethyl acetate layers were dried with sodium sulfate, and N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline was precipitated with 0.6 g of maleic acid. The precipitate was filtered off and dried in vacuum at 40°C. 1.5 g (61%) of the title compound was thereby obtained.
Eksempel 3 Example 3
N- [1(S)-karboksy-3-fenylpropyl]-L-alanyl-L-prolin. N-[1(S)-carboxy-3-phenylpropyl]-L-alanyl-L-proline.
1 g av N [1(S)-etoksykarbonyl-3-fenylpropyl]-L-alanyl-L-prolin, som ble oppnådd ifølge eksempel 1, ble løst i 5 ml etanol og 5 ml vann som inneholdt 320 mg natriumhydroksid, og løsningen ble omrørt inntil hydrolysen var fullstendig. Etter at hydrolysen var fullført ble løsningsmidlet avdampet under senket trykk. Resten ble løst i 10 ml vann, som var mettet med natriumklorid. Den resulterende løsning ble dekket med 10 ml etylacetat, og pH-verdien ble regulert til 4,2 med saltsyre. Det vandige sjikt ble ekstrahert med 2 x 10 ml etylacetat. Deretter ble de kombinerte etylacetatsjikt tørket og inndampet. Derved ble 0,71 g (76%) av tittelforbindelsen oppnådd, smp. 146-152°C. 1 g of N [1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline, which was obtained according to Example 1, was dissolved in 5 ml of ethanol and 5 ml of water containing 320 mg of sodium hydroxide, and the solution was stirred until hydrolysis was complete. After the hydrolysis was complete, the solvent was evaporated under reduced pressure. The residue was dissolved in 10 ml of water, which was saturated with sodium chloride. The resulting solution was covered with 10 ml of ethyl acetate and the pH was adjusted to 4.2 with hydrochloric acid. The aqueous layer was extracted with 2 x 10 ml ethyl acetate. Then the combined ethyl acetate layers were dried and evaporated. Thereby 0.71 g (76%) of the title compound was obtained, m.p. 146-152°C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU135588A YU46919B (en) | 1988-07-13 | 1988-07-13 | PROCESS FOR PREPARATION OF L-ALANYL-L-PROLINE DERIVATIVES |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO892813D0 NO892813D0 (en) | 1989-07-07 |
| NO892813L NO892813L (en) | 1990-01-15 |
| NO172894B true NO172894B (en) | 1993-06-14 |
| NO172894C NO172894C (en) | 1993-09-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO892813A NO172894C (en) | 1988-07-13 | 1989-07-07 | PROCEDURE FOR THE PREPARATION OF L-ALANYL-L-PROLINE DERIVATIVES |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JP2714447B2 (en) |
| AT (1) | AT394726B (en) |
| DD (1) | DD284028B5 (en) |
| ES (1) | ES2015723A6 (en) |
| NO (1) | NO172894C (en) |
| PL (1) | PL154625B1 (en) |
| SI (1) | SI8811355A (en) |
| SU (1) | SU1757471A3 (en) |
| UA (1) | UA18634A1 (en) |
| YU (1) | YU46919B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003272077A1 (en) * | 2003-07-31 | 2005-02-14 | Lupin Limited | Alpha-amino acid benzothiazolylthio ester as intermediates for manufacture of ace inhibitors and process for preparation thereof |
| ATE446946T1 (en) * | 2006-06-27 | 2009-11-15 | Sandoz Ag | NEW PROCESS FOR PRODUCING SALT |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4442089A (en) * | 1982-07-06 | 1984-04-10 | E. R. Squibb & Sons, Inc. | Method for treating glaucoma with topical or systemic ACE inhibitor compositions |
| JPS6248696A (en) * | 1985-08-27 | 1987-03-03 | Kanegafuchi Chem Ind Co Ltd | Production of n-(1(s)-ethoxycarbonyl-3-phenylpropyl)-l-alanyl-l-proline |
-
1988
- 1988-07-13 SI SI8811355A patent/SI8811355A/en unknown
- 1988-07-13 YU YU135588A patent/YU46919B/en unknown
-
1989
- 1989-07-07 NO NO892813A patent/NO172894C/en unknown
- 1989-07-10 ES ES8902425A patent/ES2015723A6/en not_active Expired - Lifetime
- 1989-07-11 AT AT168189A patent/AT394726B/en not_active IP Right Cessation
- 1989-07-11 DD DD33068889A patent/DD284028B5/en active IP Right Maintenance
- 1989-07-11 PL PL28052689A patent/PL154625B1/en unknown
- 1989-07-12 UA UA4614532A patent/UA18634A1/en unknown
- 1989-07-12 SU SU894614532A patent/SU1757471A3/en active
- 1989-07-13 JP JP1179211A patent/JP2714447B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2714447B2 (en) | 1998-02-16 |
| JPH0272195A (en) | 1990-03-12 |
| NO892813D0 (en) | 1989-07-07 |
| DD284028B5 (en) | 1996-08-08 |
| ES2015723A6 (en) | 1990-09-01 |
| YU135588A (en) | 1990-02-28 |
| AT394726B (en) | 1992-06-10 |
| NO892813L (en) | 1990-01-15 |
| SU1757471A3 (en) | 1992-08-23 |
| SI8811355A (en) | 1995-04-30 |
| YU46919B (en) | 1994-06-24 |
| PL280526A1 (en) | 1990-02-05 |
| UA18634A1 (en) | 1997-12-25 |
| NO172894C (en) | 1993-09-22 |
| PL154625B1 (en) | 1991-08-30 |
| ATA168189A (en) | 1991-11-15 |
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