SI9600169A - Process for preparation of compounds with ace inhibitory effect - Google Patents
Process for preparation of compounds with ace inhibitory effect Download PDFInfo
- Publication number
- SI9600169A SI9600169A SI9600169A SI9600169A SI9600169A SI 9600169 A SI9600169 A SI 9600169A SI 9600169 A SI9600169 A SI 9600169A SI 9600169 A SI9600169 A SI 9600169A SI 9600169 A SI9600169 A SI 9600169A
- Authority
- SI
- Slovenia
- Prior art keywords
- formula
- cooh
- etooc
- compounds
- optionally
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 6
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 18
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- DNONRONPDMTKGS-UHFFFAOYSA-N 1,1,2-trimethylsilinane Chemical compound C[Si]1(C(CCCC1)C)C DNONRONPDMTKGS-UHFFFAOYSA-N 0.000 claims 1
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 claims 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 150000001412 amines Chemical class 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- CEIWXEQZZZHLDM-AAEUAGOBSA-N (2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoic acid Chemical compound CCOC(=O)[C@@H](N[C@@H](C)C(O)=O)CCC1=CC=CC=C1 CEIWXEQZZZHLDM-AAEUAGOBSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- -1 (2S, 3aS, 7aS) -octahydro-1H-indole-2-carboxylic acid silyl ester Chemical class 0.000 description 1
- CQYBNXGHMBNGCG-CSMHCCOUSA-N (2s,3ar,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indol-1-ium-2-carboxylate Chemical compound C1CCC[C@@H]2N[C@H](C(=O)O)C[C@H]21 CQYBNXGHMBNGCG-CSMHCCOUSA-N 0.000 description 1
- CQYBNXGHMBNGCG-FXQIFTODSA-N (2s,3as,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indol-1-ium-2-carboxylate Chemical compound C1CCC[C@@H]2[NH2+][C@H](C(=O)[O-])C[C@@H]21 CQYBNXGHMBNGCG-FXQIFTODSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
KRKA, tovarna zdravil, p.o.KRKA, Medicines Factory, p.o.
Postopek za pripravo spojin z ACE inhibitornim delovanjemA process for the preparation of compounds with ACE inhibitory activity
Področje tehnike, v katero spada izumFIELD OF THE INVENTION
Predloženi izum je s področja organske kemijske sinteze in se nanaša na postopek za pripravo spojin z ACE inhibitornim delovanjem.The present invention relates to the field of organic chemical synthesis and relates to a process for the preparation of compounds with ACE inhibitory activity.
Tehnični problemA technical problem
Obstajala je potreba po enostavnem, učinkovitem, ekonomičnem in industrijsko primernem postopku za pripravo spojin z ACE inhibitornim delovanjem.There was a need for a simple, effective, economical and industrially appropriate process for the preparation of compounds with ACE inhibitory activity.
Stanje tehnikeThe state of the art
Iz literature so znane mnoge sinteze ACE inhibitorjev. Za ACE inhibitorje, ki imajo gradnik (S,S)-N-(l-etoksikarbonil-3-fenilpropil)-L-alanin (formula II v nadaljevanju), se v praksi najpogosteje uporabljata dva postopka, in sicer postopek reduktivnega aminiranja (EP 12401) ali aktivacija (S,S)-N-(l-etoksikarbonil-3-fenilpropil)-Lalanina (US 4,716,235, US 5,359,086).Many syntheses of ACE inhibitors are known from the literature. For ACE inhibitors having the constituent (S, S) -N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanine (formula II below), two methods are most commonly used in practice, namely the reductive amination process (EP 12401) or the activation of (S, S) -N- (1-ethoxycarbonyl-3-phenylpropyl) -alanine (US 4,716,235, US 5,359,086).
Pri doslej znanih postopkih poteka aktivacija s tionilkloridom težavno in z nizkimi dobitki (US 4,760,162).Thionyl chloride activation is difficult and low-yield (US 4,760,162) for the known methods.
V EP 84164 je opisan postopek z uporabo (S,S)-N-(l-etoksikarbonil-3-fenilpropil)L-alanina, pri katerem je potrebna izolacija s kolonsko kromatografijo in odcepitev zaščitne skupine s katalitskim hidrogeniranjem.EP 84164 describes a process using (S, S) -N- (1-ethoxycarbonyl-3-phenylpropyl) L-alanine, which requires isolation by column chromatography and cleavage of the protecting group by catalytic hydrogenation.
Opis rešitve tehničnega problema z izvedbenimi primeriDescription of solution to a technical problem with implementation examples
Predmet izuma je postopek za pripravo spojin z ACE inhibitornim delovanjem s formulo IThe subject of the invention is a process for the preparation of compounds with ACE inhibitory activity of formula I
EtOOC MeEtOOC Me
in njihovih farmacevtsko sprejemljivih soli, kjer Z pomeni alkilni, arilni ali heterocikličen ostanek, prednostno fenil, in ima Rx naslednje pomene:and their pharmaceutically acceptable salts, wherein Z is an alkyl, aryl or heterocyclic radical, preferably phenyl, and R x has the following meanings:
'COOH'COOH
HH
COOHCOOH
H /H /
COOH /COOH /
-N-N
N t-ΒιΓ s ) COOHN t-ΒιΓ s ) COOH
Θ' ,COOH označen s tem, da spojino s formulo II"COOH", wherein the compound of formula II
EtOOCEtOOC
MeMe
OHOH
II kjer ima Z zgoraj navedeni pomen, sililiramo z reagentom za sililiranje, ki uvede trimetilsililno zaščitno skupino, v organskem brezvodnem topilu, v danem primeru v prisotnosti baze, pri čemer nastane spojina s formulo IIIII wherein Z has the above meaning, silylates with a silylating reagent introducing a trimethylsilyl protecting group in an organic anhydrous solvent, optionally in the presence of a base, to give the compound of formula III
EtOOC Me 's-N 'OSiMejEtOOC Me 's- N ' OSiMej
ŠiMejShiMei
OOh
III ki jo aktiviramo s sredstvi za pripravo kislinskih kloridov pri temperaturi med -10°C in -50°C v spojino s formulo IVIII which is activated by acid chloride preparation agents at a temperature between -10 ° C and -50 ° C to a compound of formula IV
EtOOC MeEtOOC Me
nato pa spojino IV presnovimo z amino derivati s formulothen compound IV is reacted with amino derivatives of formula
RtH, kjer ima R3 gornji pomen in je karboksilna skupina v R} v danem primeru zaščitena, odstranimo trimetilsililno skupino in v danem primeru ostale prisotne zaščitne skupine ter dobljene spojine s formulo I na običajen način prevedemo v njihove farmacevtsko sprejemljive soli.R t H, wherein R 3 have the above meaning, and is a carboxyl group in R} is an optionally protected, remove a trimethylsilyl group and optionally the other protecting groups present, and the resulting compound of formula I in the customary manner into their pharmaceutically acceptable salts.
Farmacevtsko sprejemljive soli so npr. maleat, sulfat, fosfat.Pharmaceutically acceptable salts are e.g. maleate, sulfate, phosphate.
Prednostno organsko topilo je diklorometan.Preferably the organic solvent is dichloromethane.
Prednosten reagent za sililiranje je trimetilklorsilan, v poštev pa pridejo tudi trimetilsilazan (CH3)3SiNHSi(CH3)3, dimetildiklorsilan Cl2Si(CH3)2 ali trimetilsililester trifluorometansulfonske kisline F3C-SO3Si(CH3)3.A preferred reagent for silylation is trimethylchlorosilane, applicable also comes trimetilsilazan (CH 3) 3 SiNHSi (CH 3) 3, dimetildiklorsilan Cl 2 Si (CH 3) 2, trimethylsilyl trifluoromethanesulfonic acid F 3 C-SO 3 Si (CH 3) 3 .
Kot bazo lahko uporabimo trietilamin.Triethylamine can be used as the base.
Kot sredstvo za pripravo kislinskih kloridov prednostno uporabimo tionilklorid.Thionyl chloride is preferably used as acid chloride preparation agent.
Karboksilna skupina v Rx je lahko zaščitena, in to z znanimi zaščitnimi skupinami.The carboxyl group in R x may be protected by known protecting groups.
Prednostno delamo pri temperaturi od -20°C do -25°C.Preferably, the temperature is -20 ° C to -25 ° C.
Zaradi uporabe sililimega sredstva, ki uvede trimetilsililno zaščito, so dobitki reakcije zelo visoki in tudi ne dobimo zasmoljenih produktov, to sredstvo pa se da reciklirati.Due to the use of a silylime agent which introduces trimethylsilyl protection, the yields of the reaction are very high and the products obtained are not desalted, and this product is recyclable.
Reakcija je selektivna. Amino in karboksi skupina se hkrati zaščitita. V primeru uporabe trimetilklorsilana kot sililirnega sredstva in tionilklorida kot aktivacijskega sredstva dobimo pri aktivaciji v spojino IV stranski produkt trimetilklorsilan, ki v sledeči reakciji z amino derivati le-te zaščiti, to pa je še dodatna prednost postopkaThe reaction is selective. The amino and carboxy groups are protected at the same time. In the case of the use of trimethylchlorosilane as a silylating agent and thionyl chloride as the activating agent, by-product activation of compound IV gives trimethylchlorosilane, which in the subsequent reaction with the amino derivatives thereof, protects it, which is an additional advantage of the process
Izum natančneje opisujemo, nikakor pa ga ne omejujemo z naslednjimi primeri.The invention is described in more detail, but in no way limited by the following examples.
PrimeriExamples
Sinteza fSVl-{N-[l-fetoksikarbonin-3-fenilpropil]-L-alanil}-L-prolin maleataSynthesis of fSVl- {N- [1-Fetoxycarbonin-3-phenylpropyl] -L-alanyl} -L-proline maleate
K raztopini 1,4 g (S,S)-N-(l-etoksikarbonil-3-fenilpropil)-L-alanina v 25 ml diklorometana pri -10 do -15°C dodamo 1,27 ml trimetilklorsilana in 1,38 ml trietilamina ter mešamo 15 minut. K zmesi nato dodamo 0,36 ml SOC12 v 4 ml diklorometana in mešamo dodatnih 20 minut, zatem pa dodamo 0,58 g L-prolina in 0,7 ml trietilamina. Zmes mešamo pri -20 do -25°C 67 ur. Hlapne komponente oddestiliramo pri znižanem tlaku. Na preostanek nalijemo raztopino 4,5 g NaCl v 15 ml H2O in 5 ml etil acetata. S 33% NaOH uravnamo pH na 4,24 in ekstrahiramo. Po ločitvi organsko fazo sušimo z Na2SO4, filtriramo in dodamo 0,7 g maleinske kisline v 4 ml etil acetata. Nastalo suspenzijo mešamo pri sobni temperaturi 20 minut. Po filtraciji dobimo 2,1 g produkta s tal. 142 do 144°C.To a solution of 1.4 g (S, S) -N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanine in 25 ml of dichloromethane at -10 to -15 ° C was added 1.27 ml of trimethylchlorosilane and 1.38 ml. triethylamine and stirred for 15 minutes. To the mixture was then added 0.36 ml of SOCl 2 in 4 ml of dichloromethane and stirred for an additional 20 minutes, then 0.58 g of L-proline and 0.7 ml of triethylamine were added. The mixture was stirred at -20 to -25 ° C for 67 hours. The volatile components are distilled off under reduced pressure. Pour a solution of 4.5 g of NaCl into 15 ml of H 2 O and 5 ml of ethyl acetate. The pH was adjusted to 4.24 with 33% NaOH and extracted. After separation, the organic phase was dried with Na 2 SO 4 , filtered and 0.7 g of maleic acid was added to 4 ml of ethyl acetate. The resulting suspension was stirred at room temperature for 20 minutes. Filtration gave 2.1 g of the product from the ground. 142 to 144 ° C.
Primer 2Example 2
Sinteza sulfata (3aS.7aS)-l-{N-[l-(S)-(etoksikarbonil)-3-fenilpropill-Salanil}oktahidroindol-2-(S)-karboksilne kislineSynthesis of sulphate (3aS.7aS) -1- {N- [1- (S) - (ethoxycarbonyl) -3-phenylpropyl-salanyl} octahydroindole-2- (S) -carboxylic acid
0,9 g (2S,3aS,7aS)-oktahidro-lH-indol-2-karboksilne kisline v 25 ml diklorometana dodamo 0,74 ml trietilamina in 0,66 ml trimetilklorsilana ter mešamo pri sobni temperaturi 1,5 do 2 uri. Medtem pripravimo raztopino 1,4 g (S,S)-N-(l-etoksikarbonil3-fenilpropil)alanina v 25 ml diklorometana, ohladimo na -10 do -15°C in dodamo 1,27 ml trimetilklorsilana in 1,38 ml trietilamina. Po 15 minutah dodamo 0,36 ml SOC12 v 4 ml diklorometana in mešamo še 90 minut, nato pa dodamo prej pripravljen sililni ester (2S,3aS,7aS)-oktahidro-lH-indol-2-karboksilne kisline. Zmes mešamo 22 ur pri sobni temperaturi. Dodamo 3 g NaCl v 10 ml vode in uravnamo pH s 33% NaOH na 0,88. Organski fazi ponovno dodamo 3 g NaCl v 10 ml vode in uravnamo pH s 33% NaOH na 4,22. Organsko fazo oddestiliramo pri znižanem tlaku, na preostanek pa nalijemo 30 ml vode in 15 ml metil t-butil etra. V organsko fazo dodamo 13 g silikagela, 1,5 g aktivnega oglja in mešamo 90 minut. Filtriramo preko Celita®, filtrat ohladimo na -10°C in dokapavamo 0,14 ml 96% H2SO4 v 3,5 ml metil t-butil etra. Mešamo še 3 ure in odfiltriramo 2,04 g produkta s tal. 102 do 106°C in m/z = 430 (M+).0.9 g (2S, 3aS, 7aS) -octahydro-1H-indole-2-carboxylic acid in 25 ml of dichloromethane was added 0.74 ml of triethylamine and 0.66 ml of trimethylchlorosilane and stirred at room temperature for 1.5 to 2 hours. Meanwhile, prepare a solution of 1.4 g (S, S) -N- (1-ethoxycarbonyl3-phenylpropyl) alanine in 25 ml of dichloromethane, cool to -10 to -15 ° C and add 1.27 ml of trimethylchlorosilane and 1.38 ml of triethylamine . After 15 minutes, 0.36 ml of SOCl 2 in 4 ml of dichloromethane was added and stirred for a further 90 minutes, and then the (2S, 3aS, 7aS) -octahydro-1H-indole-2-carboxylic acid silyl ester was added. The mixture was stirred for 22 hours at room temperature. Add 3 g of NaCl in 10 ml of water and adjust the pH from 33% NaOH to 0.88. 3 g of NaCl in 10 ml of water are again added to the organic phase and the pH is adjusted from 33% NaOH to 4.22. The organic phase was distilled off under reduced pressure, and 30 ml of water and 15 ml of methyl t-butyl ether were poured into the residue. To the organic phase was added 13 g of silica gel, 1.5 g of activated carbon and stirred for 90 minutes. Filtered through Celite®, the filtrate was cooled to -10 ° C and 0.14 ml of 96% H 2 SO 4 was added dropwise to 3.5 ml of methyl t-butyl ether. The mixture was stirred for a further 3 hours and 2.04 g of the product was filtered off the soil. 102 to 106 ° C and m / z = 430 (M + ).
Primer 3Example 3
Sinteza {2S-[l[R*(R*)],2o!.3aQ:.7aj3]}-l-{2-[fl-(etoksikarbonil)-3fenilpropil]amino]-l-oksopropil}oktahidro -lH-indol-2-karboksilne kislineSynthesis of {2S- [1 [R * (R *)], 2 O .3aQ: 7aj3]} - 1- {2- [fluoro (ethoxycarbonyl) -3phenylpropyl] amino] -1-oxopropyl} octahydro -1H- indole-2-carboxylic acids
Raztopino 1,4 g (S,S)-N-(l-etoksikarbonil-3-fenilpropil)alanina v 25 ml diklorometana ohladimo na -10 do -15°C ter dodamo 1,27 ml trimetilklorsilana in 1,38 ml trietilamina. Mešamo 15 minut in dodamo 0,36 ml SOC12 v 4 ml diklorometana, mešamo dodatnih 20 minut, zatem pa dodamo 0,85 g (2S,3aR,7aS)-oktahidro-lHindol-2-karboksilne kisline in 0,7 ml trietilamina. Pri -20 do -25°C mešamo 20 ur ter še 22 ur pri sobni temperaturi. Po dodatku 3 g NaCl v 10 ml vode uravnamo pH s 33% NaOH na 8,5 do 9, fazi ločimo in organsko fazo speremo z raztopino 4,5 g NaCl v 15 ml vode. Fazi ločimo in uravnamo pH združenih vodnih faz s 35% HC1 na 4,30. Ekstrahiramo z diklorometanom (2 x 25 ml), fazi ločimo, organsko fazo oddestiliramo pri znižanem tlaku, na preostanek pa nalijemo metil t-butil eter in odfiltriramo 1,98 g produkta. Surov produkt očistimo s preobaijanjem iz vročega etanola in vode. Ko se suspenzija ohladi, odfiltriramo produkt s tal. 122 do 124°C in m/z = 431 (M+ + 1).A solution of 1.4 g of (S, S) -N- (1-ethoxycarbonyl-3-phenylpropyl) alanine in 25 ml of dichloromethane was cooled to -10 to -15 ° C and 1.27 ml of trimethylchlorosilane and 1.38 ml of triethylamine were added. Stirred for 15 minutes and added 0.36 ml of SOCl 2 in 4 ml of dichloromethane, stirred for an additional 20 minutes, then added 0.85 g (2S, 3aR, 7aS) -octahydro-1Hindole-2-carboxylic acid and 0.7 ml of triethylamine . The mixture is stirred at -20 to -25 ° C for 20 hours and at room temperature for 22 hours. After the addition of 3 g of NaCl in 10 ml of water, the pH was adjusted from 33% NaOH to 8.5 to 9, the phase was separated and the organic phase was washed with a solution of 4.5 g of NaCl in 15 ml of water. The phases were separated and the pH of the combined aqueous phases was adjusted from 35% HCl to 4.30. It was extracted with dichloromethane (2 x 25 ml), the phase separated, the organic phase was distilled off under reduced pressure, and methyl t-butyl ether was poured onto the residue and 1.98 g of product was filtered off. The crude product is purified by digestion with hot ethanol and water. When the suspension cools, filter the product from the ground. 122 to 124 ° C and m / z = 431 (M + + 1).
ZaFor
KRKA, tovarna zdravil, p.o.:KRKA, medicines factory, p.o .:
UG-ILMs/, C' : KUG-ILMs /, C ': K
Claims (4)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9600169A SI9600169A (en) | 1996-05-22 | 1996-05-22 | Process for preparation of compounds with ace inhibitory effect |
| DE19721290A DE19721290A1 (en) | 1996-05-22 | 1997-05-21 | ACE-inhibiting substituted alanyl-derivatives of e.g. proline preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9600169A SI9600169A (en) | 1996-05-22 | 1996-05-22 | Process for preparation of compounds with ace inhibitory effect |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SI9600169A true SI9600169A (en) | 1997-12-31 |
Family
ID=20431852
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI9600169A SI9600169A (en) | 1996-05-22 | 1996-05-22 | Process for preparation of compounds with ace inhibitory effect |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE19721290A1 (en) |
| SI (1) | SI9600169A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2289060T3 (en) * | 2002-01-30 | 2008-02-01 | Les Laboratoires Servier | PROCESS FOR THE PREPARATION OF HIGH PURITY PERINDOPRILE AND USEFUL INTERMEDIATES IN ITS SYNTHESIS. |
| ATE395913T1 (en) | 2003-02-28 | 2008-06-15 | Servier S A Lab | METHOD FOR PRODUCING PERINDOPRIL |
| SI21704A (en) * | 2004-01-14 | 2005-08-31 | Lek Farmacevtska Druzba Dd | New crystal form of perindopril, procedure of its preparation, pharmaceutical preparations containing this form and their application in treatment of hypertensia |
| PL367931A1 (en) * | 2004-05-12 | 2005-11-14 | Instytut Farmaceutyczny | Method for manufacture of 2-[n-[(s)-1- etoxycarbonyl-3-phenyl propyl]-(s)-alanyl] -(1s,3s,5s)-2-azabicyclo [3.3.0] octane-3-carboxylic acid |
| SI21800A (en) * | 2004-05-14 | 2005-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | New procedure of synthesis of perindopril |
-
1996
- 1996-05-22 SI SI9600169A patent/SI9600169A/en unknown
-
1997
- 1997-05-21 DE DE19721290A patent/DE19721290A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| DE19721290A1 (en) | 1997-12-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Barlos et al. | Efficient" one-pot" synthesis of N-tritylamino acids | |
| US4618708A (en) | Amino acid derivative | |
| CA1205476A (en) | Substituted acyl derivatives of octahydro-1h-indole-2- carboxylic acids | |
| US4885283A (en) | Phosphinic acid derivatives | |
| CN100503568C (en) | Process for the preparation of perindopril, its analgous compounds and salts therof using 2,5 dioxo-oxazolidine intermediate compounds | |
| CA2125080A1 (en) | Peptidic phosphinyloxymethyl ketones as interleukin-1beta-converting enzyme inhibitors | |
| US5750555A (en) | Bis-indolyl maleinimide or indolopyrrolo carbazole containing an amino acid as PKC inhibitors | |
| KR0121793B1 (en) | L-proline derivatives, their preparation and biological applications | |
| SI9600169A (en) | Process for preparation of compounds with ace inhibitory effect | |
| EP4009962A1 (en) | Compositions of trofinetide | |
| JPS61100564A (en) | Peptide-substituted heterocyclic immunostimulants | |
| US4698442A (en) | ω-Guanidino-substituted-α-amino acids | |
| AU2004270429B2 (en) | Novel method for the synthesis of perindopril and the pharmaceutically-acceptable salts thereof | |
| CA2169335A1 (en) | Production of aldehyde derivatives | |
| US4325886A (en) | Optical resolution of acylthiopropionic acid | |
| KR100297180B1 (en) | Phospholipid derivatives and preparation methods thereof | |
| US3891692A (en) | N-(cyclopropylalkoxycarbonyl)amino acids | |
| CA1304388C (en) | Process of preparing carboxyalkyl dipeptides | |
| JPH11509850A (en) | Method for producing dolastatin 15 and intermediates thereof | |
| JPH049800B2 (en) | ||
| Elmore et al. | Thioesters of amino acid derivatives as thioacylating agents in thiopeptide synthesis | |
| Houssin et al. | Aminoalkyl derivatives of 2, 4′‐bithiazole‐4‐carboxylic acid, the intercalating part of bleomycin | |
| SI21507A (en) | Procedure of preparation of compounds with ace inhibition effect | |
| SU664560A3 (en) | Method of obtaining peptides or salts thereof | |
| CA2015827A1 (en) | Amino acid derivatives possessing renin-inhibitory activities |