DK173730B1 - Process for the synthesis of Alpha-N-alkylated amino acids and esters thereof and intermediate by the process - Google Patents
Process for the synthesis of Alpha-N-alkylated amino acids and esters thereof and intermediate by the process Download PDFInfo
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Abstract
Description
i DK 173730 B1in DK 173730 B1
Den foreliggende opfindelse angår en fremgangsmåde til industriel syntese af N-al kylerede, eventuelt forestrede a-amino-d i syrer, 5The present invention relates to a process for the industrial synthesis of N-alkylated, optionally esterified α-amino-d in acids.
Mere specielt angår opfindelsen en hidtil ukendt fremgangsmåde til industriel syntese af derivater med den almene formel (I): i1 10 HO - OC - CH - NH - CH - CO - 0R2 (I) CH3 og deres additionsalte med en mineralsyre eller organisk syre eller en base, i hvilken formel: 15More particularly, the invention relates to a novel process for the industrial synthesis of derivatives of the general formula (I): II - OC - CH - NH - CH - CO - OR2 (I) CH3 and their addition salts with a mineral acid or organic acid or a base in which formula:
Rj er lineært eller forgrenet lavere alkyl med 1 til 6 carbon-atomer , R2 er hydrogen eller en lineær eller forgrenet lavere alkyl- 20 gruppe med 1 til 4 carbonatomer.R 1 is linear or branched lower alkyl of 1 to 6 carbon atoms, R 2 is hydrogen or a linear or branched lower alkyl group of 1 to 4 carbon atoms.
Derivaterne med formlen (I), der fås ved fremgangsmåden ifølge opfindelsen, kan anvendes til syntese af carboxyalkyldipepti- der med formlen (II) 25 i1 R30 - OC - CH - N - OC - CH - NH - CH - CO - 0R2 (II)The derivatives of formula (I) obtained by the process of the invention can be used for the synthesis of carboxyalkyl dipeptides of formula (II) 25 R 30 - OC - CH - N - OC - CH - NH - CH - CO - OR 2 (II )
^ A J I^ A J I
ch3 30 og deres farmaceutisk acceptable salte, i hvilken formel:ch3 30 and their pharmaceutically acceptable salts, in which formula:
Ri og R2 har samme betydning som i formel (I), 35 R3 er et hydrogenatom eller en lavere alkylgruppe med 1 til 4 carbonatomer, 2 DK 173730 B1 strukturen CH - N betegner indolin, isoindolin, tetrahydroqui-^ A ) nolin, tetrahydro isoqui no 1 in, perhydro 1ndoΊ, perhydro 1 so i ndo 1 , perhydroisoquinolin, perhydroquinol in, perhydrocyklopenta[b)-5 pyrrol, 2-azabicyk1 o[2,2,2]octan og 2-azabi cykl o[2,2,1]heptan.R 1 and R 2 have the same meaning as in formula (I), R 3 is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, the structure CH - N represents indoline, isoindoline, tetrahydroquin (A) noline, tetrahydro isoqui no 1 in, perhydro 1ndoΊ, perhydro 1 so i ndo 1, perhydroisoquinoline, perhydroquinol in, perhydrocyclopenta [b) -5 pyrrole, 2-azabicyclo [2,2,2] octane and 2-azabicyclo [2.2, 1] heptane.
Den foretrukne forbindelse med formlen (II) er perindopril med form!en (III) 10 (S)l L(S) ^ -^“COOH (III) I (S) (S) .C — CH — NH—CH— COOC2H.The preferred compound of formula (II) is perindopril of formula (III) 10 (S) 1 L (S) + - COOH (III) I (S) (S) .C - CH - NH - CH COOC2H.
15 O* I I15 O * I I
CH, CHjCMjCH, eller (2S,3aS,7aS)-l-{2-[i-(ethoxycarbonyl)-(S)-bytylamino]- (S)-propionyl)octahydroindol-2-carboxy1syre og dens addi t ion - 20 salte med en farmaceutisk acceptabel syre eller base, i hvilket tilfælde fremgangsmåden ifølge opfindelsen specielt kan anvendes.CH, CH2CMjCH, or (2S, 3aS, 7aS) -1- {2- [1- (ethoxycarbonyl) - (S) -butylamino] - (S) -propionyl) octahydroindole-2-carboxylic acid and its addition - 20 salts with a pharmaceutically acceptable acid or base, in which case the process according to the invention can be especially used.
Forbindelserne med formlen (II) og deres salte har interessan-25 te farmakologiske egenskaber. Specielt udøver de en hæmmende virkning på visse enzymer, såsom carboxypo1ypepti daser , enke-phalinaser eller kininase II. Især hæmmer de omdannelsen af angiotensin I decapeptid til angiotensin II octapeptid, som i visse tilfælde er ansvarlig for arteriel hypertension, ved at 3 ^ virke på omdannelsesenzymet.The compounds of formula (II) and their salts have interesting pharmacological properties. In particular, they exert an inhibitory effect on certain enzymes, such as carboxypolypepti dases, monkey phalinases or kininase II. In particular, they inhibit the conversion of angiotensin I decapeptide to angiotensin II octapeptide, which in some cases is responsible for arterial hypertension, by acting on the conversion enzyme.
Brugen af disse forbindeler i terapeutiske midler gør det derfor muligt at reducere eller endog undertrykke aktiviteten af disse enzymer, som er ansvarlige for hypertensiv forstyrrelse 35 eller hjerte i nsufficiens. Virkningen på kininase II resulterer i en stigning i cirkulerende bradykinin og også i nedsættelse af arterietrykket ad denne vej.Therefore, the use of these compounds in therapeutic agents makes it possible to reduce or even suppress the activity of these enzymes, which are responsible for hypertensive disorder or cardiac failure. The effect on kininase II results in an increase in circulating bradykinin and also in the reduction of arterial pressure along this route.
3 DK 173730 B13 DK 173730 B1
Forbindelser med formlen (II) og især forbindelsen med formlen (III), dens fremstilling og anvendelse i terapeutiske midler er beskrevet i europæisk patent nr. 0.049.658.Compounds of formula (II) and in particular the compound of formula (III), its preparation and use in therapeutic agents are disclosed in European Patent No. 0.049,658.
5 Forbindelserne med formlen (I) kan anvendes til fremstilling af forbindelser med formlen (II).The compounds of formula (I) can be used to prepare compounds of formula (II).
Forbindelserne med formlen (II) omfatter to såkaldte asymmetriske carbonatomer, der hver er i stand til at have to kon-10 figurat i oner R eller S: (R, S) (R , S ) # # Ri HO - OC - CH - NH - CH - CO - OR2 (I) 15 CH3The compounds of formula (II) comprise two so-called asymmetric carbon atoms, each capable of having two conjugates in ones R or S: (R, S) (R, S) # # Ri HO - OC - CH - NH - CH - CO - OR 2 (I) CH 3
Forbindelserne med formlen (I) eksisterer derfor i form af fire stereoisomerer, der kan betegnes (R,R), (R,S), (S,R) eller (S,S), afhængende af konfigurationen af de to såkaldte asymme-2 0 t r i ske carbonatomer.The compounds of formula (I) therefore exist in the form of four stereoisomers which may be designated (R, R), (R, S), (S, R) or (S, S), depending on the configuration of the two so-called asymmetries. 2 0 tri carbon atoms.
De mest aktive forbindelser med formlen (II) er de, hvori de to carbonatomer i sidekæden begge har S-konfiguration.The most active compounds of formula (II) are those in which the two carbon atoms in the side chain both have S configuration.
2 5 Fremgangsmåden ifølge opfindelsen angår specielt den industrielle syntese af forbindelser med formlen (I), hvori de to asymmetriske carbonatomer begge har S-konfi-guration.In particular, the process of the invention relates to the industrial synthesis of compounds of formula (I), wherein the two asymmetric carbon atoms both have S configuration.
30 Der er kun beskrevet få fremgangsmåder til industriel syntese af derivaterne med formlen (I). Europæisk patentansøgning nr. 0.117.488, som er meget almen, er kendt, og ifølge denne anvendes cc-carboxylerede trifluormethansulfonater. Stereokemien af begge udgangsmaterialer må imidlertid vælges nøje for at 35 opnå den ønskede di astereo isomer af produktet med formlen (I).Only a few methods for industrial synthesis of the derivatives of formula (I) have been described. European Patent Application No. 0,117,488, which is very general, is known and according to this cc-carboxylated trifluoromethanesulfonates are used. However, the stereochemistry of both starting materials must be carefully selected to obtain the desired di-astereo isomer of the product of formula (I).
Ansøgerne har nu fundet en fremgangsmåde til industriel syntese af derivater med formlen (I), som har stor interesse, 4 DK 173730 B1 idet den på den ene side er meget enkel at udføre og på den anden side anvender et naturligt udgangsmateriale alanin og derfor er billig og således indfører et kædeled, der på forhånd har S-konfiguration.Applicants have now found a process for industrial synthesis of derivatives of formula (I) which is of great interest, on the one hand, it is very simple to perform and on the other hand uses a natural starting material alanine and is therefore cheap and thus introduces a chain link which has S configuration in advance.
5 Når syntesen er afsluttet adskilles de fremkomne (S,S) og (R,S) isomerer ved en enkelt fraktioneret krystallisation i nærværelse af en syre valgt fortrinsvis blandt maleinsyre, vinsyre og citronsyre.When the synthesis is complete, the resulting (S, S) and (R, S) isomers are separated by a single fractional crystallization in the presence of an acid selected preferably from maleic, tartaric and citric acids.
10 Kombinationen af disse valg, der foretages efter streng udvælgelse, gør det muligt at få en syntese af forbindelserne med formlen (I), som er særlig fordelagtig at anvende i industriel målestok. Mere specielt består fremgangsmåden ifølge opfindel- sen i at L-alanin med formlen (IV): 15 ' (S) H2N - CH - C00H (IV) ch3 hvori det asymmetriske carbonatom har S-konfiguration, beskyttes ved forestring med 20 benzylalkohol i nærværelse af para-toluensulfonsyre og under afdestillering af vand dannet under reaktionsforløbet, til opnåelse af et para-toluensulfonatsalt af forbindelsen med formlen (V): H;N - Cl I - COOCHAH5 (V)The combination of these choices, made after rigorous selection, makes it possible to obtain a synthesis of the compounds of formula (I) which is particularly advantageous to use on an industrial scale. More particularly, the process of the invention consists in L-alanine of formula (IV): 15 '(S) H2N - CH - C00H (IV) ch3 wherein the asymmetric carbon atom has S configuration is protected by esterification with 20 benzyl alcohol in the presence of para-toluenesulfonic acid and, under distillation of water formed during the course of the reaction, to give a para-toluenesulfonate salt of the compound of formula (V): H; N - Cl I - COOCHAH5 (V)
25 I25 I
CII3 hvilket salt ved alkalisering med ammoniak omdannes til den tilsvarende base med formlen (V), hvilken base i nærværelse af en tertiær amin kondenseres med et bromderivat med 3 0 formlen (VI):CII3 which, by alkalization with ammonia, is converted to the corresponding base of formula (V), which in the presence of a tertiary amine is condensed with a bromine derivative of formula (VI):
Br - CH - COOR, (VI) R, hvoi i R, og R, har samme betydning som i formenl (I), til dannelse af en blanding af (S,R)-3 5 og (S.S)-isomere med formlen (VTT): 5 DK 173730 B1 (S) (R,S) C6H5CH2OCO - CH - NH - CH - COOR2 (VII)Br - CH - COOR, (VI) R, wherein R, and R, have the same meaning as in Formula (I) to form a mixture of (S, R) -3 and (SS) isomers of formula (VTT): 5 DK 173730 B1 (S) (R, S) C6H5CH2OCO - CH - NH - CH - COOR2 (VII)
I II I
ch3 r, 5 hvori Rj og R2 har samme betydning som i formel (I), hvorfra (S.S)-isomeren isoleres i form af sit maleinsyresait ved opløsning i et organisk opløsningsmiddel og tilsætning af maleinsyre, hvorefter det dannede bundfald frafiltreres, tørres og om ønsket omkrystalliseres, hvilket salt omdannes til (S,S)-isomeren med formlen (VII) ved at alkalisere en vandig opløsning efterfulgt af ekstraktion og afdampning af opløsningsmidlet, hvorefter den derved 10 fremkomne (S,S)-isomer underkastes hydrogenering i nærværelse af palladium-på-carbon til dannelse af en forbindelse med formlen (I).wherein R 1 and R 2 have the same meaning as in formula (I) from which the (SS) isomer is isolated in the form of its maleic acid by dissolving in an organic solvent and adding maleic acid, after which the precipitate formed is filtered off, dried and refined the salt is converted to the (S, S) isomer of formula (VII) by alkalizing an aqueous solution followed by extraction and evaporation of the solvent and then the resulting (S, S) isomer is subjected to hydrogenation in the presence of palladium-on-carbon to form a compound of formula (I).
Opfindelsen angår også maleinsyresaltet af (S,S)-isomeren af forbindelsen med formlen (Vila).The invention also relates to the maleic acid salt of the (S, S) isomer of the compound of formula (Vila).
(S) (R,S) 15 C6H5CH2OCO-CH-NH-CH-COOC2H5 (Vira) ch3 ch2ch2ch3(S) (R, S) C6H5CH2OCO-CH-NH-CH-COOC2H5 (Viruses) ch3 ch2ch2ch3
Det følgende eksempel illustrerer opfindelsen.The following example illustrates the invention.
EKSEMPEL i N-[(S)-1-carbathoxybuty1]-(S)-alanfn 20 TRIN A: Ben zy1 ester af (S)-alanin, para-toluensulfonat.EXAMPLE I N - [(S) -1-Carbathoxybutyl] - (S) -alanine STEP A: Benzyl ester of (S) -alanine, para-toluenesulfonate.
En suspension af 8,2 kg (S)-alanin, 1,78 kg para - to 1uensu1 fonsyre og 2 kg benzy1 a 1koho1 1 3,30 liter toluen opvarmes under t i 1 bagesvaling og omrøring, og det dannede vand afdestilleres efterhånden som det dannes.A suspension of 8.2 kg of (S) -alanine, 1.78 kg of para - two 1U of sulfonic acid and 2 kg of benzyl of 1ChoI 1 of 3.30 liters of toluene is heated under ten liters of reflux and stirring, and the water formed is distilled off as the is formed.
T i 1 bagesva Ting fortsattes indtil der er fremkommet den teoretiske mængde vand.T in 1 baking soda Things continued until the theoretical amount of water was obtained.
6 DK 173730 B16 DK 173730 B1
Reakt ionsb1andi ngen afkøles til 70°C og inddampes i vakuum. I den fremkomne pastaagtige remanens hældes 12,30 liter isopro-pylether og der omrøres i 5 timer ved 20-22eC.The reaction mixture is cooled to 70 ° C and evaporated in vacuo. Into the resulting paste-like residue is poured 12.30 liters of isopropyl ether and stirred for 5 hours at 20-22 ° C.
5 Den fremkomne suspension fraf i 1treres, og bundfaldet vaskes med to portioner på 1,50 liter isopropylether.The resulting suspension is filtered off and the precipitate is washed with two portions of 1.50 liters of isopropyl ether.
Efter tørring fås 32 g af para-toluensulfonatet af benzyleste-ren af (S)-alanin.After drying, 32 g of the para-toluene sulfonate of the benzyl ester of (S) -alanine is obtained.
1010
Udbytte: 99,0%.Yield: 99.0%.
Drejningsevne: [a]20 = -3,7° (c » 1/MeOH)Turning Capability: [α] 20 = -3.7 ° (c »1 / MeOH)
DD
1515
Smeltepunkt: 98®C.Melting point: 98 ° C.
Spektometri i det infrarøde (nujol): Bånd ved 1760, 1730 cm"!.Spectrometry in the infrared (nujol): bands at 1760, 1730 cm
2020
Kernemagnetisk resonansspektrometri Ih - 60 MHz:Nuclear Magnetic Resonance Spectrometry Ih - 60 MHz:
Opløsningsmiddel: methanol-d^ 6 = 1,41 ppm, dublet, 3H, CH-CH3, J = 6,9 Hz δ = 2,29 ppm, singlet, 3H, CH3-CgH,j δ = 4,02 ppm, quadruplet, IH, CH-CH3, J=6,9 Hz 2 5 δ = 4,85 ppm, bredt signal, 3H, NH2, SO3H δ * 5,21 ppm, singlet, 2H, COO-CH2 6 = 7,0 til 7,8 ppm, uopløste toppe, 9H, aromatisk.Solvent: methanol-d 6 = 1.41 ppm, doublet, 3H, CH-CH 3, J = 6.9 Hz δ = 2.29 ppm, singlet, 3H, CH 3 -CgH, j δ = 4.02 ppm, quadrupled, 1H, CH-CH3, J = 6.9 Hz 2 δ = 4.85 ppm, broad signal, 3H, NH2, SO3H δ * 5.21 ppm, singlet, 2H, COO-CH2 6 = 7.0 to 7.8 ppm, unresolved peaks, 9H, aromatic.
TRIN B; Benzylester af S-alanin 30STEP B; Benzyl ester of S-alanine 30
Til en opløsning af 3,14 kg para-to 1uensu 1 fonat af benzyleste-ren af (S)-alanin i 9,30 liter vand sættes ammoniak indtil a 1 -ka1 i n i te t.To a solution of 3.14 kg of para-two 1ensu 1 phonate of the benzyl ester of (S) -alanine in 9.30 liters of water is added ammonia until a 1-ka1 i n i te t.
3535
Der holdes omrørt i 30 minutter, og derefter ekstraheres med 1,25 liter methylenchlorid. Den organiske fase fraskilles, og den vandige fase ekstraheres med to portioner på 1 liter methy1ench1 or i d.Stir for 30 minutes, then extract with 1.25 liters of methylene chloride. The organic phase is separated and the aqueous phase is extracted with two 1 liter portions of methylene chloride or d.
7 DK 173730 B17 DK 173730 B1
Methy1ench1 or idfaserne forenes, vaskes med vand og tørres over magn iumsu1 fat.The methylene or id phases are combined, washed with water and dried over magnesium sulfate.
Efter afdampning af methylenchloridet fås 1,5 kg benzylester 5 af (S)-alanin i form af en gul olieagtig veske.After evaporation of the methylene chloride, 1.5 kg of benzyl ester 5 of (S) -alanine is obtained in the form of a yellow oily bag.
Udbytte: 95%.Yield: 95%.
Spektrometri i det infrarøde (nujol): 10 Bånd ved 1760 og 1730 cm-1.Spectrometry in the infrared (nujol): 10 bands at 1760 and 1730 cm -1.
Kernemagnetisk resonansspektrometri Ih - 60 MHZ: δ 1,39 ppm, dublet, 3H, CH-CH3, J«6,9 Hz δ * 3,98 ppm, quadruplet, IH, CH-CH3, J«6,9 Hz 15 δ » 4,90 ppm, bredt signal, 2H, NH2 δ * 5,23 ppm, singlet, 2H, COO-CH2 δ * 7,10 uopløste toppe, 5H, aromatisk.Nuclear Magnetic Resonance Spectrometry Ih - 60 MHz: δ 1.39 ppm, doublet, 3H, CH-CH3, J + 6.9 Hz δ * 3.98 ppm, quadruplet, IH, CH-CH3, J »4.90 ppm, broad signal, 2H, NH2 δ * 5.23 ppm, singlet, 2H, COO-CH2 δ * 7.10 unresolved peaks, 5H, aromatic.
TRIN C: Benzylester af N-[l-carbethoxybutyl]-(S)-alanin 20STEP C: Benzyl ester of N- [1-carbethoxybutyl] - (S) -alanine
En blanding af 1,43 kg af benzylesteren af (S)-alanin, 1,84 kg ethyl-α-bromvalerat og 8,9 kg tri ethyl am in i 12 liter N,N-di-methyl formamid opvarmes gradvis under omrøring til 90®C. Der holdes omrørt i 3 timer ved 90°C før reaktionsblandingen afkø-25 les til 70“C.A mixture of 1.43 kg of the benzyl ester of (S) -alanine, 1.84 kg of ethyl α-bromovalerate and 8.9 kg of triethyl amine in 12 liters of N, N-dimethyl formamide is gradually heated under stirring to 90®C. Stir for 3 hours at 90 ° C before the reaction mixture is cooled to 70 ° C.
Ν,Ν-dimethylformamid afdampes i vakuum, og den olieagt ige rest optages i 7 liter i sop ropy 1 ether. Der tilsattes 7 liter vand og holdes omrørt i en halv time. Den organiske fase fraskil-30 les, og den vandige fase ekstraheres med 3,5 liter isopropyl-ether. De organiske faser forenes og ekstraheres med 9 liter af en molar opløsning af saltsyre. Den derved fremkomne vandige fase gøres alkalisk under anvendelse af natriumcarbonat og derefter ekstraheres med isopropy1ether . De organiske faser 35 forenes og vaskes med vand. Der tørres over magniumsulfat og inddampes så i vakuum.The Ν, Ν-dimethylformamide is evaporated in vacuo and the oily residue is taken up in 7 liters in sump ropy 1 ether. 7 liters of water were added and kept stirring for half an hour. The organic phase is separated and the aqueous phase is extracted with 3.5 liters of isopropyl ether. The organic phases are combined and extracted with 9 liters of a molar solution of hydrochloric acid. The resulting aqueous phase is made alkaline using sodium carbonate and then extracted with isopropyl ether. The organic phases 35 are combined and washed with water. Dry over magnesium sulfate and then evaporate in vacuo.
Der fås 2,11 kg af benzylesteren af N-[1-carbethoxybuty 1]-(S)-alanin i form af en svagt farvet olie.2.11 kg of the benzyl ester of N- [1-carbethoxybuty 1] - (S) -alanine is obtained in the form of a slightly colored oil.
DK 173730 B1 eDK 173730 B1 e
Udbytte: 86%Yield: 86%
Spektrometri 1 det infrarøde: Bånd ved 1760 og 1730 c»'1.Spectrometry 1 the infrared: bands at 1760 and 1730 c »1.
55
Kernemagnetisk resonansspektrometri 1H - 60 MHz·.Nuclear Magnetic Resonance Spectrometry 1H - 60 MHz ·.
Opløsningsmiddel: CC14Solvent: CC14
δ 0,65-1,60 ppm, uopløste toppe 13H (2 x CH3 + C3H7) δ » 2,11 ppm, singlet, NH 10 δ 2,95 til 3,49 ppm, multiplet, 2 x CHδ 0.65-1.60 ppm, unresolved peaks 13H (2 x CH3 + C3H7) δ »2.11 ppm, singlet, NH 10 δ 2.95 to 3.49 ppm, multiplet, 2 x CH
δ » 3,99 ppm, quadruplet, 2H, CH2-CH3, J=6,6 Hz δ s 5,02 ppm, singlet, 2H, CH2-0 6 7,20 ppm, uopløste toppe, 5H, aromatisk.δ »3.99 ppm, quadruplet, 2H, CH 2 -CH 3, J = 6.6 Hz δ s 5.02 ppm, singlet, 2H, CH 2-0 6 7.20 ppm, unresolved peaks, 5H, aromatic.
15 TRIN D: Maleat af benzyl esteren af N-[(S)-1-carbethoxybuty1]- (S )-a 1an i n 376 g maleinsyre sættes til en opløsning af 1,9 kg af benzyl-esteren af N - [ 1-carbethoxybuty1]-(S)-a 1 an in i en blanding af 20 10,44 liter cyklohexan og 5,22 liter acetone. Blandingen op varmes så til 80*C under omrøring, og den fremkomne opløsning holdes under tilbagesvaling i 1 time. Man afkøler til omgivelsernes temperatur og holder omrørt i 12 timer før der isafkøles i 2 timer til 0-5ftC.STEP D: Maleate of the benzyl ester of N - [(S) -1-carbethoxybutyl] - (S) -alan in 376 g of maleic acid is added to a solution of 1.9 kg of the benzyl ester of N - [1- carbethoxybutyl] - (S) -α1 an into a mixture of 10.44 liters of cyclohexane and 5.22 liters of acetone. The mixture is then heated to 80 ° C with stirring and the resulting solution is refluxed for 1 hour. Cool to ambient temperature and keep stirring for 12 hours before cooling for 2 hours to 0-5ftC.
2525
Bundfaldet frafiltreres og vaskes med cyklohexan på filteret.The precipitate is filtered off and washed with cyclohexane on the filter.
Efter tørring fås 1070 g råt salt, som omkrystalliseres af en blanding af cyklohexan og acetone.After drying, 1070 g of crude salt is obtained, which is recrystallized from a mixture of cyclohexane and acetone.
30 På denne måde fås 955 g maleat af benzyl esteren af N-[{S)-l-carbethoxybutyl]-(S)-alanin i form af et hvidt krystallinsk pulver.In this way, 955 g of maleate of the benzyl ester of N - [(S) -1-carbethoxybutyl] - (S) -alanine is obtained in the form of a white crystalline powder.
35 Drejningsevne: [α]20 = -19,0° (c - 1/EtOH) 0Rotation: [α] 20 = -19.0 ° (c - 1 / EtOH) 0
Spektrometri i det infrarøde (nujol):Spectrometry in the infrared (nujol):
Et bånd ved 1740 cu'l.A band at 1740 cu'l.
9 DK 173730 B19 DK 173730 B1
Kernemagneti sk resonans - 60 MHz:Nuclear Magnetic Resonance - 60 MHz:
Opløsningsmiddel: CC13 6 » 0,80-2,10 ppm, uopløste toppe 13H (2 x CH3 + C3H7) δ 3,89 ppm, uopløste toppe, 2H, 2CH 5 6 » 4,19 ppm, quadruplet, 2H, CH2“CH3, 0 = 6,8 Hz H2 δ 5,02 ppm, singlet, 2H, C6H5-CH2Solvent: CC13 6 »0.80-2.10 ppm, unresolved peaks 13H (2 x CH3 + C3H7) δ 3.89 ppm, unresolved peaks, 2H, 2CH 5 6» 4.19 ppm, quadruplet, 2H, CH2 CH3.0 = 6.8 Hz H2 δ 5.02 ppm, singlet, 2H, C6H5-CH2
δ 5,89 ppm, singlet, 3H, 2 x COOH + NHδ 5.89 ppm, singlet, 3H, 2 x COOH + NH
δ 6,15 ppm, singlet, 2H, CH=CHδ 6.15 ppm, singlet, 2H, CH = CH
δ * 7,31 ppm, singlet, 5H, aromatisk.δ * 7.31 ppm, singlet, 5H, aromatic.
10 TRIM E: Benzylester af N-[{S)-1-carbethoxybuty 1]-(S)-a 1 an inTRIM E: Benzyl Ester of N - [(S) -1-Carbethoxybutyl 1] - (S) -α 1 an
Vandig ammoniak sættes dråbevis til en suspension af 0,72 kg maleat af benzylesteren af N-[ (S)-1-carbethoxybutyl]-(S)-ala-15 nin i 13,50 liter vand indtil alkalinitet, medens temperaturen holdes under 20°C.Aqueous ammonia is added dropwise to a suspension of 0.72 kg of maleate of the benzyl ester of N- [(S) -1-carbethoxybutyl] - (S) -alanine in 13.50 liters of water until alkalinity while keeping the temperature below 20 ° C.
Den dannede olie fraskilles, og den vandige fase ekstraheres med fire portioner på 2,25 liter isopropy1 ether. De forenede 20 organiske faser tørres over magniumsulfat fer de inddampes i vakuum.The oil formed is separated and the aqueous phase is extracted with four portions of 2.25 liters of isopropyl ether. The combined organic phases are dried over magnesium sulfate until evaporated in vacuo.
Der fås 500 g benzylester af N-[{S)-1-carbethoxybuty1]-(S) -alanin i form af en svagt gul væske.500 g of benzyl ester of N - [(S) -1-carbethoxybutyl] - (S) -alanine is obtained in the form of a pale yellow liquid.
2525
Udbytte : 95,5%Yield: 95.5%
Drejningsevne: [a]2° = -48,2° (c « 1/EtOH) 30Rotation: [α] 2 ° = -48.2 ° (c + 1 / EtOH) 30
Spektrometri i det infrarøde (nujol):Spectrometry in the infrared (nujol):
Et bånd ved 1730 cm~l.A band at 1730 cm ~ l.
Kernemagnetisk resonansspektrometri Ih - 60 MHz:Nuclear Magnetic Resonance Spectrometry Ih - 60 MHz:
Opløsningsmiddel: CCI4 3 5Solvent: CCI4 3 5
δ = 0,65-1,60 ppm, uopløste toppe 13H (2 χ CH3 + C3H7) δ * 2,11 ppm, singlet, NH δ * 5,89 ppm, singlet, 3H, 2 x C00H + NHδ = 0.65-1.60 ppm, unresolved peaks 13H (2 χ CH3 + C3H7) δ * 2.11 ppm, singlet, NH δ * 5.89 ppm, singlet, 3H, 2 x C00H + NH
10 DK 173730 B1 <5 2,95-3,49 ppm, multiplet, 2 * CH δ » 3,99 ppm, quadruplet, 2H, CH2"CH3' Hz <5 * 5,02 ppm, singlet, 2H, CH2"0 δ « 7,2 ppm, uopløste toppe, 5H, aromatisk, 5 TRIN F: N-[(S)-1-carbethoxybuty1]-(S )-a 1 an in 4,5 kg af benzy1esteren af N-[(S)-1-carbethoxybuty1]-(S )-a 1 a -nin opløses i 75 liter ethanol, og der tilsættes en katalysa-10 tor indeholdende 5% palladium på trækul og derefter hydrogeneres ved atmosfæretryk ved 20-22°C.DK 173730 B1 <5 2.95-3.49 ppm, multiplet, 2 * CH δ »3.99 ppm, quadruplet, 2H, CH2" CH3 'Hz <5 * 5.02 ppm, singlet, 2H, CH2 " 0 δ «7.2 ppm, unresolved peaks, 5H, aromatic, STEP F: N - [(S) -1-carbethoxybutyl] - (S) -α 1 an in 4.5 kg of the benzyl ester of N - [( S) -1-Carbethoxybutyl] - (S) -α1α-nine is dissolved in 75 liters of ethanol and a catalyst containing 5% palladium on charcoal is added and then hydrogenated at atmospheric pressure at 20-22 ° C.
Derefter fortyndes blandingen med ethanol og opvarmes til 70eC til dannelse af en opløsning. Opløsningen filtreres varmt, og 15 katalysatoren skylles med 10 ml varm ethanol.The mixture is then diluted with ethanol and heated to 70 ° C to form a solution. The solution is filtered hot and the catalyst is rinsed with 10 ml of warm ethanol.
Opløsningsmidlet afdampes i vakuum, og remanensen krystalliseres af acetoni tril.The solvent is evaporated in vacuo and the residue is crystallized by acetone tril.
20 Der fås 2,61 kg N-[(S)-l-carbethoxybutyl]-(S)-alanin i form af et hvidt pulver.2.61 kg of N - [(S) -1-carbethoxybutyl] - (S) -alanine is obtained in the form of a white powder.
Udbytte: 82% 25 Drejningsevne: [a]20 “ +4,7° (c = 1/H20)Yield: 82% 25 Turning capacity: [a] 20 ° + 4.7 ° (c = 1 / H2 O)
Smeltepunkt: 149®CMelting point: 149 ° C
Elementær analyse: C10H19NO4 3 0 3 5 11 DK 173730 B1Elemental Analysis: C10H19NO4 3 0 3 5 11 DK 173730 B1
Grundstof Teoretisk Resultat C 55,28 55,28 5---------- H 8,81 8,97 N 6,45 6,35 10Element Theoretical Result C 55.28 55.28 5 ---------- H 8.81 8.97 N 6.45 6.35 10
Tyndt 1agskromatografi:Thin Layer Chromatography:
Opløsningsmiddel: ch1oroform:70 methanol:30 edd i kesyre: 1 15 Rf : 0,45Solvent: chloroform: 70 methanol: 30 acetic acid: 1 Rf: 0.45
Spektrometri i det i nf rarøde: Bånd ved 3050, 2250, 1740, 1620 og 1205 cm"*.Spectrometry in the in red: Bands at 3050, 2250, 1740, 1620 and 1205 cm "*.
2020
Kernemagnetisk resonansspektrometri *H - 200 MHz:Nuclear Magnetic Resonance Spectrometry * H - 200 MHz:
Opløsningsmiddel: DMSO-dg 6 * 0,86 ppm, triplet 3H, (CH2)2"CH3 δ = 1,17 ppm, dublet, 3H, CH-CH3 ^ <5 = 1,18 ppm, triplet, 3H, COO-CH2"OH3 6 = 1,30 ppm, multiplet, 2H, CH2'C^2"^^3 δ * 1,50 ppm, multiplet, 2H, CH2'^H2-C^3 δ = 3,17 ppm, quadruplet, IH, CH, CH3 6 = 3,26 ppm, triplet IH, CH-C3H7 30 δ « 4,10 ppm, quadruplet, 2H, C00-CH2-CH3 δ - 5,6 til 7,7 ppm, uopløste toppe, ombyttelige 2H, C00H og NH .Solvent: DMSO-d6 6 * 0.86 ppm, triplet 3H, (CH2) 2 "CH3 δ = 1.17 ppm, doublet, 3H, CH-CH3 + <5 = 1.18 ppm, triplet, 3H, COO CH2 "OH3 6 = 1.30 ppm, multiplet, 2H, CH2'C ^ 2" ^^ 3 δ * 1.50 ppm, multiplet, 2H, CH2 '^ H2-C ^ 3 δ = 3.17 ppm, quadrupled = 3.26 ppm, triplet IH, CH-C3H7 30 δ «4.10 ppm, quadruplet, 2H, C00-CH2-CH3 δ - 5.6 to 7.7 ppm, unresolved peaks, interchangeable 2H, C00H and NH.
Kernemagnetisk resonansspektrometri 13C - 50 MHz:Nuclear Magnetic Resonance Spectrometry 13C - 50 MHz:
Opløsningsmiddel DMS0-d6 173,9 og 175,4 signaler svarende til carboxylerne.Solvent DMSO-d6 173.9 and 175.4 signals corresponding to the carboxyls.
3535
Claims (3)
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FR8712902A FR2620700B1 (en) | 1987-09-17 | 1987-09-17 | PROCESS FOR THE SYNTHESIS OF ALPHA AMINO ACIDS N ALKYLS AND THEIR ESTERS. APPLICATION TO THE SYNTHESIS OF CARBOXYALKYL DIPEPTIDES |
FR8712902 | 1987-09-17 |
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DK515288D0 DK515288D0 (en) | 1988-09-15 |
DK515288A DK515288A (en) | 1989-03-18 |
DK173730B1 true DK173730B1 (en) | 2001-08-06 |
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DK198805152A DK173730B1 (en) | 1987-09-17 | 1988-09-15 | Process for the synthesis of Alpha-N-alkylated amino acids and esters thereof and intermediate by the process |
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EP (1) | EP0309324B1 (en) |
JP (2) | JPH0725723B2 (en) |
AT (1) | ATE61567T1 (en) |
AU (1) | AU607260B2 (en) |
CA (1) | CA1341380C (en) |
DE (1) | DE3862006D1 (en) |
DK (1) | DK173730B1 (en) |
ES (1) | ES2034324T3 (en) |
FR (1) | FR2620700B1 (en) |
GR (1) | GR3001874T3 (en) |
HK (1) | HK55196A (en) |
IE (1) | IE60995B1 (en) |
NZ (1) | NZ226222A (en) |
OA (1) | OA08941A (en) |
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ZA (1) | ZA886933B (en) |
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FR2620699B1 (en) * | 1987-09-17 | 1990-06-01 | Adir | PROCESS FOR THE SYNTHESIS OF ALPHA AMINO N ALKYL ACIDS AND THEIR ESTERS. APPLICATION TO THE SYNTHESIS OF CARBOXYALKYL DIPEPTIDES |
DE19804100C1 (en) | 1998-02-03 | 1999-05-12 | Daimler Chrysler Ag | Automobile seat with incorporated ventilation |
JP3892963B2 (en) * | 1998-03-17 | 2007-03-14 | 住友化学株式会社 | Method for producing L-valine benzyl ester p-toluenesulfonate |
JP2000247934A (en) * | 1999-02-23 | 2000-09-12 | Toray Ind Inc | Production of amino acid benzyl ester having high optical purity |
US6706916B1 (en) | 1999-02-23 | 2004-03-16 | Toray Fine Chemicals Co., Ltd. | Optically active amino acid derivatives and processes for the preparation of the same |
FR2807431B1 (en) * | 2000-04-06 | 2002-07-19 | Adir | NOVEL PROCESS FOR THE SYNTHESIS OF PERINDOPRIL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS |
FR2807430B1 (en) * | 2000-04-11 | 2002-05-17 | Adir | NOVEL PROCESS FOR THE SYNTHESIS OF N - [(S) -1- CARBOXYBUTYL] - (S) -ALANINE ESTERS AND APPLICATION TO THE SYNTHESIS OF PERINDOPRIL |
AR036187A1 (en) * | 2001-07-24 | 2004-08-18 | Adir | A PROCESS FOR THE PREPARATION OF PERINDOPRIL, ANALOG COMPOUNDS AND ITS SALTS, INTERMEDIARY COMPOUND 2,5-DIOXO-OXAZOLIDINE AND PROCESS TO PREPARE A INTERMEDIARY |
ATE395913T1 (en) | 2003-02-28 | 2008-06-15 | Servier S A Lab | METHOD FOR PRODUCING PERINDOPRIL |
SI21800A (en) | 2004-05-14 | 2005-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | New procedure of synthesis of perindopril |
EP1792896A1 (en) | 2005-12-01 | 2007-06-06 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for the preparation of perindopril and salts thereof |
JP4929938B2 (en) | 2006-09-12 | 2012-05-09 | 住友化学株式会社 | Process for producing optically active α-amino acid benzyl esters |
JP5785045B2 (en) * | 2011-10-06 | 2015-09-24 | エヌ・イーケムキャット株式会社 | Selective debenzylation method and selective hydrogenation catalyst used therefor |
WO2016178591A2 (en) | 2015-05-05 | 2016-11-10 | Gene Predit, Sa | Genetic markers and treatment of male obesity |
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US4344949A (en) * | 1980-10-03 | 1982-08-17 | Warner-Lambert Company | Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids |
US4296110A (en) * | 1980-10-28 | 1981-10-20 | E. I. Du Pont De Nemours And Company | Antihypertensive I-substituted cyclic lactam-2-carboxylic acids |
JPS6058233B2 (en) * | 1982-05-24 | 1985-12-19 | 田辺製薬株式会社 | 2-oxoimidazolidine derivative and its production method |
FR2620709B1 (en) * | 1987-09-17 | 1990-09-07 | Adir | PROCESS FOR THE INDUSTRIAL SYNTHESIS OF PERINDOPRIL AND ITS MAIN INTERMEDIATE SYNTHESIS |
-
1987
- 1987-09-17 FR FR8712902A patent/FR2620700B1/en not_active Expired - Lifetime
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1988
- 1988-09-07 CA CA000577079A patent/CA1341380C/en not_active Expired - Fee Related
- 1988-09-15 DK DK198805152A patent/DK173730B1/en active IP Right Grant
- 1988-09-16 DE DE8888402340T patent/DE3862006D1/en not_active Expired - Lifetime
- 1988-09-16 NZ NZ226222A patent/NZ226222A/en unknown
- 1988-09-16 OA OA59436A patent/OA08941A/en unknown
- 1988-09-16 IE IE280788A patent/IE60995B1/en not_active IP Right Cessation
- 1988-09-16 ES ES198888402340T patent/ES2034324T3/en not_active Expired - Lifetime
- 1988-09-16 AT AT88402340T patent/ATE61567T1/en not_active IP Right Cessation
- 1988-09-16 JP JP63232122A patent/JPH0725723B2/en not_active Expired - Lifetime
- 1988-09-16 AU AU22356/88A patent/AU607260B2/en not_active Expired
- 1988-09-16 EP EP19880402340 patent/EP0309324B1/en not_active Expired - Lifetime
- 1988-09-16 PT PT88530A patent/PT88530B/en not_active IP Right Cessation
- 1988-09-16 ZA ZA886933A patent/ZA886933B/en unknown
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1991
- 1991-04-29 GR GR91400546T patent/GR3001874T3/en unknown
-
1994
- 1994-10-05 JP JP6241178A patent/JP2524489B2/en not_active Expired - Lifetime
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Also Published As
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ES2034324T3 (en) | 1993-04-01 |
DK515288A (en) | 1989-03-18 |
PT88530A (en) | 1988-10-01 |
OA08941A (en) | 1989-10-31 |
JPH0725723B2 (en) | 1995-03-22 |
JPH07206792A (en) | 1995-08-08 |
PT88530B (en) | 1992-11-30 |
JP2524489B2 (en) | 1996-08-14 |
AU2235688A (en) | 1989-03-23 |
AU607260B2 (en) | 1991-02-28 |
IE882807L (en) | 1989-03-17 |
ZA886933B (en) | 1989-05-30 |
EP0309324A1 (en) | 1989-03-29 |
CA1341380C (en) | 2002-08-06 |
IE60995B1 (en) | 1994-09-07 |
NZ226222A (en) | 1990-06-26 |
FR2620700B1 (en) | 1990-06-01 |
FR2620700A1 (en) | 1989-03-24 |
ATE61567T1 (en) | 1991-03-15 |
DK515288D0 (en) | 1988-09-15 |
JPH01110651A (en) | 1989-04-27 |
GR3001874T3 (en) | 1992-11-23 |
EP0309324B1 (en) | 1991-03-13 |
HK55196A (en) | 1996-04-03 |
DE3862006D1 (en) | 1991-04-18 |
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B1 | Patent granted (law 1993) |