NO148069B - PROCEDURE FOR THE PREPARATION OF ALFA-L-ASPARTYL-L-PHENYLALANINE METHYL ESTES - Google Patents
PROCEDURE FOR THE PREPARATION OF ALFA-L-ASPARTYL-L-PHENYLALANINE METHYL ESTES Download PDFInfo
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- NO148069B NO148069B NO774440A NO774440A NO148069B NO 148069 B NO148069 B NO 148069B NO 774440 A NO774440 A NO 774440A NO 774440 A NO774440 A NO 774440A NO 148069 B NO148069 B NO 148069B
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- aspartyl
- phenylalanine
- mol
- reaction medium
- apm
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- 238000000034 method Methods 0.000 title claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YZQCXOFQZKCETR-UWVGGRQHSA-N Asp-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 YZQCXOFQZKCETR-UWVGGRQHSA-N 0.000 claims description 30
- 239000012429 reaction media Substances 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 19
- 239000012433 hydrogen halide Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 15
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- WYYUBJAMROQJSF-QWRGUYRKSA-N (3s)-4-[[(1s)-1-carboxy-2-phenylethyl]amino]-3-formamido-4-oxobutanoic acid Chemical compound OC(=O)C[C@H](NC=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 WYYUBJAMROQJSF-QWRGUYRKSA-N 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000005886 esterification reaction Methods 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- -1 N-protected L-aspartic anhydride Chemical class 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- ZZHKWSZWCXFKJP-PEBLQZBPSA-N 1-[3-[(2s,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]ethanone Chemical compound CC(=O)C1=CC=CC(O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=C1 ZZHKWSZWCXFKJP-PEBLQZBPSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical group Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- DFTMVZIUYVECNW-VKHMYHEASA-N n-[(3s)-2,5-dioxooxolan-3-yl]formamide Chemical compound O=CN[C@H]1CC(=O)OC1=O DFTMVZIUYVECNW-VKHMYHEASA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
- C07K5/06113—Asp- or Asn-amino acid
- C07K5/06121—Asp- or Asn-amino acid the second amino acid being aromatic or cycloaliphatic
- C07K5/0613—Aspartame
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- 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)
- Seasonings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av a-L-aspartyl-L-fenylalaninmethylester(a-APM). a-APM er vel kjent som søtningsmiddel. The present invention relates to a method for the production of α-L-aspartyl-L-phenylalanine methyl ester (α-APM). a-APM is well known as a sweetener.
Syntesen av a-APM ifølge US patentskrift 3 933 781 for-løper etter følgende generelle reaksjonsrekke: The synthesis of α-APM according to US Patent 3,933,781 proceeds according to the following general reaction sequence:
I de ovenfor angitte reaksjonsligninger betegner X In the reaction equations given above, X denotes
en aminobeskyttende gruppe. an amino protecting group.
Som vist i ligning 1) er utgangsmaterialene et N-beskyttet L-aspartinsyreanhydrid og L-fenylalanin som omsettes under dannelse av N-beskyttet a-L-aspartyl-L-fenylalanin. Den aminobeskyttende gruppe kan være"en hvilken som helst av de som er kjent innen faget og kan eksemplifiseres ved formyl, acetyl, benzoyl, substituert og usubstituert carbobenzoxy, t-butoxy-carbonyl og hydrohalogenidsaltet. Særlig foretrukket er N-formyl-L-aspartinsyreanhydrid. As shown in equation 1), the starting materials are an N-protected L-aspartic anhydride and L-phenylalanine which react to form N-protected α-L-aspartyl-L-phenylalanine. The amino-protecting group can be any of those known in the art and can be exemplified by formyl, acetyl, benzoyl, substituted and unsubstituted carbobenzoxy, t-butoxy-carbonyl and the hydrohalide salt. Particularly preferred is N-formyl-L-aspartic anhydride .
N-beskyttet a-L-aspartyl-L-fenylalanin kan skilles fra N-beskyttet 3-L-aspartyl-L-fenylalanin og behandles for å fjerne den beskyttende gruppe under dannelse av a-L-aspartyl-L-fenylalanin som angitt i ligning 2). Den tidligere kjente prosess tok særlig i betraktning isoleringen av a-L-aspartyl-L-fenylalanin som deretter ble forestret med methanol som vist i ligning 3, under dannelse av a-APM. N-protected α-L-aspartyl-L-phenylalanine can be separated from N-protected 3-L-aspartyl-L-phenylalanine and treated to remove the protecting group to form α-L-aspartyl-L-phenylalanine as indicated in equation 2). The previously known process particularly considered the isolation of α-L-aspartyl-L-phenylalanine which was then esterified with methanol as shown in equation 3, forming α-APM.
Som beskrevet i US patentskrift 3 933 781 ble for-estringsreaksjonen fortrinnsvis "utført med så lite tilstede-værende vann som mulig". En slik forestringsreaksjon ble i illu-strasjonsøyemed utført i methanol i nærvær av hydrogenklorid. As described in US Patent 3,933,781, the esterification reaction was preferably "carried out with as little water present as possible". For illustrative purposes, such an esterification reaction was carried out in methanol in the presence of hydrogen chloride.
På dette tidspunkt var man av den oppfatning at nærvær av enhver betydelig mengde vann under forestringen ville bevirke en ned-settelse av den ønskede forestring ved L bevirke at uønskede de-forestringsreaksjoner ville finne sted. At this time, it was believed that the presence of any significant amount of water during the esterification would cause a reduction in the desired esterification at L causing unwanted de-esterification reactions to take place.
En foretrukken metode for utvinning av a-APM fremstilt ved den fremgangsmåte som er beskrevet i US patentskrift 3 933 781, var å omdanne dette til HCl-saltet, som ble utvunnet som et fast A preferred method for recovering α-APM prepared by the process described in US Patent 3,933,781 was to convert this to the HCl salt, which was recovered as a solid
•materiale og overført til a-APM. •material and transferred to a-APM.
Et slikt fast HCl-salt av a-APM er også beskrevet i Such a solid HCl salt of α-APM is also described in
US patentskrift 3 798 207, som anvendte dette i renseprosedyren for erholdelse av a-APM ved separering fra 3-APM og andre uønskede biprodukter. I begge de tidligere kjente prosedyrer ble HCl-saltet dannet som et middel for utvinning av a-APM etter at det var fremstilt. US Patent 3,798,207, which used this in the purification procedure for obtaining α-APM by separation from 3-APM and other unwanted by-products. In both prior art procedures, the HCl salt was formed as a means of recovering α-APM after it had been prepared.
Et hovedmål med foreliggende oppfinnelse er å tilveie-bringe en ny og forbedret fremgangsmåte for fremstilling av a-APM, hvor omsetningen foretas i et vandig medium. A main aim of the present invention is to provide a new and improved method for the production of α-APM, where the reaction is carried out in an aqueous medium.
I henhold til oppfinnelsen tilveiebringes det således According to the invention it is thus provided
en fremgangsmåte ved fremstilling av a-L-aspartyl-L-fenylalaninmethylester, som utmerker seg ved at a-L-aspartyl-L-fenylalanin bringes i kontakt med et reaksjonsmedium inneholdende fra 0,1 a method for the production of α-L-aspartyl-L-phenylalanine methyl ester, characterized in that α-L-aspartyl-L-phenylalanine is brought into contact with a reaction medium containing from 0.1
til 0,8 mol hydrogenhalogenid, som er hydrogenklorid og/eller hydrogenbromid, pr. 100 g reaksjonsmedium og fra 0,1 til 1,1 mol methanol pr. 100 g reaksjonsmedium, idet resten av de 100 g av reaksjonsmediet utgjøres av vann, forutsatt at minst fra 1,0 to 0.8 mol of hydrogen halide, which is hydrogen chloride and/or hydrogen bromide, per 100 g of reaction medium and from 0.1 to 1.1 mol of methanol per 100 g of reaction medium, the rest of the 100 g of the reaction medium being made up of water, provided that at least from 1.0
til 20,0 mol av hydrogenhalogenidet og minste 1,0 mol methanol pr. mol a-L-aspartyl-L-fenylalanin er tilstede i reaksjonsmediet, hvorved det dannes et fast hydrogenhalogenidsalt av a-L-aspartyl-L-f enylalaninmethylester , som fraskilles og overføres til a-L-asparty1-L-fenylalaninmethylesteren. to 20.0 mol of the hydrogen halide and at least 1.0 mol of methanol per mol of a-L-aspartyl-L-phenylalanine is present in the reaction medium, whereby a solid hydrogen halide salt of a-L-aspartyl-L-phenylalanine methyl ester is formed, which is separated and transferred to the a-L-aspartyl-L-phenylalanine methyl ester.
Det som a-L-aspartyl-L-fenylalanin anvendte utgangs-materiale kan erholdes ved behandling av N-beskyttet a-L-aspartyl-L-f enylalanin for å fjerne den beskyttende gruppe (ligning 2). En hvilken som helst metode som er egnet for å The starting material used as α-L-aspartyl-L-phenylalanine can be obtained by treating N-protected α-L-aspartyl-L-phenylalanine to remove the protecting group (equation 2). Any method suitable to
fjerne beskyttende grupper fra aminer er egnet. Eksempler på slike metoder er katalytisk hydrogenering og behandling av uorganiske syrer eller baser. Det foretrekkes a fjerne den beskyttende gruppe, i særdeleshet formylgruppen, ved syrehydrolyse. Denne hydrolyse kan utføres for eksempel i en fortynnet vandig saltsyreløsning. Omdannelsen til a-L-aspartyl-L-fenylalanin er vanligvis meget removing protecting groups from amines is suitable. Examples of such methods are catalytic hydrogenation and treatment of inorganic acids or bases. It is preferred to remove the protecting group, in particular the formyl group, by acid hydrolysis. This hydrolysis can be carried out, for example, in a dilute aqueous hydrochloric acid solution. The conversion to α-L-aspartyl-L-phenylalanine is usually very high
høy, dvs. av størrelsesorden 95% eller høyere basert på det be-handlede N-beskyttet a-L-aspartyl-L-fenylalanin. Et annet medium for en slik behandling er en éddiksyre-saltsyreløsning (vandig). high, i.e. of the order of 95% or higher based on the treated N-protected α-L-aspartyl-L-phenylalanine. Another medium for such treatment is an acetic acid-hydrochloric acid solution (aqueous).
a-L-asparty1-L-fenylalanin kan deretter utvinnes ved utfelling og væske/faststoffseparering. En slik utfelling kan for eksempel utføres ved pH-justering når den beskyttende gruppe er blitt fjernet i en syreløsning. α-L-aspartyl-L-phenylalanine can then be recovered by precipitation and liquid/solid separation. Such precipitation can, for example, be carried out by pH adjustment when the protective group has been removed in an acid solution.
Det uønskede hovedbiprodukt som forblir i modervæsken, er (3-L-aspartyl-L-fenylalanin, såfremt dets forløper videreføres, og dette kan behandles, f.eks. ved hydrolyse, for å gjenvinne L-aspartinsyre og L-fenylalanin for resirkulering til tidligere trinn. Imidlertid kan noe Ø-L-aspartyl-L-fenylalanin videreføres til fremgangsmåten ifølge oppfinnelsen uten skade, da hydrogen-halogenidsaltet av a-APM som dannes, vil muliggjøre en tilstrekke-lig separering fra denne uønskede isomer eller dens estere. The main undesired by-product that remains in the mother liquor is (3-L-aspartyl-L-phenylalanine, provided its precursor is passed on, and this can be treated, e.g. by hydrolysis, to recover L-aspartic acid and L-phenylalanine for recycling to previous step However, some Ø-L-aspartyl-L-phenylalanine may be carried on to the process of the invention without harm, as the hydrogen halide salt of α-APM which is formed will enable sufficient separation from this undesired isomer or its esters.
Det er også mulig ved fremgangsmåten ifølge oppfinnelsen å anvende N-beskyttet a-L-aspartyl-L-fenylalanin under dannelse av a-L-aspartyl-L-fenylalanin in situ i reaksjonsmediet eller å danne a-L-aspartyl-L-fenylalanin i reaksjonsmediet uten nødvendigheten av isolering. Et særlig foretrukket N-beskyttet a-L-aspartyl-L-fenylalanin som er anvendbart i denne sistnevnte metode,er N-formyl-a-L-aspartyl-L-fenylalanin. It is also possible with the method according to the invention to use N-protected α-L-aspartyl-L-phenylalanine while forming α-L-aspartyl-L-phenylalanine in situ in the reaction medium or to form α-L-aspartyl-L-phenylalanine in the reaction medium without the necessity of isolation . A particularly preferred N-protected α-L-aspartyl-L-phenylalanine which is useful in this latter method is N-formyl-α-L-aspartyl-L-phenylalanine.
Mengden av hydrogenhalogenid som er anvendbar i reaksjonsmediet,er fra 0,1 mol til 0,80 mol pr. 100 g reaksjonsmedium. En særlig anvendbar mengde av hydrogenhalogenid er fra 0,3 mol til 0,7 mol pr. 100 g reaksjonsmedium. Mengden av methanol som er anvendbar i reaksjonsmediet, er fra 0,1 til 1,1 mol pr. 100 g reaksjonsmedium. En særlig anvendbar mengde av methanol er fra 0,4 til 0,8 mol pr. 100 g reaksjonsmedium. The amount of hydrogen halide that can be used in the reaction medium is from 0.1 mol to 0.80 mol per 100 g of reaction medium. A particularly useful amount of hydrogen halide is from 0.3 mol to 0.7 mol per 100 g of reaction medium. The amount of methanol that can be used in the reaction medium is from 0.1 to 1.1 mol per 100 g of reaction medium. A particularly useful amount of methanol is from 0.4 to 0.8 mol per 100 g of reaction medium.
Det skal bemerkes at den gjenværende mengde av reaksjonsmediet er vann. Det vil erkjennes av fagmannen at andre materialer kan innføres, men det ovenfor beskrevne angir anvend-bare konsentrasjoner av trekomponent-reaksjonsmediet. It should be noted that the remaining amount of the reaction medium is water. It will be recognized by the person skilled in the art that other materials can be introduced, but the above described indicates applicable concentrations of the three-component reaction medium.
Hydrogenhalogenidet som er tilstede i reaksjonsmediet, må være tilstede i en mengde av fra minst 1,0 til 20,0 mol hydrogenhalogenid pr. mol a-L-aspartyl-L-fenylalanin som omsettes. The hydrogen halide present in the reaction medium must be present in an amount of at least 1.0 to 20.0 moles of hydrogen halide per moles of α-L-aspartyl-L-phenylalanine that are converted.
En særlig foretrukket mengde er fra 1,15 til 10,0 mol pr. mol a-L-aspartyl-L-fenylalanin. Hydrogenklorid er det foretrukne hydrogenhalogenid. A particularly preferred amount is from 1.15 to 10.0 mol per moles of α-L-aspartyl-L-phenylalanine. Hydrogen chloride is the preferred hydrogen halide.
Fagmannen vil erkjenne at reaksjonsmediet også må inneholde minst 1,0 mol methanol pr. mol a-L-aspartyl-L-fenylalanin, og høyere konsentrasjoner kan også anvendes. The person skilled in the art will recognize that the reaction medium must also contain at least 1.0 mol of methanol per mol α-L-aspartyl-L-phenylalanine, and higher concentrations can also be used.
Når a-L-aspartyl-L-fenylalanin skal dannes in situ, When α-L-aspartyl-L-phenylalanine is to be formed in situ,
er det funnet å være fordelaktig å tilsette en mindre mengde av hydrogenhalogenid etterfulgt av oppvarmning av reaksjonen opp til 65°C og deretter foreta avkjøling. Dette bevirker hydrolyse av N-beskyttet a-L-aspartyl-L-fenylalanin til a-L-aspartyl-L- it has been found advantageous to add a small amount of hydrogen halide followed by heating the reaction up to 65°C and then cooling. This causes hydrolysis of N-protected α-L-aspartyl-L-phenylalanine to α-L-aspartyl-L-
fenylalanin. Etter en slik oppvarmning kan ytterligere vandig hydrogenhalogenid tilsettes til reaksjonsmassen for å tilveie-bringe et reaksjonsmedium som ovenfor beskrevet som fører til dannelsen av det faste hydrogenhalogenidsalt av a-APM. phenylalanine. After such heating, further aqueous hydrogen halide can be added to the reaction mass to provide a reaction medium as described above which leads to the formation of the solid hydrogen halide salt of α-APM.
De temperaturer som anvendes,skal være opp til koke-punktet i— or reaksjonsmassen. Temperaturer fra 5 til 50 oC er foretrukket, i særdeleshet fra 20 til 40° C. Selv om den mest foretrukne temperatur er nær omgivende temperatur, skal det bemerkes at høyere temperaturer er tilbøyelige til å øke graden av dannelse av a-APM men har den ulempe at de fremkaller spaltningsreaksjoner og øker løseligheten av hydrogenhalogenidsaltene av a-APM. På den annen side vil lavere tempeaturer være tilbøyelige til å nedsette dannelsen av a-APM, inhibere spaltningsreaksjoner og gi høyere konsentrasjoner av faste hydrogenhalogenidsalter av a-APM. Fagmannen vil erkjenne behovet for å balansere disse konsentrasjoner for å oppnå den mest økonomiske temperatur for de angjeldende konsentrasjoner. The temperatures used must be up to the boiling point of the reaction mass. Temperatures from 5 to 50°C are preferred, in particular from 20 to 40°C. Although the most preferred temperature is close to ambient temperature, it should be noted that higher temperatures tend to increase the degree of formation of α-APM but have the disadvantage that they induce cleavage reactions and increase the solubility of the hydrogen halide salts of α-APM. On the other hand, lower temperatures will tend to slow down the formation of α-APM, inhibit cleavage reactions and give higher concentrations of solid hydrogen halide salts of α-APM. Those skilled in the art will recognize the need to balance these concentrations in order to achieve the most economical temperature for the concentrations in question.
Innbefattet i de reaksjoner som finner sted ved fremgangsmåten ifølge oppfinnelsen, er dannelsen av følgende uønskede biprodukter: Included in the reactions that take place in the method according to the invention is the formation of the following unwanted by-products:
(heretter angitt som "aspartylester"). (hereinafter referred to as "aspartyl ester").
I tillegg til disse to uønskede biprodukter kan reaksjonsmassen også inneholde uforestret a-L-aspartyl-L-fenylalanin og mindre mengder av (3-analogene hvis denne isomer overføres. In addition to these two unwanted by-products, the reaction mass may also contain unesterified α-L-aspartyl-L-phenylalanine and smaller amounts of the (3-analogues if this isomer is transferred.
De reaksjoner som fører til detønskede produkt og biproduktene er alle likevektsreaksjoner. The reactions leading to the desired product and the by-products are all equilibrium reactions.
Det har vist seg at fremgangsmåten ifølge oppfinnelsen gir et stort utbytte av a-APM. Ved for eksempel romtemperatur kan det erholdes et utbytte så høyt som 55 til 60 % a-APM basert på a-L-aspartyl-L-fenylalanin. Dette er særlig overraskende i lys av de utbytter som kan erholdes etter den kjente teknikk. Således oppnåes det vesentlig lavere utbytter ved fremgangsmåten ifølge det innledningsvis omtalte US patentskrift 3 933 781, hvor det benyttes et forestringsreaksjonsmedium som inneholder så lite vann som mulig. US patentskriftets eksempler 7-12 viser at det ved den kjente fremgangsmåte kan oppnåes utbytter av størrelsesordenen 15 - 45%, mens de nedenstående eksempler 2, 5 og 6, som illustrerer den foreliggende fremgangsmåte, viser utbytter på henholdsvis 55,5%, 53,2 og 59,2%. It has been shown that the method according to the invention gives a large yield of α-APM. At, for example, room temperature, a yield as high as 55 to 60% of α-APM based on α-L-aspartyl-L-phenylalanine can be obtained. This is particularly surprising in light of the yields that can be obtained according to the known technique. Thus, significantly lower yields are achieved with the method according to the initially mentioned US patent 3,933,781, where an esterification reaction medium containing as little water as possible is used. The US patent's examples 7-12 show that yields of the order of 15 - 45% can be obtained with the known method, while the following examples 2, 5 and 6, which illustrate the present method, show yields of 55.5%, 53, 2 and 59.2%.
Det faste hydrogenhalogenidsalt av a-APM kan gjenvinnes ved faststoff/væskeseparasjonsprosedyrer. Hovedsakelig hele mengden av de øvrige komponenter forblir i modervæsken og kan hydrolyseres, gjenvinnes og/eller resirkuleres til de tidligere reaksjoner. Det fraskilte salt kan deretter omdannes til hovedsakelig rent a-APM, eksempelvis som vist i US patentskrifter 3 798 207 og 3 933 781. The solid hydrogen halide salt of α-APM can be recovered by solid/liquid separation procedures. Essentially the entire quantity of the other components remains in the mother liquor and can be hydrolysed, recovered and/or recycled to the previous reactions. The separated salt can then be converted into essentially pure α-APM, for example as shown in US patents 3,798,207 and 3,933,781.
De etterfølgende eksempler er gitt for å illustrere oppfinnelsen i detalj. The following examples are given to illustrate the invention in detail.
De materialer og prosedyrer som ble anvendt ved tynn-skiktkromatograferingsanalyser (TCL) i eksemplene, er som følger: The materials and procedures used in thin-layer chromatography (TCL) analyzes in the examples are as follows:
A. Platemateriale A. Sheet material
Silicagel F på glassplate Silica gel F on glass plate
B. Løsningsmiddelsystemer B. Solvent systems
C. Påvisende sprøyteløsninger C. Detecting syringe solutions
1. 0,3 g ninhydrin løst i en blanding av 100 ml n-butanol og 3 ml iseddik. 2. lg kaliumjodid og 1 g løselig stivelse løst i 100 ml destillert vann. 1. 0.3 g of ninhydrin dissolved in a mixture of 100 ml of n-butanol and 3 ml of glacial acetic acid. 2. lg of potassium iodide and 1 g of soluble starch dissolved in 100 ml of distilled water.
D. Prosedyrer D. Procedures
Etter flekkdannelse og fremkalling i det egnede løs-ningsmiddelsystem ble platen lufttørket i 30 minutter. Ninhydrin sprøytning: Platen ble sprøytet og holdt ved 100° C i en ovn i 15 minutter. After spot formation and development in the suitable solvent system, the plate was air-dried for 30 minutes. Ninhydrin spraying: The plate was sprayed and kept at 100°C in an oven for 15 minutes.
Stivelse-jodid sprøytning: Platen ble holdt i et kam-mer mettet med t-butylhypokloritdamp i 15 minutter, lufttørket i 30 minutter og ble deretter sprøytet med friskt fremstilt stivelse-jodidløsning. Starch-iodide spraying: The plate was kept in a chamber saturated with t-butyl hypochlorite vapor for 15 minutes, air-dried for 30 minutes and then sprayed with freshly prepared starch-iodide solution.
Eksempel 1 Example 1
I et egnet kar ble innført 140 ml methanol og 420 ml 9N saltsyre som ble avkjølt på isbad. Den resulterende løsning ble tilsatt 113,8 g (0,4 mol) a-L-aspartyl-L-fenylalanin (98,5 140 ml of methanol and 420 ml of 9N hydrochloric acid were introduced into a suitable vessel, which was cooled in an ice bath. To the resulting solution was added 113.8 g (0.4 mol) α-L-aspartyl-L-phenylalanine (98.5
% renhet). Utfellingen startet kort deretter. Den resulterende masse ble fjernet fra isbadet og omrørt i 30 minutter som bevirket at tempeaturen steg til 20° C. Den resulterende masse ble igjen avkjølt på isbad, omrørt i 1,5 time,hvilket førte til betydelig utfelling, og ble deretter plasert i et kjøleskap over natten. % purity). The precipitation started shortly thereafter. The resulting mass was removed from the ice bath and stirred for 30 minutes causing the temperature to rise to 20° C. The resulting mass was again cooled in an ice bath, stirred for 1.5 hours, which resulted in significant precipitation, and then placed in a refrigerator overnight.
Neste morgen ble reaksjonsmassen omrørt i 1 time på et isbad,og det utfelte (130,5 g våt kake) ble fraskilt ved filtrering. Den resulterende kake ble oppløst i 750 ml avionisert vann ved 40° C og pri ble justert til 4,2 i løpet av 1,5 times periode med 36,7 g 50 %-ig vandig natriumhydroxyd. Den resulterende masse ble kjølt til ca. 5° C og holdt ved denne temperatur i 4 timer. Bunnfallet som ble dannet,ble fraskilt ved filtrering og vasket med 35 ml's porsjoner av avionisert vann ved 5° C og tør-ket. Det resulterende produkt var 51,8 g a-APM som ble oppnådd i et utbytte på 44 %, basert på a-L-aspartyl-L-fenylalanin. TLC og natriumkloridanalyse fastslo at renheten for a-APM-produktet var større enn 95 %. The next morning, the reaction mass was stirred for 1 hour in an ice bath, and the precipitate (130.5 g wet cake) was separated by filtration. The resulting cake was dissolved in 750 ml of deionized water at 40°C and the pH was adjusted to 4.2 over a 1.5 hour period with 36.7 g of 50% aqueous sodium hydroxide. The resulting mass was cooled to approx. 5° C and held at this temperature for 4 hours. The precipitate that formed was separated by filtration and washed with 35 ml portions of deionized water at 5° C. and dried. The resulting product was 51.8 g of α-APM which was obtained in a yield of 44%, based on α-L-aspartyl-L-phenylalanine. TLC and sodium chloride analysis determined the purity of the α-APM product to be greater than 95%.
Eksempel 2 Example 2
Til en omrørt løsning av 34,2 ml (0,41 mol) 37 %-ig saltsyre, 60 ml vann og 40 ml methanol ble tilsatt 110 g To a stirred solution of 34.2 ml (0.41 mol) 37% hydrochloric acid, 60 ml water and 40 ml methanol was added 110 g
(0,357 mol) N-formyl-a-L-aspartyl-L-fenylalanin i løpet av en 20 minutters periode med en temperaturøkning fra 40° C til 58° C. Den resulterende masse ble omrørt ved 58 - 60° C i 3 timer for å tillate fjerning av formylgruppen ved hydrolyse. (0.357 mol) of N-formyl-α-L-aspartyl-L-phenylalanine over a 20 minute period with a temperature increase from 40° C. to 58° C. The resulting mass was stirred at 58 - 60° C. for 3 hours to allow removal of the formyl group by hydrolysis.
Reaksjonsmassen ble kjølt til 25° C og 65,8 ml (0,79 mol) 37 %-ig saltsyre ble tilsatt i løpet av 10 minutter. Et bunnfall begynte å dannes kort deretter. Den resulterende masse ble holdt under omrøring i 45 timer ved omgivende temperatur og i 1., 5 time ved 5°C, hvilket bevirket ytterligere utfélning. Det faste bunnfall ble fraskilt ved sentrifugering/og filterkaken ble vasket med 10 0 ml avionisert vann ved 5° C. Den våte kake (110,2 g) ble løst i 410 ml avionisert vann ved 45° C. pH ble justert til 2,5 i løpet av en 10 minutters periode med 80,1 g 4,8 %-ig vandig natriumhydroxyd og omrørt i 1 time ved 40° C. Mens temperaturen ble holdt ved 40 - 42° C ble 151,9 g av 4,8 %-ig vandig natriumhydroxyd tilsatt i løpet av 3 timer for å heve pH til 4,2. Blandingen ble omrørt i 1 time ved 0-5° C,og de resulterende fjærlignende krystaller ble fraskilt ved sentrifu-gering. Filterkaken ble vasket med 200 ml avionisert vann ved 5° C og tørket over natten i vakuum ved 55 - 60° C. Utbyttet av a-APM var 58,3 g (55,5 % basert på N-formyl-a-L-aspartyl-L-fenylalanin)„ + 16,2° (c=4, 15 N maursyre); TLC analyse større enn 9 8 % renhet av a-APM. The reaction mass was cooled to 25° C. and 65.8 ml (0.79 mol) of 37% hydrochloric acid was added over 10 minutes. A precipitate began to form shortly thereafter. The resulting mass was stirred for 45 hours at ambient temperature and for 1.5 hours at 5°C, causing further precipitation. The solid precipitate was separated by centrifugation and the filter cake was washed with 100 ml of deionized water at 5° C. The wet cake (110.2 g) was dissolved in 410 ml of deionized water at 45° C. The pH was adjusted to 2, 5 over a 10 minute period with 80.1 g of 4.8% aqueous sodium hydroxide and stirred for 1 hour at 40° C. While the temperature was maintained at 40 - 42° C, 151.9 g of 4.8 % aqueous sodium hydroxide added over 3 hours to raise pH to 4.2. The mixture was stirred for 1 hour at 0-5°C and the resulting feather-like crystals were separated by centrifugation. The filter cake was washed with 200 ml of deionized water at 5° C and dried overnight in vacuum at 55 - 60° C. The yield of α-APM was 58.3 g (55.5% based on N-formyl-α-L-aspartyl- L-phenylalanine)„ + 16.2° (c=4, 15 N formic acid); TLC analysis greater than 9 8% purity of a-APM.
Eksempel 3 Example 3
Ved å følge den samme prosedyre som beskrevet i eksempel 2 med det unntak at 32,5 ml 3 7-ig saltsyre og 33,3 ml vann ble tilsatt til reaksjonsmassen hvoretter formylgruppen ble fjernet ved hydrolyse og avkjøling til 25° C, ble det erholdt 33,0 % utbytte av a-APM, basert på N-formyl-a-L-aspartyl-L-fenylalanin. I*]^ + 15,3° (c=4, 15 N maursyre). ;Eksempel 4 ;Den samme prosedyre som, den beskrevet i ;eksempel 2,med det unntak at tiden for å fjerne formylgruppen ved hydrolyse ble begrenset til 1 time, ga 46,2 % utbytte av a-APM, basert på N-formyl-a-L-aspartyl-L-fenylalanin. ;[a]^° + 15,5° (c=4, 15 N maursyre). ;Eksempel 5 ;Ved å følge den samme prosedyre som den beskrevet i eksempel 2, med det unntak at 38,7 ml 37%-ig saltsyre ble anvendt i begynnelsesløsningen i stedet for 34,2 ml 37%-ig saltsyre, ;og ved å redusere den innførte syre etter hydrolyse til 61,3 ml 37%-ig saltsyre ble det oppnådd et utbytte på 53,2% a-APM, basert på N-formyl-a-L-aspartyl-L-fenylalanin, [a]^ + 15,4° (c=4 , ;15 N maursyre). ;Eksempel 6 ;Ved å følge den samme prosedyre som beskrevet i eksempel 2, med det unntak at oppholdstiden for å bevirke utfelling av fast materiale ble øket til 4 dager, ble det oppnådd et utbytte på 59,2% av a-APM, basert på N-formyl-a-L-aspartyl-L-fenylalanin. ;20 ;[a]D + 15,2 (c=4, 15 N maursyre). ;Eksempel 7 ;Ved å følge den samme prosedyre som beskrevet i eksempel 2, med det unntak at oppholdstiden for å bevirke utfelling ble nedsatt til 1 dag, ble det oppnådd et utbytte på 36,3% a-APM, basert på N-formyl-a-L-aspartyl-L-fenylalanin. [alD 20 + 15,5 ;(c=4, 15 N maursyre) ;Eksempler 1 - 7 er oppført i tabell 1 under anvendelse ;av de tidligere beskrevne parametre. ; *By following the same procedure as described in example 2 with the exception that 32.5 ml of 3 7-mg hydrochloric acid and 33.3 ml of water were added to the reaction mass after which the formyl group was removed by hydrolysis and cooling to 25° C, it was obtained 33.0% yield of α-APM, based on N-formyl-α-L-aspartyl-L-phenylalanine. I*]^ + 15.3° (c=4, 15 N formic acid). ;Example 4 ;The same procedure as that described in ;Example 2, with the exception that the time to remove the formyl group by hydrolysis was limited to 1 hour, gave a 46.2% yield of α-APM, based on N-formyl- α-L-aspartyl-L-phenylalanine. ;[a]^° + 15.5° (c=4, 15 N formic acid). ;Example 5 ;By following the same procedure as that described in example 2, with the exception that 38.7 ml of 37% hydrochloric acid was used in the initial solution instead of 34.2 ml of 37% hydrochloric acid, ;and by reducing the introduced acid after hydrolysis to 61.3 ml of 37% hydrochloric acid, a yield of 53.2% a-APM was obtained, based on N-formyl-a-L-aspartyl-L-phenylalanine, [a]^ + 15.4° (c=4 , ;15 N formic acid). ;Example 6 ;By following the same procedure as described in example 2, with the exception that the residence time to effect precipitation of solid material was increased to 4 days, a yield of 59.2% of a-APM was obtained, based on N-formyl-α-L-aspartyl-L-phenylalanine. ;20 ;[a]D + 15.2 (c=4, 15 N formic acid). ;Example 7 ;By following the same procedure as described in example 2, with the exception that the residence time to cause precipitation was reduced to 1 day, a yield of 36.3% a-APM, based on N-formyl -α-L-aspartyl-L-phenylalanine. [alD 20 + 15.5 ;(c=4, 15 N formic acid) ;Examples 1 - 7 are listed in table 1 using the previously described parameters. ; *
Claims (2)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75429776A | 1976-12-27 | 1976-12-27 |
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| NO774440L NO774440L (en) | 1978-06-28 |
| NO148069B true NO148069B (en) | 1983-04-25 |
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| JP (1) | JPS6050200B2 (en) |
| AU (1) | AU515038B2 (en) |
| BE (1) | BE862258A (en) |
| BR (1) | BR7708632A (en) |
| CA (1) | CA1100487A (en) |
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| DE (1) | DE2757771A1 (en) |
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| FR (1) | FR2375194A1 (en) |
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| JPS59219258A (en) * | 1983-05-28 | 1984-12-10 | Ajinomoto Co Inc | Preparation of alpha-l-aspartyl-l-phenylalanine methyl ester or its hydrochloride |
| US4618695A (en) * | 1983-06-02 | 1986-10-21 | Ajinomoto Co., Inc. | Method of preparing methyl ester and its hydrochloride |
| JPS59225152A (en) * | 1983-06-02 | 1984-12-18 | Ajinomoto Co Inc | Preparation of alpha-l-aspartyl-l-phenylalanine-methyl ester of its hydrochloride |
| GB8321802D0 (en) * | 1983-08-12 | 1983-09-14 | Erba Farmitalia | Aspartame synthesis |
| JPH07636B2 (en) * | 1984-12-17 | 1995-01-11 | 三井東圧化学株式会社 | Process for producing N-formyl-α-aspartyl phenylalanine |
| CA1277098C (en) * | 1984-12-27 | 1990-11-27 | Mitsui Toatsu Chemicals, Inc. | Preparation process of -l-aspartyl-l-phenylalanine methyl ester |
| AU561384B2 (en) * | 1985-03-26 | 1987-05-07 | Mitsui Toatsu Chemicals Inc. | Preparation of -l-aspartyl-l-phenylalanine methyl ester or hydrochloride thereof |
| AU586669B2 (en) * | 1985-03-29 | 1989-07-20 | Mitsui Toatsu Chemicals Inc. | Preparation process of ```-L-aspartyl-L-phenylalanine methyl ester or hydrochloride thereof |
| DE3600731A1 (en) * | 1986-01-13 | 1987-07-16 | Green Cross Korea | METHOD FOR PRODUCING (ALPHA) -L-ASPARTYL-L-PHENYLALANINE METHYLESTER |
| JPS6383098A (en) * | 1986-09-27 | 1988-04-13 | Ajinomoto Co Inc | Production of alpha-l-aspartyl-l-phenylalanine or derivative thereof |
| ES2042583T3 (en) * | 1986-12-05 | 1993-12-16 | Mitsui Toatsu Chemicals | PREPARATION OF METHYL ESTER OF ALPHA-L-ASPARTIL-L-FENIL-ALANINA OR ONE OF ITS HYDROHALIDES. |
| JPH0832719B2 (en) * | 1986-12-19 | 1996-03-29 | 三井東圧化学株式会社 | Method for producing α-L-aspartyl-L-phenylalanine methyl ester having low hygroscopicity |
| JPS6411999U (en) * | 1987-07-13 | 1989-01-23 |
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| US3933781A (en) * | 1973-11-05 | 1976-01-20 | Monsanto Company | Process for the preparation of α-L-aspartyl-L-phenylalanine alkyl esters |
| JPS5223001A (en) * | 1975-08-14 | 1977-02-21 | Ajinomoto Co Inc | Process for elimination of formyl group |
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1977
- 1977-12-16 MX MX776726U patent/MX4704E/en unknown
- 1977-12-22 ZA ZA00777614A patent/ZA777614B/en unknown
- 1977-12-23 GB GB53633/77A patent/GB1546979A/en not_active Expired
- 1977-12-23 DE DE19772757771 patent/DE2757771A1/en active Granted
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- 1977-12-23 AU AU32014/77A patent/AU515038B2/en not_active Expired
- 1977-12-23 NO NO774440A patent/NO148069C/en unknown
- 1977-12-23 IT IT31246/77A patent/IT1088938B/en active
- 1977-12-23 SE SE7714709A patent/SE440506B/en not_active IP Right Cessation
- 1977-12-23 CA CA293,911A patent/CA1100487A/en not_active Expired
- 1977-12-23 BE BE183786A patent/BE862258A/en not_active IP Right Cessation
- 1977-12-23 NL NLAANVRAGE7714351,A patent/NL185211C/en not_active IP Right Cessation
- 1977-12-24 HU HU77MO1000A patent/HU179735B/en unknown
- 1977-12-26 BR BR7708632A patent/BR7708632A/en unknown
- 1977-12-26 FR FR7739203A patent/FR2375194A1/en active Granted
- 1977-12-26 SU SU772557552A patent/SU884564A3/en active
- 1977-12-26 JP JP52155755A patent/JPS6050200B2/en not_active Expired
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Also Published As
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| JPS6050200B2 (en) | 1985-11-07 |
| SE440506B (en) | 1985-08-05 |
| DE2757771A1 (en) | 1978-07-06 |
| AU515038B2 (en) | 1981-03-12 |
| CH631435A5 (en) | 1982-08-13 |
| DE2757771C2 (en) | 1988-08-25 |
| DK149432B (en) | 1986-06-09 |
| SU884564A3 (en) | 1981-11-23 |
| JPS5382752A (en) | 1978-07-21 |
| DK149432C (en) | 1987-04-21 |
| DK577977A (en) | 1978-06-28 |
| NL185211C (en) | 1990-02-16 |
| BE862258A (en) | 1978-06-23 |
| BR7708632A (en) | 1978-08-22 |
| FR2375194A1 (en) | 1978-07-21 |
| NL7714351A (en) | 1978-06-29 |
| ZA777614B (en) | 1978-10-25 |
| FR2375194B1 (en) | 1984-04-13 |
| SE7714709L (en) | 1978-06-28 |
| NO774440L (en) | 1978-06-28 |
| NL185211B (en) | 1989-09-18 |
| GB1546979A (en) | 1979-06-06 |
| CA1100487A (en) | 1981-05-05 |
| MX4704E (en) | 1982-08-04 |
| AU3201477A (en) | 1979-06-28 |
| NO148069C (en) | 1983-08-03 |
| IT1088938B (en) | 1985-06-10 |
| HU179735B (en) | 1982-12-28 |
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