NO744632L - - Google Patents
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- NO744632L NO744632L NO744632A NO744632A NO744632L NO 744632 L NO744632 L NO 744632L NO 744632 A NO744632 A NO 744632A NO 744632 A NO744632 A NO 744632A NO 744632 L NO744632 L NO 744632L
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- 150000001875 compounds Chemical class 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims description 5
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 5
- -1 oxyalkyl compound Chemical class 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 230000006340 racemization Effects 0.000 claims description 3
- 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 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- 235000011002 L(+)-tartaric acid Nutrition 0.000 claims 1
- 239000001358 L(+)-tartaric acid Substances 0.000 claims 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- DFNYGALUNNFWKJ-UHFFFAOYSA-N aminoacetonitrile Chemical compound NCC#N DFNYGALUNNFWKJ-UHFFFAOYSA-N 0.000 claims 1
- 150000004718 beta keto acids Chemical class 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 229940071870 hydroiodic acid Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 229930182555 Penicillin Natural products 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 150000002960 penicillins Chemical class 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- XQXPVVBIMDBYFF-UHFFFAOYSA-N para-hydroxyphenylacetic acid Natural products OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 2
- 235000019371 penicillin G benzathine Nutrition 0.000 description 2
- NJVJSULZTHOJGT-UHFFFAOYSA-N 2-(4-methoxyanilino)acetic acid Chemical compound COC1=CC=C(NCC(O)=O)C=C1 NJVJSULZTHOJGT-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cephalosporin Compounds (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte forThe present invention relates to a method for
fremstilling av nye D(-)-substituerte oc-amino benzyl penicilliner.preparation of new D(-)-substituted oc-amino benzyl penicillins.
Nevnte penicilliner har følgende generelle formel:Said penicillins have the following general formula:
hvorR^, Rg og R^hver kan være OH og halogen. I where R^, Rg and R^ can each be OH and halogen. IN
Disse semi-syntetiske penicilliner er viktige midlerThese semi-synthetic penicillins are important agents
for bekjempelse av gram-negative og gram-positive mikroorganismer.for combating gram-negative and gram-positive microorganisms.
Skjønt de forbindelser som er nevnt her har genereltAlthough the compounds mentioned here generally have
de samme terapeutiske egenskaper og samme vide antibakterielle spek-the same therapeutic properties and the same wide antibacterial spec-
trum som andre od^åm-ino benzyl penicilliner, så er de dog forskjellig ved at de har ekstraordinær god absorbsjon ved oral tilførsel og ved at de tilveiebringes i høy konsentrasjon i blodet i en kortere tids- trum like other od^åm-ino benzyl penicillins, they differ, however, in that they have extraordinarily good absorption when administered orally and in that they are provided in high concentration in the blood for a shorter time
periode.period.
Foreliggende oppfinnelse innbefatter også følgende syn-te semellomprodukter: The present invention also includes the following synthetic bran products:
D(-) isomer D(-) isomer
^ / og M er K og Na.] ^ / and M are K and Na.]
Det er tidligere kjent forskjellige fremgangsmåter for fremstilling av penicilliner, for eksempel av den type som er beskrevet i: Different methods for the production of penicillins are previously known, for example of the type described in:
G.A. Hardcastle et al.GO. Hardcastle et al.
J. Org. Chem., 31, 897 (1966) J. Org. Chem., 31, 897 (1966)
J.R. Hoover et al.J. R. Hoover et al.
J. Med. Chem. 7, (3) 245 (1964) J. Med. Chem. 7, (3) 245 (1964)
G. Pifferi et al.G. Pifferi et al.
Il Farmaco, 21 (9), 6ll (1966).Il Farmaco, 21 (9), 6ll (1966).
b De fremgangsmåter som er beskrevet i nevnte referanse skiller seg fra den foreliggende ved at man innev.nte synteser bruker en acylering av 6-APA fra et syreklorid. b The methods described in said reference differ from the present one in that said syntheses use an acylation of 6-APA from an acid chloride.
Med hensyn til syntesen av mellomprodukter, skal det bemerkes at fremstillin<g>en av derivatet: With regard to the synthesis of intermediates, it should be noted that the preparation of the derivative:
fra et passende aldehyd, er kun en anvendelse av en generell fremgangsmåte som er beskrevet i mange forskjellige lærebøker i orga-nisk kjemi. Det nye trekk ved foreliggende oppfinnelse er' at man skiller de dannede optiske isomerer ved å bruke en meget enkel og økonomisk fremgangsmåte sammenlignet med de som tidligere er kjent, hvor man anvender optisk aktive aminer (brucin, efedrin etc). Disse. from a suitable aldehyde, is only an application of a general procedure described in many different organic chemistry textbooks. The new feature of the present invention is that the formed optical isomers are separated by using a very simple and economical method compared to those previously known, where optically active amines (brucine, ephedrine, etc.) are used. These.
fremgangsmåter gir lave utbytter og omkostningene er høyere enn ved den fremgangsmåte som er beskrevet i foreliggende søknad. methods give low yields and the costs are higher than with the method described in the present application.
For å få fremstilt forbindelser med formel I, er det nødvendig å fremstille mellomprodukter med formel II. Det er ikke hensiktsmessig direkte å omsette dette produkt (formel II) med 6-amino penicillansyren (i) etter som det lett skjer en racemisering av forbindelsen med formel II. For å unngårdette problem bruker man addisjonsforbindelsen med formel III, idet én-slik forbindelse hindrer en racemisering av aminosyren(II) og gjør syntesen lettere. In order to prepare compounds of formula I, it is necessary to prepare intermediate products of formula II. It is not appropriate to directly react this product (formula II) with the 6-amino penicillanic acid (i) as racemization of the compound of formula II easily occurs. To avoid this problem, the addition compound of formula III is used, since such a compound prevents racemization of the amino acid (II) and makes the synthesis easier.
hvor R^er alkylgruppe med fra 1-4 karbonatomer^og R^, R^, R^ og R^har samme betydning som angitt ovenfor. where R^ is alkyl group with from 1-4 carbon atoms^ and R^, R^, R^ and R^ have the same meaning as stated above.
Mellomproduktet med formel II kan fremstilles gjennom flere trinn, og første trinn er at man starter ut fra et aromatisk aldehyd (V) ved hjelp av en "strekker-syntese som består i at man behandler et alkalisk cyanid i nærvær av ammoniumklorid. The intermediate with formula II can be prepared through several steps, and the first step is to start from an aromatic aldehyde (V) by means of a "stretch synthesis" which consists in treating an alkaline cyanide in the presence of ammonium chloride.
Det fremgår av formelen at nevnte ^-amino aryl aceto-nitril (VI) er racemisk, og det aktive derivat som er nødvendig og ønskelig for den videre syntese, er D(-)-isomeren. It is clear from the formula that said ^-amino aryl acetonitrile (VI) is racemic, and the active derivative that is necessary and desirable for the further synthesis is the D(-) isomer.
Foreliggende fremgangsmåte tilveiebringer en fremgangsmåte for separasjon og fremstilling' av optisk aktive isomerer ved at man bruker L( + ) ^tartarjsyre.. s-^jtThe present method provides a method for the separation and preparation of optically active isomers by using L( + ) ^tartaric acid.. s-^jt
Så snarTden optisk aktive isomeren er utskilt utfører man en hydrolyse av nitrilgruppen i forbindelsen med formel VI, og man får fremstilt en ^-aminosyre med formel II: As soon as the optically active isomer is separated, a hydrolysis of the nitrile group in the compound of formula VI is carried out, and a β-amino acid of formula II is produced:
Denne forbindelse kan omdannes til et derivat med formel III ved at man omsetter det med et ?>-eddiksyrederivat. This compound can be converted into a derivative of formula III by reacting it with a β-acetic acid derivative.
Forbindelsen med formel III blir så omsatt med 6-amino-penicillinsyre (IV), hvorved man får fremstilt det forønskede D(-)-substituerte cc-aminobenzyl penicillin. The compound of formula III is then reacted with 6-amino-penicillinic acid (IV), whereby the desired D(-)-substituted cc-aminobenzyl penicillin is produced.
Denne reaksjon skjer på følgende måte: derivatet med formel II i nærvær av en katalysator som vanligvis er et aminfav/ p^ridin, quinolin, N-metyl-mor-folin eller lignende, omsettes med pivaloylklorid eller alkylklorformat med fra 1-4 karbonatomer, hvorved man får dannet et blandet anhydrid som deretter omsettes med 6-amino penicillansyre som på forhånd er oppløst i en blanding av vann og aceton, hvorved man får det forønskede penicillin. Eksempel 1. D(- )- - amino- p- metoxyfenyl-- acetonitril^- tartrat 98 g natriumcyanid og 118 g ammoniumklorid i 400 ml vann ble plassert i et passende kar. Røring ble utført i 30 minutter, og man tilsatte så en oppløsning av 400 ml p-metoxybenzaldehyd i 800 ml etanol. This reaction takes place in the following way: the derivative of formula II in the presence of a catalyst which is usually an amine fav/pyridine, quinoline, N-methyl-morpholine or the like, is reacted with pivaloyl chloride or alkyl chloroformate with from 1-4 carbon atoms, whereby a mixed anhydride is formed which is then reacted with 6-amino penicillanic acid which has previously been dissolved in a mixture of water and acetone, whereby the desired penicillin is obtained. Example 1. D(-)--amino-p-methoxyphenyl--acetonitrile^-tartrate 98 g of sodium cyanide and 118 g of ammonium chloride in 400 ml of water were placed in a suitable vessel. Stirring was carried out for 30 minutes, and a solution of 400 ml of p-methoxybenzaldehyde in 800 ml of ethanol was then added.
Blandingen ble hensatt i 2 timer og så konsentrert under vakuum. Den resulterende oppløsning ble tilsatt bencen og utfylt med en oppløsning av !£,(;-+)-tart arsyre i metanol. The mixture was allowed to stand for 2 hours and then concentrated under vacuum. The resulting solution was added to benzene and supplemented with a solution of !£,(;-+)-tartaric acid in methanol.
Man fikk 108 g av et produkt med rotasjonsevne på 50°. 108 g of a product with a rotatability of 50° was obtained.
Eksempel 2.Example 2.
D(-)- p- metoxyfenylglycin.D(-)-p-Methoxyphenylglycine.
30 g av D(-)-rt-amino p-metoxyfenylacetonitriltartratet fra eksempel 1 ble oppløst ipl80 ml vann, hvorpå 50 ml konsentrert saltsyre.-ble tilsatt og blandingen oppvarmet til koking under til-bakeløp i 3 timer. 30 g of the D(-)-rt-amino p-methoxyphenylacetonitrile tartrate from example 1 was dissolved in 80 ml of water, whereupon 50 ml of concentrated hydrochloric acid was added and the mixture heated to boiling under reflux for 3 hours.
Blandingen ble så avkjølt og justert til pH 4 med en ammoniakkoppløsning, og man fikk utfylt et produkt. The mixture was then cooled and adjusted to pH 4 with an ammonia solution, and a completed product was obtained.
Vekt = 12 g.Weight = 12 g.
Rotasjonsevne = -150°.Rotability = -150°.
Eksempel 3-Example 3-
P(-)- p- metoxy- fenylglycinP(-)- p- methoxy-phenylglycine
l8,l g' D(-) p-metoxy fenylglycin fra eksempel 2 ble ti! satt et kar hvoretter man tilsatte 100 ml 48$ hydrobromsyre, og blar dingen ble oppvarmet under koking med tilbakeløp i 3 timer. l8,l g' D(-) p-methoxy phenylglycine from example 2 became ti! placed a vessel after which 100 ml of 48% hydrobromic acid was added, and the mixture was heated under reflux for 3 hours.
Mesteparten av den uomsatte hydrobromsyren ble elimine]og pH ble justert til mellom 4,0 og 4,5- Man fikk på denne måten utfylt et produkt. Most of the unreacted hydrobromic acid was eliminated] and the pH was adjusted to between 4.0 and 4.5 - A product was thus completed.
Vekt = 12 g.Weight = 12 g.
Rotasjonsevne = - 150 .Rotability = - 150 .
Eksempel 4.Example 4.
Kaliumsalt av N( l- metyl- 2( o- metoxy fenylkarbamoyl)- vin: D(-)- - amino p- hydroxy fenyl eddiksyre. Potassium salt of N(l- methyl- 2(o- methoxy phenylcarbamoyl)- wine: D(-)- - amino p- hydroxy phenyl acetic acid.
En suspensjon av 5,8 g D(-)-p-hydj70xyfenylglycin fra el sempél 3 ble i 40 ml av l-normal metanolisk kaliumhydroksydoppløsnii oppvarmet til koking under tilbakeløp i 15 minutter, hvoretter man tilsatte 7,9 g o-metoxy-acetyl-acetanilid i metanol. Blandingen ble kokt under tilbakeløp i 30 minutter, avkjølt og så filtrert. A suspension of 5.8 g of D(-)-p-hydroxyphenylglycine from sample 3 in 40 ml of 1-normal methanolic potassium hydroxide solution was heated to reflux for 15 minutes, after which 7.9 g of o-methoxy-acetyl was added -acetanilide in methanol. The mixture was refluxed for 30 minutes, cooled and then filtered.
Produktet ble utkrystallisert, filtrert og vasket med metanol. The product was crystallized, filtered and washed with methanol.
Vekt = 11 g.Weight = 11 g.
Smeltepunkt = 243°C.Melting point = 243°C.
Eksempel 5-Example 5-
Kaliumsalt av N( l- metyl- 2- etoxykarbonyl- vinyl)- D(-)- °C-amino p- hydroxyfeny1 eddiksyre. Potassium salt of N(1-methyl-2-ethoxycarbonyl-vinyl)-D(-)-°C-amino p-hydroxyphenylacetic acid.
En oppløsning av 46,8 g D(-) p-hydroxyfenylglycin fra eksempel 3 i 320 ml metanolisk kaliumhydroksydoppløsning ble oppvarmet i 10 minutter, hvoretter man tilsatte 40 g etylacetylacetat og det hele ble kokt under tilbakeløp i 15 minutter. Produktet utskiller seg ved avkjøling. A solution of 46.8 g of D(-) p-hydroxyphenylglycine from example 3 in 320 ml of methanolic potassium hydroxide solution was heated for 10 minutes, after which 40 g of ethyl acetyl acetate was added and the whole was refluxed for 15 minutes. The product separates on cooling.
Vekt = 60 gWeight = 60 g
Smeltepunkt = 236°C.Melting point = 236°C.
Eksempel 6.Example 6.
D(-)- °<:- amino p- hydroxy fenyl acetamido penicillansyre. ■ ■ • D(-)- °<:- amino p- hydroxy phenyl acetamido penicillanic acid. ■ ■ •
115 ml vannfri aceton, 2 dråper N-metyl-morfolin og 3,3 ml etylklorformat ble plassert i et kar. Blandingen ble avkjølt til -8°- -10°c, og man tilsatte 11,35 g av kaliumsaltet av nevnte N(l-metyl-2(o-metoxyfenyl karbamoyl)-vinyl) D(-)- -amino p-hydroxy fenyl eddiksyre i løpet av 30 minutter, og blandingen ble hensatt i 15 minutter. Det hele ble så tilsatt en på forhånd fremstilt oppløsning av 6,48 g 6-amino penicillansyre i 90 ml 50$ aceton samt 4,3 ml tri-etylamin. Blandingen ble hensatt i 2 timer ved temperaturer fra 30 til 40°C, ble så tilsatt 50 ml metyl-isobutyl-keton hvoretter pH ble justert til ca. 0,9- Blandingen ble hensatt, og pH ble justert til 5,5 hvorved man fikk utfelt produktet. 115 ml of anhydrous acetone, 2 drops of N-methyl-morpholine and 3.3 ml of ethyl chloroformate were placed in a vessel. The mixture was cooled to -8°- -10°c, and 11.35 g of the potassium salt of said N(1-methyl-2(o-methoxyphenyl carbamoyl)-vinyl) D(-)-amino p-hydroxy phenyl acetic acid over 30 minutes and the mixture was allowed to stand for 15 minutes. The whole was then added to a previously prepared solution of 6.48 g of 6-amino penicillanic acid in 90 ml of 50% acetone and 4.3 ml of triethylamine. The mixture was allowed to stand for 2 hours at temperatures from 30 to 40°C, then 50 ml of methyl isobutyl ketone was added, after which the pH was adjusted to approx. 0.9- The mixture was set aside, and the pH was adjusted to 5.5, whereby the product was precipitated.
Vekt = 4 g.Weight = 4 g.
På lignende fikk man fremstilt:In a similar way, the following was produced:
Eksempel 7-Example 7-
6 ( P(-)- - amino- 3, 5- diklor- 4- hydroxyfenyl) acetamido penicillansyre. 6 ( P(-)- - amino- 3, 5- dichloro- 4- hydroxyphenyl) acetamido penicillanic acid.
Rotasjonsevne = + 119°.Rotational ability = + 119°.
^- Ek§, e, m. pe. l_- 8r> ^- Ek§, e, m. pe. l_- 8r>
Farmakologi.Pharmacology.
Den antibakterielle aktiviteten fremgår ved de minimums-hemmende konsentrasjon (MIC) man fant mot følgende mikroorganismer: The antibacterial activity is shown by the minimum inhibitory concentration (MIC) found against the following microorganisms:
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AR251839A AR198262A1 (en) | 1974-01-07 | 1974-01-07 | NEW PROCEDURE FOR THE PREPARATION OF D (-) - ALPHA-AMINO BENZYL PENICILLINS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO744632L true NO744632L (en) | 1975-08-04 |
Family
ID=3465295
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO744632A NO744632L (en) | 1974-01-07 | 1974-12-20 |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS50100077A (en) |
| AR (1) | AR198262A1 (en) |
| BE (1) | BE824158A (en) |
| DD (1) | DD118647A5 (en) |
| ES (1) | ES432387A1 (en) |
| FI (1) | FI750021A (en) |
| IN (1) | IN141182B (en) |
| LU (1) | LU71554A1 (en) |
| NL (1) | NL7416606A (en) |
| NO (1) | NO744632L (en) |
| SE (1) | SE7500030L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0131174B1 (en) * | 1983-07-07 | 1989-09-13 | Beecham Group Plc | Substituted phenylglycine derivatives of beta-lactam antibiotics |
-
1974
- 1974-01-07 AR AR251839A patent/AR198262A1/en active
- 1974-11-28 ES ES432387A patent/ES432387A1/en not_active Expired
- 1974-12-19 NL NL7416606A patent/NL7416606A/en unknown
- 1974-12-20 NO NO744632A patent/NO744632L/no unknown
- 1974-12-23 LU LU71554A patent/LU71554A1/xx unknown
- 1974-12-24 IN IN2850/CAL/74A patent/IN141182B/en unknown
-
1975
- 1975-01-02 SE SE7500030A patent/SE7500030L/xx unknown
- 1975-01-06 DD DD183510A patent/DD118647A5/xx unknown
- 1975-01-06 FI FI750021A patent/FI750021A/fi not_active Application Discontinuation
- 1975-01-07 JP JP50004621A patent/JPS50100077A/ja active Pending
- 1975-01-07 BE BE152190A patent/BE824158A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NL7416606A (en) | 1975-07-09 |
| LU71554A1 (en) | 1975-06-17 |
| AR198262A1 (en) | 1974-06-07 |
| FI750021A (en) | 1975-07-08 |
| SE7500030L (en) | 1975-07-08 |
| ES432387A1 (en) | 1976-11-16 |
| IN141182B (en) | 1977-01-29 |
| DD118647A5 (en) | 1976-03-12 |
| JPS50100077A (en) | 1975-08-08 |
| BE824158A (en) | 1975-05-02 |
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