NO160922B - PROCEDURE TE FOR PREPARING A CEPHALOSPORIN. - Google Patents
PROCEDURE TE FOR PREPARING A CEPHALOSPORIN. Download PDFInfo
- Publication number
- NO160922B NO160922B NO83834737A NO834737A NO160922B NO 160922 B NO160922 B NO 160922B NO 83834737 A NO83834737 A NO 83834737A NO 834737 A NO834737 A NO 834737A NO 160922 B NO160922 B NO 160922B
- Authority
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- Prior art keywords
- acid
- amino
- chloride
- cephalosporin
- group
- Prior art date
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- 229940124587 cephalosporin Drugs 0.000 title claims description 11
- 229930186147 Cephalosporin Natural products 0.000 title claims description 9
- 150000001780 cephalosporins Chemical class 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 7
- -1 α-aminohydroxyphenylacetyl chloride Chemical compound 0.000 claims description 15
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000001569 carbon dioxide Substances 0.000 claims description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- MEAZEHJUPLREOQ-UHFFFAOYSA-N 2-amino-2-phenylacetyl chloride Chemical compound ClC(=O)C(N)C1=CC=CC=C1 MEAZEHJUPLREOQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000005810 carbonylation reaction Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000002253 acid Substances 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 230000010933 acylation Effects 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 3
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229940106164 cephalexin Drugs 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- YLHCHEBQIHXSIW-SSDOTTSWSA-N (2r)-2-amino-2-(4-hydroxyphenyl)acetyl chloride Chemical compound ClC(=O)[C@H](N)C1=CC=C(O)C=C1 YLHCHEBQIHXSIW-SSDOTTSWSA-N 0.000 description 1
- MEAZEHJUPLREOQ-SSDOTTSWSA-N (2r)-2-amino-2-phenylacetyl chloride Chemical compound ClC(=O)[C@H](N)C1=CC=CC=C1 MEAZEHJUPLREOQ-SSDOTTSWSA-N 0.000 description 1
- SBUCDZYLTRYMFG-PBFPGSCMSA-N (6r,7r)-7-[[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](N)C=3C=CC(O)=CC=3)[C@H]2SC1 SBUCDZYLTRYMFG-PBFPGSCMSA-N 0.000 description 1
- VLOIVYPDUSVCLZ-UHFFFAOYSA-N 2-[2-(azaniumylmethyl)phenyl]acetate Chemical compound NCC1=CC=CC=C1CC(O)=O VLOIVYPDUSVCLZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 1
- HGXLJRWXCXSEJO-GMSGAONNSA-N cefazaflur Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CSC(F)(F)F)[C@H]2SC1 HGXLJRWXCXSEJO-GMSGAONNSA-N 0.000 description 1
- 229950004359 cefazaflur Drugs 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av et cefalosporin med formelen The present invention relates to a method for producing a cephalosporin with the formula
der there
betyr oc-aroino-fenylacetyl eller a-amino-p-hydroksyfenyl- means oc-aroino-phenylacetyl or a-amino-p-hydroxyphenyl-
acetyl og B betyr metyl. acetyl and B means methyl.
Selve patentlitteraturen rommer et stort antall beskrivelser vedrørende fremstillingen av cefalosporiner ved omsetning av en silylert kjerne (slik som 7-aminocefalosporansyre (7-ACA) eller 7-aminodesacetoksycefalosporansyre) med en sidekjede- The patent literature itself contains a large number of descriptions regarding the production of cephalosporins by reacting a silylated core (such as 7-aminocephalosporanic acid (7-ACA) or 7-aminodesacetoxycephalosporanic acid) with a side chain
syre i form av dennes syreklorid. Når denne syre inneholder en fri aminogruppe, er denne gruppe fortrinnsvis blokkert, acid in the form of its acid chloride. When this acid contains a free amino group, this group is preferably blocked,
slik som ved protonisering, og det anvendes således f.eks. 2- fenylglycylklorid, hydroklorid til fremstilling av cefaleksin. Kjernens 4-karboksylgruppe kan blokkeres ved silylering eller ved forestring. Noen eksempler er US-PS 3 671 449, 3 694 437, 3 741 959, 3 957 773, 3 965 098, 4 051 131 og GB-PS 1 073 530. I mange tilfeller fjernes 3- acetoksygruppen i 7-ACA før acylering med et heterocyklisk tiol, f.eks. ceforanid (US-PS 4 100 346 og den deri omtalte kjente teknikk), cefratrizin (US-PS 3 867 380), cefaparol (US-PS 3 641 021), cefazolin (US-PS 3 516 997 og 3 819 623), cefazaflur (US-PS 3 828 037) og lignende eller ved hjelp av andre typer tioler som omtalt i US-PS 3 928 336. such as with protonation, and it is thus used e.g. 2- phenylglycyl chloride, hydrochloride for the manufacture of cephalexin. The core's 4-carboxyl group can be blocked by silylation or by esterification. Some examples are US-PS 3,671,449, 3,694,437, 3,741,959, 3,957,773, 3,965,098, 4,051,131 and GB-PS 1,073,530. In many cases, the 3-acetoxy group in 7-ACA is removed prior to acylation with a heterocyclic thiol, e.g. ceforanid (US-PS 4,100,346 and the prior art disclosed therein), cefratrizin (US-PS 3,867,380), cefaparol (US-PS 3,641,021), cefazolin (US-PS 3,516,997 and 3,819,623), cefazaflur (US-PS 3 828 037) and similar or by means of other types of thiols as mentioned in US-PS 3 928 336.
Fra "Synthesis", mai 1970, side 259-260, er det kjent en fremgangsmåte for fremstilling av N-silyloksykarbonylamino-syrederivater ut fra N-silylerte aminosyrederivater ved tilførsel av karbondioksyd. Den angjeldende artikkel inneholder dog intet som kan henlede tanken på å anvende en slik reaksjon på en cefalosporinforbindelse for å oppnå et karbamat-mellomprodukt som tåler acylering under dannelse av ønskede cefalosporiner, da det er kjent at P-laktamringen i cefalosporin er meget følsom. From "Synthesis", May 1970, pages 259-260, a method is known for the preparation of N-silyloxycarbonylamino acid derivatives from N-silylated amino acid derivatives by the addition of carbon dioxide. However, the article in question does not contain anything that could lead to the idea of applying such a reaction to a cephalosporin compound to obtain a carbamate intermediate that withstands acylation during the formation of desired cephalosporins, as it is known that the β-lactam ring in cephalosporin is very sensitive.
Cefalosporinet med den ovenfor angitte formel fremstilles ved at man: 1) omdanner en N-trimetylsilylaminocefalsporinforbindelse med formelen hvor A betyr trimetylsilyl og B har den ovenfor angitte betydning, til en N-trimetylsilyloksykarbonylamino-cefalosporinforbindelse med formelen The cephalosporin with the above formula is produced by: 1) converting an N-trimethylsilylaminocephalosporin compound with the formula where A means trimethylsilyl and B has the meaning given above, to an N-trimethylsilyloxycarbonylamino-cephalosporin compound of the formula
der A og B har den ovenfor angitte betydning, ved at man til en ' < oppløsning av N-trimetylsilylaminocefalosporin-forbindelsen i et vannfritt, inert organisk oppløsnings-middel setter tørr karbondioksyd ved en temperatur over where A and B have the meaning stated above, by adding dry carbon dioxide to a solution of the N-trimethylsilylaminocephalosporin compound in an anhydrous, inert organic solvent at a temperature above
0°C inntil karbonyleringsreaksjonen er avsluttet, 0°C until the carbonylation reaction is finished,
hvoretter man after which one
2) acylerer det oppnådde produkt med a-amino-fenylacetyl-klorid eller a-aminohydroksyfenylacetylklorid og deretter omdanner gruppen A til hydrogen. , 2) acylates the product obtained with α-amino-phenylacetyl chloride or α-aminohydroxyphenylacetyl chloride and then converts the group A into hydrogen. ,
Når acylgruppen som skal innføres inneholder en aminogruppe, kan det være nødvendig å beskytte denne under de forskjellige reaksjonsstadier. Den beskyttende gruppe er hensiktsmessig en som kan fjernes ved hydrolyse uten å påvirke resten av molekylet, særlig laktam- og 7-amido-bindingene. Den amin-bekyttende gruppe og den forestrende gruppe i 4-C00H-stillingen kan fjernes under anvendelse av samme reagens. En fordelaktig fremgangsmåte består i å fjerne begge grupper i det siste trinn i sekvensen. Beskyttede amingrupper omfatter uretan, arylmetyl (f.eks. trityl)-amino, arylmetylenamino, sulfenylamino eller enamin-typer. Enamin-blokkerte grupper er spesielt verdifulle i tilfelle o-aminometylfenyleddiksyre. Slike grupper kan vanligvis fjernes ved hjelp av én eller flere reagenser valgt blant fortynnede mineralsyrer, f.eks. fortynnet saltsyre, konsentrerte organiske syre, f.eks. konsentrert eddiksyre, trifluoreddiksyre og flytende hydrogenbromid ved meget lave temperaturer, f.eks. -80°C. En hensiktsmessig beskyttende gruppe er t-butoksykarbonylgruppen som lett fjernes ved hydrolyse med fortynnet mineralsyre, f.eks. fortynnet saltsyre, eller fortrinnsvis med en sterk organisk syre (f.eks. maursyre eller trifluoreddiksyre), f.eks. ved en temperatur på 0-40°C og helst ved romtempe-ratur, 15-25°C. En annen hensiktsmessig beskyttende gruppe er 2,2,2-trikloretoksykarbonylgruppen som kan fraspaltes ved hjelp av et middel som sink/eddiksyre, sink/maursyre, sink/lavere alkoholer eller sink/pyridin. When the acyl group to be introduced contains an amino group, it may be necessary to protect this during the various reaction stages. The protecting group is suitably one which can be removed by hydrolysis without affecting the rest of the molecule, particularly the lactam and 7-amido linkages. The amine protecting group and the esterifying group at the 4-COOH position can be removed using the same reagent. An advantageous method consists in removing both groups in the last step of the sequence. Protected amine groups include urethane, arylmethyl (eg, trityl)amino, arylmethyleneamino, sulfenylamino, or enamine types. Enamine-blocked groups are particularly valuable in the case of o-aminomethylphenylacetic acid. Such groups can usually be removed by means of one or more reagents selected from dilute mineral acids, e.g. dilute hydrochloric acid, concentrated organic acids, e.g. concentrated acetic acid, trifluoroacetic acid and liquid hydrogen bromide at very low temperatures, e.g. -80°C. A suitable protecting group is the t-butoxycarbonyl group which is easily removed by hydrolysis with dilute mineral acid, e.g. dilute hydrochloric acid, or preferably with a strong organic acid (e.g. formic acid or trifluoroacetic acid), e.g. at a temperature of 0-40°C and preferably at room temperature, 15-25°C. Another suitable protecting group is the 2,2,2-trichloroethoxycarbonyl group which can be cleaved off using an agent such as zinc/acetic acid, zinc/formic acid, zinc/lower alcohols or zinc/pyridine.
NH2~gruppen kan også beskyttes som NH3<+> ved anvendelse av aminosyrehalogenidet som et syreaddisjonssalt under betingelser der aminogruppen forblir protonisert. The NH2~ group can also be protected as NH3<+> by using the amino acid halide as an acid addition salt under conditions where the amino group remains protonated.
Den til dannelse av syreaddisjonssaltet anvendte syre er fortrinnsvis en syre med en pKa-verdi (i vann ved 25'C) på The acid used to form the acid addition salt is preferably an acid with a pKa value (in water at 25°C) of
> X+l, der X er pKa-verdien (i vann ved 25 °C) for aminosyrens karboksygrupper. Syren er fortrinnsvis monovalent. I praksis vil syren HQ (se nedenfor) vanligvis ha en pKa-verdi < 3, fortrinnsvis < 1. > X+l, where X is the pKa value (in water at 25 °C) for the amino acid's carboxyl groups. The acid is preferably monovalent. In practice, the acid HQ (see below) will usually have a pKa value < 3, preferably < 1.
Spesielt fordelaktige resultater har vist seg å kunne oppnås ved fremgangsmåten ifølge oppfinnelsen når syrehalogenidet er et salt av et aminosyrehalogenid. Aminosyrehalogenider har formelen: der R<L> angir en divalent organisk gruppe og Hal betyr klorid eller bromid. Salter av slike aminosyrehalogenider har formelen: Particularly advantageous results have been shown to be obtainable by the method according to the invention when the acid halide is a salt of an amino acid halide. Amino acid halides have the formula: where R<L> denotes a divalent organic group and Hal means chloride or bromide. Salts of such amino acid halides have the formula:
der R<1> og Hal har den ovenfor angitte betydning og Q" angir syrens anion idet HO har en pKa-verdi som definert ovenfor. Syren HQ er fortrinnsvis en sterk mineralsyre, f.eks. en hydrogenhalogenidsyre, som saltsyre eller hydrogenbromidsyre. Et viktig aminosyrehalogenid er på grunn av de verdifulle penicillinantibiotika som inneholder den derav avledede gruppe , D-N-(a-klorkarbonyl-cx-fenyl )-metylammoniumklorid, D-[PhCH(NH3)-COCl]<+>Cl, som her av letthetsgrunner kalles D-a-fenylglycylklorid*hydroklorid. where R<1> and Hal have the meaning stated above and Q" denotes the anion of the acid, HO having a pKa value as defined above. The acid HQ is preferably a strong mineral acid, for example a hydrogen halide acid, such as hydrochloric acid or hydrobromic acid. A important amino acid halide is due to the valuable penicillin antibiotics containing the group derived from it, D-N-(a-chlorocarbonyl-cx-phenyl)-methylammonium chloride, D-[PhCH(NH3)-COCl]<+>Cl, which here for convenience is called D-a-phenylglycyl chloride*hydrochloride.
^ar acyleringsprosessen ifølge foreliggende oppfinnelse anvendes for fremstilling av cefalosporiner, isoleres sluttproduktene og renses i henhold til konvensjonelle metoder, som er velkjente innenfor denne teknikk. If the acylation process according to the present invention is used for the production of cephalosporins, the end products are isolated and purified according to conventional methods, which are well known in this art.
Syreklorider fremstilles vanligvis under kraftige betingelser, slik som ved behandling av syren under tilbakeløps-koking med tionylklorid, men de kan når følsomme grupper er tilstede, herunder følsomme blokkerende grupper, fremstilles under praktisk talt nøytrale betingelser ved omsetning av et salt av syren med oksalylklorid. Acid chlorides are usually prepared under vigorous conditions, such as by treating the acid under reflux with thionyl chloride, but when sensitive groups are present, including sensitive blocking groups, they can be prepared under practically neutral conditions by reacting a salt of the acid with oxalyl chloride.
Fremgangsmåten ifølge oppfinnelsen belyses nærmere i de følgende eksempler tilsvarende følgende reaksjonsforløp: The method according to the invention is explained in more detail in the following examples corresponding to the following reaction sequence:
Eksempel 1 Example 1
Fremstilling av bls- trimetvlsilyl- 7- aminodecefalosporansyre-ester Preparation of bis-trimethylsilyl-7-aminodecephalosporanic acid ester
En suspensjon av 7-ADCA (også kalt 7-aminodesacetoksycefalosporansyre eller 7-aminodecefalosporansyre) (10 g, 46,68 mmol) 1 100 ml tørr metylenklorid behandles med trlmetylklorsllan (11,8 g, 13,7 ml, 108 mmol) (TMCS), fulgt av trletylamin (10,86 g, 14,4 ml, 107 mmol) (TEA) dråpevls 1 av trietylamin (10,86 g, 14,4 ml, 107 mmol) (TEA) dråpevis 1 løpet av 30 minutter. Reaksjonsblandingen analyseres deretter for fullstendig silylering ved NMR-spektroskopi. NMR antydet et integralforhold mellom -C02SiMe3 og 7-NHSiMe3 på 468:462. Det var således oppnådd 100# omdanning. A suspension of 7-ADCA (also called 7-aminodesacetoxycephalosporanic acid or 7-aminodecephalosporanic acid) (10 g, 46.68 mmol) in 1100 ml of dry methylene chloride is treated with trimethylchloroslane (11.8 g, 13.7 ml, 108 mmol) (TMCS ), followed by triethylamine (10.86 g, 14.4 mL, 107 mmol) (TEA) dropwise 1 of triethylamine (10.86 g, 14.4 mL, 107 mmol) (TEA) dropwise 1 over 30 minutes. The reaction mixture is then analyzed for complete silylation by NMR spectroscopy. NMR suggested an integral ratio of -CO 2 SiMe 3 to 7-NHSiMe 3 of 468:462. Thus, 100# conversion was achieved.
Eksempel 2 Example 2
Fremstilling av trimetvlsilvloksykarbonyl- 7- aminodecefalo-sporansvre- TMS- ester Preparation of trimethylsilyloxycarbonyl-7-aminodecephalosporanic acid TMS ester
Reaksjonsblandingen av bis-trimetylsilyl-7-aminodecefalo-sporansyreester ble deretter gassbehandlet med karbondioksyd ved 25'C i 4 timer under omrøring og analysert på fullstendig karbonylering ved NMR. Det ble oppnådd 9556 omdanning. The reaction mixture of bis-trimethylsilyl-7-aminodecephalo-sporanoic acid ester was then gassed with carbon dioxide at 25°C for 4 hours with stirring and analyzed for complete carbonylation by NMR. 9556 conversions were achieved.
Eksempel 3 Example 3
Fremstilling av 7( D- q- amlno- p- hydroksyfenylacetamido)- 3-metyl- 3- cefem- 4- karboksylsvre ( cefadroksll) DMF- kompleks fra trimetylsilyloksykarbonyl- 7- amlnodecefalosporansyre- TMS- ester Trimetylsi ly 1 oksykarbonyl-7-aminodecefalosporanyre-TMS-blanding (46,68 mmol) inneholdende trietylamin HC1 ble omrørt og avkjølt til 5°C. Oppslemmingen ble behandlet med propylen-oksyd (3,7 ml, 52,7 mmol). D-(-)-2-(4'-hydroksyfenyl)-glycylklorid HC1 hemidioksansolvat (13,7 g, 48,7 mmol) i fem porsjoner ble tilsatt ved 5°C i løpet av 3 timer under god omrøring. Blandingen ble omrørt ytterligere ved 5"C i 2 timer. Det ble ikke noe fasesyreklorid tilbake i reaksjonsblandingen. Den endelige acyleringsblanding ble behandlet med 5 ml metanol fulgt av 60 ml isvann. pH-verdien ble innstilt til 2,3 med trietylamin, mens temperaturen ble holdt ved 5°C. Den vandige fase ble separert, filtrert på et filter som på forhånd var belagt med diatoméjord "Dicalite" og vasket med 15 ml vann. Filtratet og vaskevæsken ble innstilt til en pH-verdi på 4,5 med trietylamin og 100 ml isopropanol og 220 ml N,N-dimetylformamid ble tilsatt. Blandingen ble podet med 10 mg cefadroksil-DMF-kompleks og fikk lov til å krystallisere ut ved 25°C i 7 timer under kraftig omrøring. Produktet ble samlet og vasket med 20 ml dimetylformamid og 2 x 20 ml aceton, og man oppnådde 11,51 g hvitt krystallinsk cefadroksil-DMF-kompleks i et utbytte på 55,9656. Preparation of 7( D- q- amlno- p- hydroxyphenylacetamido)- 3-methyl- 3- cephem- 4- carboxylic acid (cefadroxll) DMF- complex from trimethylsilyloxycarbonyl- 7- amlnodecephalosporanic acid- TMS- ester Trimethylsi ly 1 oxycarbonyl-7-aminodecephalosporanic acid -TMS mixture (46.68 mmol) containing triethylamine HCl was stirred and cooled to 5°C. The slurry was treated with propylene oxide (3.7 mL, 52.7 mmol). D-(-)-2-(4'-hydroxyphenyl)-glycyl chloride HCl hemidioxane solvate (13.7 g, 48.7 mmol) in five portions was added at 5°C over 3 hours with good stirring. The mixture was further stirred at 5°C for 2 hours. No phase acid chloride remained in the reaction mixture. The final acylation mixture was treated with 5 mL of methanol followed by 60 mL of ice water. The pH was adjusted to 2.3 with triethylamine, while the temperature was kept at 5° C. The aqueous phase was separated, filtered on a filter previously coated with diatomaceous earth "Dicalite" and washed with 15 ml of water. The filtrate and the washing liquid were adjusted to a pH value of 4.5 with triethylamine and 100 mL of isopropanol and 220 mL of N,N-dimethylformamide were added. The mixture was seeded with 10 mg of cefadroxil-DMF complex and allowed to crystallize out at 25°C for 7 hours with vigorous stirring. The product was collected and washed with 20 ml of dimethylformamide and 2 x 20 ml of acetone, and 11.51 g of white crystalline cefadroxil-DMF complex was obtained in a yield of 55.9656.
NMR og IR var identiske ved en standardprøve. NMR viste 1,9 mol DMF pr. mol cefadroksil. NMR and IR were identical for a standard sample. NMR showed 1.9 mol DMF per moles of cefadroxil.
Eksempel 4 Example 4
Fremstilling av 7-( D- a- amino- p- fenylacetmido)- 3- metyl- 3-cefem- 4- karboksylsyre ( cefaleksln) Preparation of 7-(D-α-amino-p-phenylacetmido)-3-methyl-3-cephem-4-carboxylic acid (cefalexln)
Trimetylsilyloksykarbonyl-7-aminodecefalosporansyre-TMS-ester (46,68 mmol) inneholdende trietylamin HC1 ble omrørt og avkjølt til 5°C. Oppslemmingen ble behandlet med propylen-oksyd (3,7 ml, 52,7 mmol). D-(-)-fenylglycylklorid HC1 (10,2 g, 47,5 mmol) ble tilsatt i fem porsjoner ved 5°C i løpet av 5 timer under god omrøring. Blandingen ble omrørt ytterligere i 2 timer ved 5°C. Tynnsjiktskromatografi (TLC) viste ufullstendig acylering. Reaksjonsblandingen ble deretter oppvarmet til 25'C og omrørt i 1 time. Den endelige acyleringsblanding ble behandlet med 50 ml vann. pH-verdien ble innstilt til 1,4 under omrøring ved 25" C i 20 minutter. Den vandige fase ble separert, filtrert med diatoméjord "Dicalite", og filterkaken vasket med 15 ml vann. 10 ml DMF ble tilsatt til den rike, klare vandige oppløsning. Den vandige oppløsning ble deretter oppvarmet til 60-63°C og behandlet med 11 ml trietylamin i løpet av 15 minutter for å opprettholde pH-verdien på 4,0. Den således fremstilte krystallinske oppslemming ble deretter omrørt ved 5-10°C i 1 time. Produktet ble samlet ved filtrering og vasket med 10 ml vann og 15 ml av en 4:l-blanding av isopropanol og vann. Man oppnådde således 4,40 g cefaleksin, H2O. NMR og IR var sammenlignbare med standardreferansen. Trimethylsilyloxycarbonyl-7-aminodecephalosporanic acid TMS ester (46.68 mmol) containing triethylamine HCl was stirred and cooled to 5°C. The slurry was treated with propylene oxide (3.7 mL, 52.7 mmol). D-(-)-phenylglycyl chloride HCl (10.2 g, 47.5 mmol) was added in five portions at 5°C over 5 hours with good stirring. The mixture was further stirred for 2 hours at 5°C. Thin layer chromatography (TLC) showed incomplete acylation. The reaction mixture was then heated to 25°C and stirred for 1 hour. The final acylation mixture was treated with 50 ml of water. The pH was adjusted to 1.4 with stirring at 25°C for 20 minutes. The aqueous phase was separated, filtered with diatomaceous earth "Dicalite", and the filter cake washed with 15 ml of water. 10 ml of DMF was added to the rich, clear aqueous solution. The aqueous solution was then heated to 60-63°C and treated with 11 ml of triethylamine over 15 minutes to maintain the pH value of 4.0. The crystalline slurry thus prepared was then stirred at 5-10° C for 1 hour. The product was collected by filtration and washed with 10 ml of water and 15 ml of a 4:1 mixture of isopropanol and water. Thus, 4.40 g of cephalexin, H 2 O were obtained. NMR and IR were comparable to the standard reference.
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US06/021,511 US4223135A (en) | 1979-03-19 | 1979-03-19 | Production of cephalosporins |
NO79793103A NO158137C (en) | 1979-03-19 | 1979-09-27 | TRIMETYLSILYLOKSYKARBONYLCEFALOSPORINMELLOMPRODUKT. |
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NO834737L NO834737L (en) | 1980-09-22 |
NO160922B true NO160922B (en) | 1989-03-06 |
NO160922C NO160922C (en) | 1989-06-14 |
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NO834737A NO160922C (en) | 1979-03-19 | 1983-12-21 | PROCEDURE FOR THE PREPARATION OF A CEPHALOSPORIN. |
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