CH400159A - Verfahren zur Herstellung von Fluorbenzyl-penicillin - Google Patents

Verfahren zur Herstellung von Fluorbenzyl-penicillin

Info

Publication number: CH400159A
Authority: CH; Switzerland
Prior art keywords: penicillin; benzyl; acid; fluoro; salt
Prior art date: 1960-04-20

Application number

CH437661A

Other languages

German (de)

English (en)

Inventor

Allan Patchett Arthur

Original Assignee

Merck & Co Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1960-04-20

Filing date

1961-04-13

Publication date

1965-10-15

1961-04-13 Application filed by Merck & Co Inc filed Critical Merck & Co Inc

1965-10-15 Publication of CH400159A publication Critical patent/CH400159A/de

Links

238000000034 method Methods 0.000 title claims description 19
-1 fluorobenzyl penicillin Chemical compound 0.000 title claims description 16
229930182555 Penicillin Natural products 0.000 title description 25
229940049954 penicillin Drugs 0.000 title description 19
238000004519 manufacturing process Methods 0.000 title description 6
229940056360 penicillin g Drugs 0.000 claims description 30
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 10
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 10
239000003795 chemical substances by application Substances 0.000 claims description 9
238000002360 preparation method Methods 0.000 claims description 4
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
229910052731 fluorine Inorganic materials 0.000 claims description 2
239000011737 fluorine Substances 0.000 claims description 2
229910052739 hydrogen Inorganic materials 0.000 claims description 2
239000001257 hydrogen Substances 0.000 claims description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
239000012346 acetyl chloride Substances 0.000 claims 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 32
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
239000000243 solution Substances 0.000 description 15
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
239000002253 acid Substances 0.000 description 9
238000005917 acylation reaction Methods 0.000 description 9
235000019371 penicillin G benzathine Nutrition 0.000 description 9
150000002960 penicillins Chemical class 0.000 description 9
NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 8
UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 8
150000003839 salts Chemical class 0.000 description 8
230000010933 acylation Effects 0.000 description 7
229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
235000017557 sodium bicarbonate Nutrition 0.000 description 7
150000008064 anhydrides Chemical class 0.000 description 6
239000000203 mixture Substances 0.000 description 6
239000007787 solid Substances 0.000 description 6
244000063299 Bacillus subtilis Species 0.000 description 5
235000014469 Bacillus subtilis Nutrition 0.000 description 5
159000000000 sodium salts Chemical class 0.000 description 5
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 4
229910052751 metal Inorganic materials 0.000 description 4
239000002184 metal Substances 0.000 description 4
230000020477 pH reduction Effects 0.000 description 4
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
238000003756 stirring Methods 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
PFKSLFZFBCIJOI-UHFFFAOYSA-N 2,2-difluoro-2-phenylacetic acid Chemical compound OC(=O)C(F)(F)C1=CC=CC=C1 PFKSLFZFBCIJOI-UHFFFAOYSA-N 0.000 description 3
ATPPNMLQNZHDOG-UHFFFAOYSA-N 2-fluoro-2-phenylacetic acid Chemical compound OC(=O)C(F)C1=CC=CC=C1 ATPPNMLQNZHDOG-UHFFFAOYSA-N 0.000 description 3
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
150000008522 N-ethylpiperidines Chemical class 0.000 description 3
239000003929 acidic solution Substances 0.000 description 3
239000006286 aqueous extract Substances 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
230000003115 biocidal effect Effects 0.000 description 3
238000006243 chemical reaction Methods 0.000 description 3
238000001704 evaporation Methods 0.000 description 3
238000000605 extraction Methods 0.000 description 3
ZUFQCVZBBNZMKD-UHFFFAOYSA-M potassium 2-ethylhexanoate Chemical compound [K+].CCCCC(CC)C([O-])=O ZUFQCVZBBNZMKD-UHFFFAOYSA-M 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
239000000047 product Substances 0.000 description 3
239000011541 reaction mixture Substances 0.000 description 3
VFWZIUUVUDYNJF-UHFFFAOYSA-N 2-fluoro-2-phenylacetyl chloride Chemical compound ClC(=O)C(F)C1=CC=CC=C1 VFWZIUUVUDYNJF-UHFFFAOYSA-N 0.000 description 2
YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
WNPVZANXRCPJPW-UHFFFAOYSA-N 5-[isocyano-(4-methylphenyl)sulfonylmethyl]-1,2,3-trimethoxybenzene Chemical compound COC1=C(OC)C(OC)=CC(C([N+]#[C-])S(=O)(=O)C=2C=CC(C)=CC=2)=C1 WNPVZANXRCPJPW-UHFFFAOYSA-N 0.000 description 2
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
241000607132 Salmonella enterica subsp. enterica serovar Gallinarum Species 0.000 description 2
241000191967 Staphylococcus aureus Species 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
229940072049 amyl acetate Drugs 0.000 description 2
PGMYKACGEOXYJE-UHFFFAOYSA-N anhydrous amyl acetate Natural products CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 2
FCPVYOBCFFNJFS-LQDWTQKMSA-M benzylpenicillin sodium Chemical compound [Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 FCPVYOBCFFNJFS-LQDWTQKMSA-M 0.000 description 2
230000036765 blood level Effects 0.000 description 2
239000002552 dosage form Substances 0.000 description 2
230000000694 effects Effects 0.000 description 2
239000000284 extract Substances 0.000 description 2
MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 2
239000000463 material Substances 0.000 description 2
238000002156 mixing Methods 0.000 description 2
YCOFRPYSZKIPBQ-UHFFFAOYSA-N penicillic acid Natural products COC1=CC(=O)OC1(O)C(C)=C YCOFRPYSZKIPBQ-UHFFFAOYSA-N 0.000 description 2
VOUGEZYPVGAPBB-UHFFFAOYSA-N penicillin acid Natural products OC(=O)C=C(OC)C(=O)C(C)=C VOUGEZYPVGAPBB-UHFFFAOYSA-N 0.000 description 2
WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
238000010992 reflux Methods 0.000 description 2
230000000717 retained effect Effects 0.000 description 2
KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical class O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 1
VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical class ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
208000035473 Communicable disease Diseases 0.000 description 1
241000901842 Escherichia coli W Species 0.000 description 1
YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
241000588747 Klebsiella pneumoniae Species 0.000 description 1
241000192041 Micrococcus Species 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
241000588767 Proteus vulgaris Species 0.000 description 1
241000589517 Pseudomonas aeruginosa Species 0.000 description 1
241000607142 Salmonella Species 0.000 description 1
229960000583 acetic acid Drugs 0.000 description 1
150000001266 acyl halides Chemical class 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
230000000172 allergic effect Effects 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
150000001412 amines Chemical class 0.000 description 1
239000012431 aqueous reaction media Substances 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
238000009835 boiling Methods 0.000 description 1
239000002775 capsule Substances 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
239000007795 chemical reaction product Substances 0.000 description 1
150000001875 compounds Chemical class 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
238000004821 distillation Methods 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
QKLCQKPAECHXCQ-UHFFFAOYSA-N ethyl phenylglyoxylate Chemical compound CCOC(=O)C(=O)C1=CC=CC=C1 QKLCQKPAECHXCQ-UHFFFAOYSA-N 0.000 description 1
230000037406 food intake Effects 0.000 description 1
238000004108 freeze drying Methods 0.000 description 1
239000012362 glacial acetic acid Substances 0.000 description 1
125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
239000005457 ice water Substances 0.000 description 1
239000007972 injectable composition Substances 0.000 description 1
238000002955 isolation Methods 0.000 description 1
239000007788 liquid Substances 0.000 description 1
229910052753 mercury Inorganic materials 0.000 description 1
244000000010 microbial pathogen Species 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
239000002674 ointment Substances 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
229960003424 phenylacetic acid Drugs 0.000 description 1
239000003279 phenylacetic acid Substances 0.000 description 1
UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
235000015497 potassium bicarbonate Nutrition 0.000 description 1
239000011736 potassium bicarbonate Substances 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
239000000843 powder Substances 0.000 description 1
229960004919 procaine Drugs 0.000 description 1
229940007042 proteus vulgaris Drugs 0.000 description 1
238000000746 purification Methods 0.000 description 1
239000002904 solvent Substances 0.000 description 1
230000003595 spectral effect Effects 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
239000007858 starting material Substances 0.000 description 1
210000002784 stomach Anatomy 0.000 description 1
239000000126 substance Substances 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
QHMQWEPBXSHHLH-UHFFFAOYSA-N sulfur tetrafluoride Chemical compound FS(F)(F)F QHMQWEPBXSHHLH-UHFFFAOYSA-N 0.000 description 1
239000000725 suspension Substances 0.000 description 1
239000003826 tablet Substances 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
238000001665 trituration Methods 0.000 description 1
238000005406 washing Methods 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)
Preparation Of Compounds By Using Micro-Organisms (AREA)

CH437661A 1960-04-20 1961-04-13 Verfahren zur Herstellung von Fluorbenzyl-penicillin CH400159A (de)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US2338260A	1960-04-20	1960-04-20

Publications (1)

Publication Number	Publication Date
CH400159A true CH400159A (de)	1965-10-15

Family

ID=21814761

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CH437661A CH400159A (de)	1960-04-20	1961-04-13	Verfahren zur Herstellung von Fluorbenzyl-penicillin

Country Status (4)

Country	Link
BE (1)	BE602494A (fr)
CH (1)	CH400159A (fr)
ES (1)	ES266718A1 (fr)
FR (1)	FR1428M (fr)

1961
- 1961-04-12 BE BE602494A patent/BE602494A/fr unknown
- 1961-04-13 CH CH437661A patent/CH400159A/de unknown
- 1961-04-13 ES ES0266718A patent/ES266718A1/es not_active Expired
- 1961-07-17 FR FR868129A patent/FR1428M/fr not_active Expired

Also Published As

Publication number	Publication date
BE602494A (fr)	1961-10-12
ES266718A1 (es)	1961-08-16
FR1428M (fr)	1962-08-06

Publication	Publication Date	Title
DE2332878C2 (de)	1983-07-28	Salze von Cephalosporinen mit Arginin und Lysin, ihre Herstellung und injizierbare pharmazeutische Zubereitungen
DE1445154C3 (de)	1974-02-14	1,4-Dihydro-1,8-naphthyridinderi vate und ein Verfahren zu ihrer Herstellung
DE2228012C3 (de)	1980-01-17	Phthalidester der 6- [D(-)- a Aminophenylacetamido] -penicillansäure und Verfahren zu seiner Herstellung
CH454148A (de)	1968-04-15	Verfahren zur Herstellung von Anhydropenicillinen
DE1795861C2 (de)	1979-10-31	deren Salze, Verfahren zu deren Herstellung und diese Verbindungen enthaltende antibakterielle Mittel
CH400159A (de)	1965-10-15	Verfahren zur Herstellung von Fluorbenzyl-penicillin
DE2121648B2 (de)	1974-03-07	Monoacetate der Antibiotica SF-837 und SF 83 7-A tief 2
DE1929997C2 (de)	1983-12-08	Acylureidopenicilline, Verfahren zu ihrer Herstellung und antibakterielle Mittel, die diese Verbindungen enthalten
AT230540B (de)	1963-12-10	Verfahren zur Herstellung neuer säurebeständiger und therapeutisch wirksamer α-Fluorbenzylpenicilline
DE1670163B2 (de)	1973-04-26	Cephaloglycinderivat und verfahren zu seiner herstellung
CH629814A5 (de)	1982-05-14	Verfahren zur herstellung von cephalosporinantibiotika.
CH394206A (de)	1965-06-30	Verfahren zur Herstellung von Abkömmlingen der 6-Amino-penicillansäure
AT247519B (de)	1966-06-10	Verfahren zur Herstellung neuer Additionsverbindungen von Antibiotika
CH586708A5 (fr)	1977-04-15
DE2356755A1 (de)	1975-01-30	Neue penicilline und verfahren zu ihrer herstellung
AT303258B (de)	1972-11-27	Verfahren zur Herstellung von neuen 6-Aminopenicillansäurederivaten
AT335611B (de)	1977-03-25	Verfahren zur herstellung von neuem alfa- (4-oxo-4h-thiopyran-3-yl) carboxamido-p-hydroxybenzylpenicillin
DE972336C (de)	1959-07-02	Verfahren zur Gewinnung von stabilen, besonders fuer die Oraltherapie geeigneten Penicillinen
DE2154027C3 (de)	1977-02-03	alpha- (N-2-Pyrimidylf ormamidlno) benzylpenicillin sowie dessen nichttoxische Salze, Verfahren zu seiner Herstellung sowie es enthaltende Arzneimittel
DE2362978A1 (de)	1974-06-20	Vinylaminoacetylpenicilline und -cephalosporine
AT220288B (de)	1962-03-12	Verfahren zur Herstellung von neuen therapeutisch wirksamen Estern des Erythromycins
AT259132B (de)	1967-12-27	Verfahren zur Herstellung von neuen Penicillinderivaten
AT337365B (de)	1977-06-27	Verfahren zur herstellung von neuen derivaten des cephalosporins und von ihren salzen
AT375081B (de)	1984-06-25	Verfahren zur herstellung von 7-aminocephalosporansaeure und ihren estern
AT228397B (de)	1963-07-10	Verfahren zur Herstellung von Verbindungen mit antibakterieller Wirkung