EP0000078B1 - Preparation of salts of hydroxyphosphinylureidobenzylpenicillins. - Google Patents
Preparation of salts of hydroxyphosphinylureidobenzylpenicillins. Download PDFInfo
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- EP0000078B1 EP0000078B1 EP78200017A EP78200017A EP0000078B1 EP 0000078 B1 EP0000078 B1 EP 0000078B1 EP 78200017 A EP78200017 A EP 78200017A EP 78200017 A EP78200017 A EP 78200017A EP 0000078 B1 EP0000078 B1 EP 0000078B1
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- European Patent Office
- Prior art keywords
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- salt
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- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims description 26
- 238000002360 preparation method Methods 0.000 title claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 24
- -1 organic acid salt Chemical class 0.000 claims description 22
- 150000001768 cations Chemical class 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid group Chemical group C(CCCCCC)(=O)O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid group Chemical group C(CCCCC)(=O)O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 229910052710 silicon Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 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
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N pentanoic acid group Chemical group C(CCCC)(=O)O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 1
- 239000008117 stearic acid Substances 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 7
- 229940093499 ethyl acetate Drugs 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- 229960003022 amoxicillin Drugs 0.000 description 5
- 229960000723 ampicillin Drugs 0.000 description 5
- LULXBAGMGMJJRW-UHFFFAOYSA-N n,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)CC(=O)N[Si](C)(C)C LULXBAGMGMJJRW-UHFFFAOYSA-N 0.000 description 5
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 5
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 4
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 0 *C(C(NC(C1S*C(*)N11)C1=O)=O)N Chemical compound *C(C(NC(C1S*C(*)N11)C1=O)=O)N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical class CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- WNIUDMQDRHJSFT-UHFFFAOYSA-N [ethoxy(isocyanato)phosphoryl]oxymethylbenzene Chemical compound CCOP(=O)(N=C=O)OCC1=CC=CC=C1 WNIUDMQDRHJSFT-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 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 1
- 229940106164 cephalexin Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000005473 octanoic acid group Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- GHDSUFBKFKLPHO-UHFFFAOYSA-N oxo(phosphorosoimino)methane Chemical compound O=PN=C=O GHDSUFBKFKLPHO-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000005603 pentanoic acids Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65611—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. penicillins and analogs
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to a new process for .the preparation of salts of hydroxyphosphinylureidobenzylpenicillins.
- cephalexin Benzylcar- boxamido-desacetoxycephalosporanic acid
- the disodium salt of D - 6 - [a - ⁇ 3 - (Hydroxy(ethoxy) - phosphinyl)ureidolbenzyl- carboxamido]penicillinic acid may also be prepared by another process as described in Example 35 of the above-mentioned Specification. Silylated ampicillin is reacted with benzyloxy(ethoxy)phosphinyl-isocyanate [C 6 H 5 CH 2 O(C 2 H 5 O)P - (O)NCO] and the compound formed, after separation, is reduced with hydrogen using palladium-on-charcoal as a catalyst, in the presence of sodium bicarbonate. Although this results in a much higher yield of the product, i.e. 50% based on the ampicillin starting material, the process has drawbacks in that palladium-on-charcoal is expensive and the reduction step takes a considerable length of time.
- the present invention accordingly provides a process for the preparation of compounds of the general formula:
- lower as used in connection with alkyl and alkoxy groups means that the groups in question contain 1 to 6 carbon atoms.
- the salt formation when carried out in an organic medium is preferably carried out in organic solvents having moderately polar properties, such as ethanol, butanol, acetone, ethyl acetate, methyl isobutyl ketone, methylene chloride or mixtures of two or more of these solvents.
- organic solvents having moderately polar properties such as ethanol, butanol, acetone, ethyl acetate, methyl isobutyl ketone, methylene chloride or mixtures of two or more of these solvents.
- useful salts are salts of acetic acid, propionic acid, butyric acids, pentanoic acids, hexanoic acids, heptanoic acids, octanoic acids, stearic acids, etc.
- salts of 2-ethylhexanoic acid are used.
- the precipitated partial salt is collected and converted into a di- or tri-salt, as the case may be, in any conventional manner, e.g. by means of aqueous sodium carbonate.
- the hydrolysed compound is washed with water before salt formation, care must be taken that the compound has been dissolved in an organic medium not or substantially not soluble in water, in order that the compound remains in the organic phase during this washing.
- suitable solvents are methylene chloride, ethyl acetate, etc., but solvents like acetone should then be avoided.
- the water may be acidified by a solution of an inorganic acid, such as hydrochloric, phosphoric, nitrile and sulphuric acid, etc. Hydrochloric acid is conveniently used.
- the salt formation afterwards may be effected by the use of solutions of a hydroxide or a salt of cations hereinbefore defined, such as sodium hydroxide.
- the starting compounds of formula II may be prepared by methods known per se.
- the phos- phinylisocyanates of formula III may be prepared, for example, as described by Narbut et al, Zh. Obshch. Khim. 38 (1968) page 1321 and Gubnitskaya et al, Zh. Obshch.Khim. (1970) page 1205.
- the cations E and Me are preferably nontoxic, pharmaceutically acceptable cations for penicillins, preferably sodium, potassium or calcium.
- the starting penicillin compounds from which the compounds of general formula II are prepared contain a carboxylic acid or a carboxylic salt group and may contain other groups which may also interfere with the reaction. These groups are protected by a group Qz as hereinbefore defined by methods known per se.
- silyl esters are prepared by reacting the free carboxyl group with, e.g. trimethylchlorosilane, N,O-bistrimethylsilylacetamide, tri- methylsilylacetamide, dimethyldichlorosilane, bistrimethylsilylurea, bistrimethylsilylcarbamate or bistrimethylsilylsulphamate.
- silylhalo compounds it is preferred to carry out the silylation reaction in the presence of an acid-binding compound such as triethylamine or ethylenediamine.
- a solution of 16.8 g (0.10 mole) of sodium 2-ethylhexanoate in 200 ml of dry acetone is added to the filtrate at +5°C, and the mixture is stirred for 10 minutes at the same temperature, and for a further 15 minutes at ambient temperature.
- a precipitate is formed which is filtered off and suspended in 1 litre of dry acetone.
- the mixture is stirred mechanically for 45 minutes and the precipitate is then filtered off. This operation is repeated, resulting in a much purer product.
- the precipitate from the repeated operation is suspended in 750 ml of water. The suspension is cooled by the exterior application of ice and nitrogen bubbled through the mixture, and the precipitate dissolved by the addition of 5.3 g of sodium bicarbonate at pH 6.8.
- the sodium potassium double salt is prepared in the same manner, but instead of sodium 2-ethylhexanoate, 10 g (0.10 mole) of potassium acetate, dissolved in butanol, are added. A precipitate is formed slowly. The precipitate is treated with sodium bicarbonate in the manner described above, yielding 26 g (45%) of the title sodium potassium compound having physicochemical properties identical to those of the disodium salt given above.
- the disodium salt may also be prepared by using a sodium stearate suspension in acetone, instead of the sodium 2-ethylhexanoate.
- a white powder is obtained consisting of the monosodium salt containing a fair amount of sodium stearate. 3.3 g of this product are suspended in 30 ml of water at 0°C.
- the suspension is cooled by the exterior application of ice and nitrogen is bubbled through the mixture.
- a 1 N sodium hydroxide solution By addition of a 1 N sodium hydroxide solution, until a pH-value of 7 is obtained, the precipitate dissolves.
- 90 ml of ethanol and 1.2 g of activated carbon are added and the reaction mixture is stirred at 0°C for t hour.
- the mixture is filtered and the filtrate is concentrated in vacuo (bath temperature not exceeding 20°C), during which 2 portions of 80 ml of dry ethanol are added to remove as much water as possible.
- When concentrated to about 15 ml the residue is, with stirring, poured into a mixture of 55 ml of 2,2-dimethoxypropane and 120 ml of acetone.
- the resulting precipitate is filtered off, washed with acetone and dried in vacuo, yielding 2.4 g of the disodium title compound.
- the mixture is stirred for 1t hours and 25 ml (1.39 mole) of water and 1 I of ethylacetate are added at a temperature of -70°C. The temperature is allowed to rise to -40°C in 1 hour and then to 0°C in 1 hours. After separation of the layers the organic layer is washed twice with 200 ml of water. The 600 ml 1 N sodium hydroxide are added slowly at a pH-value of 5 or slightly lower. After completion of the addition the pH-value of the waterlayer is brought to 7 with 1N sodium hydroxide in 1 hour.
- the solution is treated with 10 g of activated carbon, and, after filtration, concentrated in vacuo during which several portions of dry ethanol are added in order to remove as much water as possible.
- the residue is dissolved in 1 I of methanol and concentrated in the same manner to 750 ml after which ethanol is added slowly during the concentration, thus keeping the volume 750 ml, till almost all methanol is removed.
- the precipitate formed is filtered off, washed with ethanol and diethylether and dried in vacuo over phosphoruspentoxide, yielding 100 g (60%) of the disodium title compound.
- the mixture is stirred for 75 minutes and then a mixture of 1.26 ml (0.07 mole) of water, 2.4 ml (0.03 mole) of pyridine and 30 ml of acetone is added. After completion of the addition the temperature is raised rapidly to -35°C and then slowly to 0°C over a period of time of 2 hours. A solution of 4.9 g (0.03 mole) of sodium 2-ethylhexanoate in 30 ml of dry acetone is added to the reaction mixture at 0°C, and the mixture is stirred for 1 hours, the temperature being allowed to rise to about ambient temperature. A precipitate is formed which is filtered off and suspended in 150 ml of dry acetone.
- Disodium salt of D-6- ⁇ a - [3 - (hydroxy(benzyloxy) - phosphinyl)ureido] - p - hydroxybenzylcarboxamido ⁇ penicillanic acid having the following physicochemical properties:-IR (KBr-disc, values in cm -1 ): about 3100-3600, shoulders at ⁇ 3050, 2970 and 2935, 1765, 1690 (sh), 1640-1660, 1595-1615, ⁇ 1550 (sh), 1515, 1455, 1400, 1380 (sh), 1320 ⁇ 1340, 1220-1260, 1180, 1135, 1090 (intensive), 1010-1035, 985,900,870,845,750,710,
- Disodium salt of D - 6 - ⁇ - [3 - hydroxy-(phenoxy) - phosphinyl)ureido] - p - hydroxybenzylcarboxamido]penicillahic acid having the following physicochemical properties:-IR (KBr-disc, values in cm -1 ): 3400, 1780, 1660,1610,1520,1400,1320,1220,1140, 1060, 780, 700.
- D - 6 - (a - amino) - p - hydroxybenzyl- carboxamidopenicillanic acid (amoxicillin) (2.17 g, 5.95 mmoles): is silylated with 3.24 ml (13.1 mmoles) of N,O-bistrimethylsilylacetamide in 15 ml of methylene chloride as a solvent. After cooling the solution to about -75°C a solution of 0.95 g (5.95 mmoles) of dichlorophosphorus- isocyanatidate in 15 ml of ethyl acetate is added dropwise in one hour.
- the mixture is stirred for 1 hours and a mixture of 0.96 ml (11.9 mmoles) of pyridine and 15 ml of ethyl acetate is added, followed by the addition of 0.69 ml (38 mmoles) of distilled water at a temperature of -70°C.
- the temperature of the reaction mixture is allowed to rise to -40°C in one hour and from -40° to 0°C in 1t hours.
- the reaction mixture is washed 3 times with 25 ml portions of acidified water at a pH-value of 1.5.
- 25 ml of water are added and the pH-value is brought slowly to 7 with 1 N sodium hydroxide.
- the layers formed are separated and the aqueous layer is freeze-dried, yielding 3.0 g of a powder of the title compound, having a purity of 80%.
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Description
- This invention relates to a new process for .the preparation of salts of hydroxyphosphinylureidobenzylpenicillins.
- Processes for the preparation of hydroxyphosphinylureidobenzylpenicillins are already known. For example, British Patent Specification No. 1,464,551 describes, in Example 26, the reaction of silylated D - 6 - (a - amino) - benzylcarboxamidopenicillanic acid (ampicillin) with chloro(ethoxy)phosphinyl- isocyanate[C2H5O―P(O)(Cl)NCO] in an organic solvent at a temperature of -65 to -70°C. The reaction mixture obtained is poured into iced water, simultaneously being neutralised with aqueous sodium hydroxide. After extracting the aqueous phase of the two-phase system formed with an organic solvent, the extract is evaporated, yielding about 5.5% of D - 6 - [α-{3-hydroxy(ethoxy) - phosphinyl) - ureido} benzyl- carboxamidolpenicillanic acid. This compound may be converted into a salt which appears to be more stable than the acid, but nevertheless, the yield remains low, if calculated on the ampicillin compound used as starting material. Using the same method but using as starting material D - 7 - (α - amino) - benzylcar- boxamido-desacetoxycephalosporanic acid (cephalexin) a much higher yield is obtained, being 61%, according to Example 30 of the same Specification. The cephalosporin is apparently more stable than the corresponding penicillin.
- The disodium salt of D - 6 - [a - {3 - (Hydroxy(ethoxy) - phosphinyl)ureidolbenzyl- carboxamido]penicillinic acid may also be prepared by another process as described in Example 35 of the above-mentioned Specification. Silylated ampicillin is reacted with benzyloxy(ethoxy)phosphinyl-isocyanate [C6H5CH2O(C2H5O)P - (O)NCO] and the compound formed, after separation, is reduced with hydrogen using palladium-on-charcoal as a catalyst, in the presence of sodium bicarbonate. Although this results in a much higher yield of the product, i.e. 50% based on the ampicillin starting material, the process has drawbacks in that palladium-on-charcoal is expensive and the reduction step takes a considerable length of time.
- By using anhydrous D - 6 - (a - amino) - p - hydroxybenzyl - carboxamido-penicillanic acid (amoxicillin) as the starting material, as described in German "Offenlegungsschrift" No. 25 46 910, Example 5, it is possible to obtain the disodium salt of D - 6 - [α{3-(hydroxy(ethoxy)phosphinyl)ureido} - p - hydroxy - benzylcarboxamido]penicillanic acid using a similar reduction method, with palladium-on-charcoal as a catalyst. A yield of 74% is obtained, calculated on the starting amoxicillin compound. However, the use of the expensive catalyst is a drawback of this process.
- It has now been found that attractive yields of salts of hydroxyphosphinylureidobenzylpenicillins can be obtained (e.g. yields of 50% or more) without use of the expensive palladium-on-charcoal catalyst by a process which is similar to that disclosed in the above mentioned British Patent Specification No. 1,464,551, Example 26, but in which some modifications are adopted.
- The present invention accordingly provides a process for the preparation of compounds of the general formula:
-
-
-
- The term "lower" as used in connection with alkyl and alkoxy groups means that the groups in question contain 1 to 6 carbon atoms.
- The salt formation, when carried out in an organic medium is preferably carried out in organic solvents having moderately polar properties, such as ethanol, butanol, acetone, ethyl acetate, methyl isobutyl ketone, methylene chloride or mixtures of two or more of these solvents. Examples of useful salts are salts of acetic acid, propionic acid, butyric acids, pentanoic acids, hexanoic acids, heptanoic acids, octanoic acids, stearic acids, etc. Preferably salts of 2-ethylhexanoic acid are used.
- Due to the difference in pKa of the P-OH and COOH groups salt formation on addition of an organic acid salt will at first take place exclusively at the POH group(s), whereupon the formed partial salt precipitates and because of this the carboxylate ion will not be formed. Therefore large amounts of the organic acid salt excessive to the amount calculated for salt formation of the P-OH group(s) are useless and should normally be avoided in order not to contaminate the final product unnecessarily. The precipitated partial salt is collected and converted into a di- or tri-salt, as the case may be, in any conventional manner, e.g. by means of aqueous sodium carbonate. In the case the hydrolysed compound is washed with water before salt formation, care must be taken that the compound has been dissolved in an organic medium not or substantially not soluble in water, in order that the compound remains in the organic phase during this washing. Examples of suitable solvents are methylene chloride, ethyl acetate, etc., but solvents like acetone should then be avoided. The water may be acidified by a solution of an inorganic acid, such as hydrochloric, phosphoric, nitrile and sulphuric acid, etc. Hydrochloric acid is conveniently used. The salt formation afterwards may be effected by the use of solutions of a hydroxide or a salt of cations hereinbefore defined, such as sodium hydroxide.
- The starting compounds of formula II may be prepared by methods known per se. The phos- phinylisocyanates of formula III may be prepared, for example, as described by Narbut et al, Zh. Obshch. Khim. 38 (1968) page 1321 and Gubnitskaya et al, Zh. Obshch.Khim. (1970) page 1205.
- By the term "methods known per se" as used in this specification is meant methods heretofore used or described in the chemical literature.
- The cations E and Me are preferably nontoxic, pharmaceutically acceptable cations for penicillins, preferably sodium, potassium or calcium.
- The starting penicillin compounds from which the compounds of general formula II are prepared contain a carboxylic acid or a carboxylic salt group and may contain other groups which may also interfere with the reaction. These groups are protected by a group Qz as hereinbefore defined by methods known per se. Preferably silyl esters are prepared by reacting the free carboxyl group with, e.g. trimethylchlorosilane, N,O-bistrimethylsilylacetamide, tri- methylsilylacetamide, dimethyldichlorosilane, bistrimethylsilylurea, bistrimethylsilylcarbamate or bistrimethylsilylsulphamate. When silylhalo compounds are used it is preferred to carry out the silylation reaction in the presence of an acid-binding compound such as triethylamine or ethylenediamine.
- An advantage of the process of the present invention over methods previously disclosed in specification as heretobefore mentioned for the preparation of hydroxyphosphinylureidobenzylpenicillins is that the reactions involved can all be carried out in one reaction vessel.
- The compounds of general formula I prepared by the process of the invention, show antibiotic activity, as described in the aforementioned British Patent Specification No. 1,464,551 and German "Offenlegungsschrift" No. 2546910.
- The invention is illustrated by the following Examples.
- Preparation of the disodium salt and the sodium potassium double salt of D - 6{α - [3 - (hydroxy(ethoxy)phosphinyl) - ureido] - p - hydroxybenzylcarboxamido}penicillanic acid.
- D - 6 - (a - amino) - p - hydroxybenzylcarboxamido penicillanic acid (amoxicillin) (36.9 g, 0.10 mole) is silylated with 53.4 ml (0.22 mole) of N,O-bistrimethylsilylacetamide in 250 ml of methylene chloride as solvent. After cooling the solution to about -70°C a solution of 17 g (0.10 mole) of (C2H5O)PO(Cl)NCO (ethyl- chlorophosphorusisocyanatidate) in 250 ml of dry acetone is added dropwise. After completion of the addition the mixture is stirred for hours and a mixture of 5.8 ml (0.32 mole) of water, 8.1 ml (0.10 mole) of pyridine and 250 ml of dry acetone are added at a temperature of -70°C. The temperature of the reaction mixture is then allowed to rise quickly to -40°C and then slowly to -10°C, during a period of 2 hours, in order to complete the hydrolysis of the chloride and protective silyl groups. 2 g of activated carbon are added and after stirring for 10 minutes the mixture is filtered. A solution of 16.8 g (0.10 mole) of sodium 2-ethylhexanoate in 200 ml of dry acetone is added to the filtrate at +5°C, and the mixture is stirred for 10 minutes at the same temperature, and for a further 15 minutes at ambient temperature. A precipitate is formed which is filtered off and suspended in 1 litre of dry acetone. The mixture is stirred mechanically for 45 minutes and the precipitate is then filtered off. This operation is repeated, resulting in a much purer product. The precipitate from the repeated operation is suspended in 750 ml of water. The suspension is cooled by the exterior application of ice and nitrogen bubbled through the mixture, and the precipitate dissolved by the addition of 5.3 g of sodium bicarbonate at pH 6.8. By freeze-drying the solution 33 g (58%) of the title disodium salt are obtained, containing only a trace of sodium 2-ethylhexanoate. The physicochemical properties of the compound obtained are as follows:, IR (KBr-disc, values in cm-1): about 3200-3600 (broad and intensive), 2975, 2930 (sh), 1765, ± 1650-1670, ± 1610, 1550 (sh), 1515, 1460, 1400 1375 (sh), ± 1325, about 1240(broad), 1180, 1135, 1085, 1050, 955, 900, 770. PMR (about 5:1 mixture of d6-DMSO and DCO2D, DSS as reference, 8-values in ppm): 1.25 (centre of two close triplets, J z 7.5 cps), 1.46 (s) and 1.59 (s) all together 9H; about 3.75 to 4.1 (multiplet, 2H), 4.22 (s, 1 H), 5.42 (s) and about 5.3 to 5.6 (broadened AB-q) together 3H; 6.65 to 7.35 (q-like, J x 8.5 cps, 4H).
- The physicochemical properties are identical to those of the compound prepared in Example 5 of German "Offenlegungsschrift" No. 25 46 910.
- The sodium potassium double salt is prepared in the same manner, but instead of sodium 2-ethylhexanoate, 10 g (0.10 mole) of potassium acetate, dissolved in butanol, are added. A precipitate is formed slowly. The precipitate is treated with sodium bicarbonate in the manner described above, yielding 26 g (45%) of the title sodium potassium compound having physicochemical properties identical to those of the disodium salt given above.
- The disodium salt may also be prepared by using a sodium stearate suspension in acetone, instead of the sodium 2-ethylhexanoate. A white powder is obtained consisting of the monosodium salt containing a fair amount of sodium stearate. 3.3 g of this product are suspended in 30 ml of water at 0°C.
- The suspension is cooled by the exterior application of ice and nitrogen is bubbled through the mixture. By addition of a 1 N sodium hydroxide solution, until a pH-value of 7 is obtained, the precipitate dissolves. 90 ml of ethanol and 1.2 g of activated carbon are added and the reaction mixture is stirred at 0°C for t hour. The mixture is filtered and the filtrate is concentrated in vacuo (bath temperature not exceeding 20°C), during which 2 portions of 80 ml of dry ethanol are added to remove as much water as possible. When concentrated to about 15 ml the residue is, with stirring, poured into a mixture of 55 ml of 2,2-dimethoxypropane and 120 ml of acetone. The resulting precipitate is filtered off, washed with acetone and dried in vacuo, yielding 2.4 g of the disodium title compound.
- Preparation of the disodium salt of D - 6 - [a{ - 3 - (hydroxy(ethoxy)phosphinyl)ureido}- p - hydroxybenzylcarboxamido] - penicillanic acid.
- D - 6 - (a - amino) - p - hydroxybenzyl- carboxamidopenicillanic acid (amoxicillin) (108.5 g, 0.2975 mole) is silylated with 162.5 ml (0.655 mole) of N,O-bistrimethylsilyl- acetamide in 750 ml of methylene chloride. After cooling the solution to about -70°C a solution of 50.5 g (0.2975 mole) of ethylchloro- phosphorusisocyanatidate in 750 ml of ethylacetate is added dropwise. After completion of the addition the mixture is stirred for 1t hours and 25 ml (1.39 mole) of water and 1 I of ethylacetate are added at a temperature of -70°C. The temperature is allowed to rise to -40°C in 1 hour and then to 0°C in 1 hours. After separation of the layers the organic layer is washed twice with 200 ml of water. The 600 ml 1 N sodium hydroxide are added slowly at a pH-value of 5 or slightly lower. After completion of the addition the pH-value of the waterlayer is brought to 7 with 1N sodium hydroxide in 1 hour. The solution is treated with 10 g of activated carbon, and, after filtration, concentrated in vacuo during which several portions of dry ethanol are added in order to remove as much water as possible. The residue is dissolved in 1 I of methanol and concentrated in the same manner to 750 ml after which ethanol is added slowly during the concentration, thus keeping the volume 750 ml, till almost all methanol is removed. The precipitate formed is filtered off, washed with ethanol and diethylether and dried in vacuo over phosphoruspentoxide, yielding 100 g (60%) of the disodium title compound.
- Preparation of the disodium salt of D - 6 - {α - [3 - hydroxy(ethoxy)phosphinyl)ureido]-benzylcarboxamido} - penicillanic acid.
- 10.5 g (0.03 mole) of D - 6 - (a - amino)benzylcarboxamidopenicillanic acid (ampicillin) is silylated with 9.6 ml (0.04 mole) of N,O-bistrimethylsilylacetamide in 50 ml of dry methylene chloride. The solution is cooled to -65°C and a solution of 5 g (0.03 mole) of (C2H5O)PO(Cl)NCO (ethylchlorophosphorus- isocyanatidate) in 55 ml dry methylene chloride is added dropwise. The mixture is stirred for 75 minutes and then a mixture of 1.26 ml (0.07 mole) of water, 2.4 ml (0.03 mole) of pyridine and 30 ml of acetone is added. After completion of the addition the temperature is raised rapidly to -35°C and then slowly to 0°C over a period of time of 2 hours. A solution of 4.9 g (0.03 mole) of sodium 2-ethylhexanoate in 30 ml of dry acetone is added to the reaction mixture at 0°C, and the mixture is stirred for 1 hours, the temperature being allowed to rise to about ambient temperature. A precipitate is formed which is filtered off and suspended in 150 ml of dry acetone. The suspension is stirred for 45 minutes and the precipitate is filtered off. This procedure is repeated once and the precipitate obtained is suspended in 100 ml of water. The suspension is cooled with ice, nitrogen is bubbled through the mixture and the precipitate is dissolved by the addition of an amount of sodium bicarbonte just sufficient for the desired salt formation. The solution obtained is freeze-dried, resulting in a yield of 8.6 g (53%) of the title compound having the following physicochemical properties:―
- IR (Kbr-disc, values in cm-1): ± 3550, ± 2600, ± 3320 and ± 3250, 1780, 1740-1710, 1640-1670, ± 1530 (intense), 1210, 1040, 700.
- PMR (d6-DMSO, 60 Mc, 8 - values in ppm, DSS as reference): 1.2 (t, J ≈ 7.0 cps, 3H), 1.44 and 1.58 (6H), 3.95 (multiplet) and 4.24 (s) together 3H, about 5.5 (multiplet, J 5,6 ≈ 4.0 cps) and about 5.65 (d) together 3H, about 7.4 (5H), 7.7 (d, J x8.5 cps), 7.9 (d, J ≈ 7.5 cps), 9.1 5 (d, J z 7.5 cps).
- Preparation of disodium salts of other hydroxyphosphinylureidobenzylpenicillins.
- In a similar manner to that described in Example 1 or 3 the following compounds are prepared in yields varying from 35 to 65%:
- Disodium salt of D - 6 - {a - [3 - (hydroxy(methoxy) - phosphinyl)ureido] - p - hydroxybenzylcarboxamido}penicillanic acid having the following physicochemical properties:- IR (KBr-disc, values in cm-1): about 3280-3600 (broad and intensive), ± 2950 (sh), 1760, 1680, (sh), about 1645 to 1665, ± 1600, ± 1540, 1500, 1455, 1395, 1370 (sh), 1345 (sh), 1310-1330, 1215-1245, 1180 (sh), 1125, 1080 (intensive), 1045, 895, ± 770.
- PMR (about 5:1 mixture of d6-DMSO and DC02D, 60 Mc, DSS as reference, 8-values in ppm): 1.47 and 1.59 (6H), 3.50 (d, J ≈ 11.6 cps, 3H), 4.27 (s, 1 H), 5.44 (s) and about 5.35 to 5.6 (broadened AB-q) together 3H, 6.7 to 7.35 (q-like, 4H).
- Disodium salt of D-6-{a - [3 - (hydroxy(benzyloxy) - phosphinyl)ureido] - p - hydroxybenzylcarboxamido}penicillanic acid having the following physicochemical properties:-IR (KBr-disc, values in cm-1): about 3100-3600, shoulders at ± 3050, 2970 and 2935, 1765, 1690 (sh), 1640-1660, 1595-1615, ± 1550 (sh), 1515, 1455, 1400, 1380 (sh), 1320―1340, 1220-1260, 1180, 1135, 1090 (intensive), 1010-1035, 985,900,870,845,750,710,
- PMR (about 4:1 mixture of d6-DMSO and DC02D, 60 Mc, DSS as reference, 8-values in ppm): 1.48 and 1.60 (6H), 4.26 (s, 1 H), 4.86 (d, J ≈ 7.0 cps, 2H), 5.45 (s) and 5.35 to 5.60 (AB- q, J ≈ 4.0 cps) together 3H); 6.65 to 7.3 (q-like, J ≈ 8.2 cps) and about 7.35 together 9H.
- Thin layer chromatography Rf about 0.9 (UV positive) (silica, 95:5:5 mixture of methanol, acetic acid and water).
- Disodium salt of D - 6 - {α - [3 - hydroxy-(phenoxy) - phosphinyl)ureido] - p - hydroxybenzylcarboxamido]penicillahic acid having the following physicochemical properties:-IR (KBr-disc, values in cm-1): 3400, 1780, 1660,1610,1520,1400,1320,1220,1140, 1060, 780, 700.
PMR (mixture of d6-DMSO and DCO2D, 8-values in ppm, TMS as reference): 1.45 (s, 3H), 1.58 (s, 3H), 4.25 (s, 1 H), 5.3-5.6 (multiplet, 3H), 6.75 (d, 2H) and 7.1-7.4 (multiplet, 7H). - The physicochemical properties of the three above-mentioned compounds are identical to those of the compounds prepared in Examples 5, 6 and 10 respectively of German "Offenlegungsschrift" No. 25 46 910.
- Preparation of the trisodium salt of D - 6 - {α - [3 - (dihydroxyphosphinyl)ureido] - p - hydroxybenzylcarboxamido) - penicillanic acid.
- D - 6 - (a - amino) - p - hydroxybenzyl- carboxamidopenicillanic acid (amoxicillin) (2.17 g, 5.95 mmoles): is silylated with 3.24 ml (13.1 mmoles) of N,O-bistrimethylsilylacetamide in 15 ml of methylene chloride as a solvent. After cooling the solution to about -75°C a solution of 0.95 g (5.95 mmoles) of dichlorophosphorus- isocyanatidate in 15 ml of ethyl acetate is added dropwise in one hour. After completion of the addition the mixture is stirred for 1 hours and a mixture of 0.96 ml (11.9 mmoles) of pyridine and 15 ml of ethyl acetate is added, followed by the addition of 0.69 ml (38 mmoles) of distilled water at a temperature of -70°C. The temperature of the reaction mixture is allowed to rise to -40°C in one hour and from -40° to 0°C in 1t hours. At that temperature the reaction mixture is washed 3 times with 25 ml portions of acidified water at a pH-value of 1.5. Then 25 ml of water are added and the pH-value is brought slowly to 7 with 1 N sodium hydroxide. The layers formed are separated and the aqueous layer is freeze-dried, yielding 3.0 g of a powder of the title compound, having a purity of 80%.
Claims (12)
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EP (1) | EP0000078B1 (en) |
JP (1) | JPS543093A (en) |
DE (1) | DE2860040D1 (en) |
DK (2) | DK239278A (en) |
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GB1523278A (en) * | 1974-10-21 | 1978-08-31 | Gist Brocades Nv | Penicillanic acid derivatives |
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1978
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JPS543093A (en) | 1979-01-11 |
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