US2746959A - Diphenylethylenediamine-penicillin salt - Google Patents
Diphenylethylenediamine-penicillin salt Download PDFInfo
- Publication number
- US2746959A US2746959A US359212A US35921253A US2746959A US 2746959 A US2746959 A US 2746959A US 359212 A US359212 A US 359212A US 35921253 A US35921253 A US 35921253A US 2746959 A US2746959 A US 2746959A
- Authority
- US
- United States
- Prior art keywords
- penicillin
- salts
- grams
- water
- salt
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
Links
- 150000002960 penicillins Chemical class 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 description 61
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical class 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 33
- 229930182555 Penicillin Natural products 0.000 description 23
- -1 heterocyclic radicals Chemical class 0.000 description 23
- 229940049954 penicillin Drugs 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 150000004985 diamines Chemical class 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000012736 aqueous medium Substances 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 150000002171 ethylene diamines Chemical class 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 239000011593 sulfur Substances 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 229940056360 penicillin g Drugs 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229910000761 Aluminium amalgam Inorganic materials 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 125000005263 alkylenediamine group Chemical group 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LPHDUZQZGZACHZ-UHFFFAOYSA-N 1-(2,2-diphenylethenyl)piperidine;hydrochloride Chemical class Cl.C1CCCCN1C=C(C=1C=CC=CC=1)C1=CC=CC=C1 LPHDUZQZGZACHZ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000002947 alkylene group Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical compound C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229960002523 mercuric chloride Drugs 0.000 description 2
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229940117803 phenethylamine Drugs 0.000 description 2
- 229940048346 phenethylamine hydrochloride Drugs 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- MLXJSLOEWNSWKU-BXXMFMFASA-N (NE)-N-[(2E)-2-hydroxyimino-1-phenylethylidene]hydroxylamine Chemical compound [H]\C(=N/O)\C(=N\O)\C1=CC=CC=C1 MLXJSLOEWNSWKU-BXXMFMFASA-N 0.000 description 1
- LJHFIVQEAFAURQ-ZPUQHVIOSA-N (NE)-N-[(2E)-2-hydroxyiminoethylidene]hydroxylamine Chemical compound O\N=C\C=N\O LJHFIVQEAFAURQ-ZPUQHVIOSA-N 0.000 description 1
- JJZONEUCDUQVGR-VCFJNTAESA-N (NE)-N-[(2Z)-2-hydroxyimino-1,2-diphenylethylidene]hydroxylamine Chemical compound O\N=C(\C(=N/O)\C1=CC=CC=C1)/C1=CC=CC=C1 JJZONEUCDUQVGR-VCFJNTAESA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZTEHOZMYMCEYRM-UHFFFAOYSA-N 1-chlorodecane Chemical compound CCCCCCCCCCCl ZTEHOZMYMCEYRM-UHFFFAOYSA-N 0.000 description 1
- 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 compound 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
- OFTKFKYVSBNYEC-UHFFFAOYSA-N 2-furoyl chloride Chemical compound ClC(=O)C1=CC=CO1 OFTKFKYVSBNYEC-UHFFFAOYSA-N 0.000 description 1
- WGTASENVNYJZBK-UHFFFAOYSA-N 3,4,5-trimethoxyamphetamine Chemical compound COC1=CC(CC(C)N)=CC(OC)=C1OC WGTASENVNYJZBK-UHFFFAOYSA-N 0.000 description 1
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- 229920001817 Agar Polymers 0.000 description 1
- 229910000497 Amalgam Inorganic materials 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
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- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- XVASOOUVMJAZNJ-MBNYWOFBSA-N Penicillin K Chemical compound S1C(C)(C)[C@H](C(O)=O)N2C(=O)[C@@H](NC(=O)CCCCCCC)[C@H]21 XVASOOUVMJAZNJ-MBNYWOFBSA-N 0.000 description 1
- AWMVMTVKBNGEAK-UHFFFAOYSA-N Styrene oxide Chemical compound C1OC1C1=CC=CC=C1 AWMVMTVKBNGEAK-UHFFFAOYSA-N 0.000 description 1
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- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- 239000004480 active ingredient Substances 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
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- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 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 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 235000015424 sodium Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229940066765 systemic antihistamines substituted ethylene diamines Drugs 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- VSRBKQFNFZQRBM-UHFFFAOYSA-N tuaminoheptane Chemical compound CCCCCC(C)N VSRBKQFNFZQRBM-UHFFFAOYSA-N 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Definitions
- This invention relates to polybasic compounds, particularly to ethylenediamine derivatives and salts thereof and more particularly to penicillin salts of alpha-substituted ethylenediamines.
- An object of the invention is to prepare salts of alkylene iamine derivatives.
- a further object is to prepare watersoluble salts of Ot-SlJbStitllted ethylenediamines.
- An important object of the invention involves theproduction of sparingly water-soluble to substantially water-insoluble salts of penicillin.
- a further important object of invention is to produce penicillin compositions for oral or parenteral use utilizing, as at least one active ingredient, ethylenediamine salts of penicillin.
- the compounds of the invention involve salts of ethylenediamine derivatives wherein the latter fall within the scope of the general formula a-N -oH- c mroH- -m l. i.
- n is intended to represent a whole number from to 10 while R and R1 represent either hydrogen or aliphatic, alicyclic, aromatic or heterocyclic radicals, with or without substituents on a ring or alkyl chain, as taught by the Szabo et al. Patent No. 2,627,491, dated February 3, 1953.
- the radicals R2 and R3 are intended to represent aromatic radicals with'or without substituents, with R3 also capable of standing for hydrogen.
- radicals R and R1 represent an aliphatic radical, straightor branched-chain alkyl, alkene or alkyne radicals are contemplated.
- R and R1 represent alicyclic or heterocyclic radicals, 5- or 6-membered rings are contemplated and, insofaras the heterocyclic nucleus is concerned, these will be
- the ring elements in the hetero? cyclic nucleus may involve oxygen, sulfur or nitrogen atoms in addition to carbon.
- the aromatic radical for either R, R1, R or R3 may involve either mono-, dior tri-nuclear benzene rings with aryl, mono-arylalkyl, diarylalkyl and naphthyl radicals specifically deemed important.
- Substitutents on a ring or alkyl chain in the above tormula may comprise either alkyl, alkoxy, cyano, halogen, oxo, hydroxy, nitro, acylamino, monoor dialkylamino groups with 3 or less of such substituents contemplated, particularly where they increase the solubility of the final product unduly.
- substituents contemplated particularly where they increase the solubility of the final product unduly.
- the only substituents that must be excluded are strong acid groups, such as sulfonic acid radicals, and those having an oxidiz-- ing action as, for example, peroxides. With these two exceptions, no substituent has been found that interferes with the reaction to form penicillin salts.
- Bra is the preferred halide; and the product obtained may then be reacted with an amine as disclosed by Reaction 6.
- the radicals R, R1, Rz and R3 have the same meanings as previously merrtioned, with R1 being similar to R.
- R and R2 are the same as indicated originally with R1 being similar to R, and Rs being similar to R2. It will be noted that the a,e'-substituents will be identical by this procedure. But by using a dilferent aldehyde to give a new Schifls base, the latter when mixed in equimolal proportions with the product of reaction 7 will yield on bimolecular reduction an ethylene-v diamine in which the a and a substituents are difierent.
- Still another method for making the ethylenediamine bases permits the e d-radicals (R2 and R3) to be either similar or dissimilar to each other as in the case of Methods A and B.
- This method involves condensing a diketone with an amine which also forms a Schifis base with the release of water. The Schiifs base is then re prised using a hydrogenation catalyst. This procedure may be illustrated as follows:
- R, R1, R2 and R3 have the meanings disclosed originally with R and R1 representing similar radicals.
- a special procedure for preparing m,u'-disubstitl1ted ethylenediamines where the amino groups are unsubstituted involves the reaction of a hydroxy-keto compound with phenylhydrazine to form an osazone. The latter is then hydrogenated catalytically to form the desired C- substituted ethylenediamine, the following reactions illus- In this reaction R2 and R3 have the originally assigned meanings.
- a broad and general method for preparing ethylenediamines including those falling within the scope of the invention involves reacting an ethylenediamine with an acyl halide to form a di-amido compound.
- the di-amido compound is reduced with a reducing agent such as lithium aluminum hydride.
- the reactions may be illustrated more specifically as follows:
- R-C O-NH-CH-(iJH-NH-C ORl 2 R a
- R, R1, R2 and Rs have the meanings previously assigned, with R and R1 being similar radicals.
- This reaction is also flexible enough for preparing many of the compounds mentioned in the Szabo et a].
- the preferred reducing agent is lithium aluminum hydride
- the reduction is carried out in diethyl ether or dioxane under refluxing conditions.
- the reaction is complete, the products are cooled and the agent decomposed with water. The solvent may then be removed by distillation and the product treated with concentrated alkali metal hydroxide.
- the desired diamine base may then be reacted with an acid to form the corresponding salt.
- Salts of the ethylenediamine derivatives may be prepared from the free bases by dissolving the latter in a solvent, such as ether, to which is added the proper acid, depending on the particular salt desired.
- a solvent such as ether
- Another method for making a selected salt of the base is by reacting a salt of the base with the desired acid or a salt thereof.
- the second method involving the double decomposition of salts, is preferred since it avoids the possibility of inactivating the penicillin.
- the salts formed may be either mono-salts or di-salts,
- Organic or inorganic acids may be used in forming salts of the ethylenediamines involved in this invention.
- the most common inorganic acids are hydrochloric, sulfuric, phosphoric, nitric or hydrobrornic acids; and, of these, the ones preferred are the acids which form substantially water-soluble salts.
- the aliphatic carboxylic acids are particularly preferred because, in general, they have also been found to form water-soluble salts.
- Organic acids which are deemed useful are the lower aliphatic carboxylic acids of the mono-carboxylic, dicarboxylic, and tri-carboxylic classes. Lower alkyl, monohydroxy lower alkyl, and di-hydroxy lower alkyl carboxylic acids are deemed useful as well as chlorosubstituted compounds and unsaturated aliphatic acids.
- organic acids there may be mentioned the acids of 1 to 6 carbon atoms as formic, acetic, propionic, butyric, isovaleric, glycolic, lactic, gluconic, chloracetic, and crotonic acids as examples of the mono-. carboxylic type. found to be particularly useful are the acids of 3 to 6 carbon atoms as malonic, succinic, glutaric, adipic, malic,
- citric, isocitric, and aconitic acids are also deemed useful.
- the penicillin salts of the diamines are substantially all waterinsoluble, or, at the most, only sparingly water-soluble. It is desirable to obtain the penicillin salts as a precipitated solid from a sub stantially aqueous medium. The desired salt may then be easily separated, as by filtration, and purified by washing. Thus, the selected ethylenediamine salt is dissolved in an aqueous medium and reacted with a water-soluble salt of penicillin.
- the desired penicillin salt being either substantially water-insoluble or only sparingly water-soluble, precipitates from the aqueous medium and is separated therefrom.
- relatively water-soluble base salts are used in preparing penicillin salts therefrom, less Examples of the di-carboxylic class.
- water-soluble, sparingly water-soluble and substantially water-insoluble salts the generally accepted meaning is intended.
- a water-soluble salt it is preferred to consider a water-soluble salt to be one which will dissolve in water to the extent of at least about 5% by weight per unit of liquid volume at C.
- a sparingly water-soluble salt would be one whose solubility in water would range from just below this figure to about 1% by weight while a substantially water-insoluble salt would be one having a solubility less than about 1% by weight per unit of liquid volume at 30 C.
- any of the known penicillin salts may be combined with the poly-substituted diamines.
- the more preferred penicillin salts are the sodium or potassium salts of penicillin G.
- One or two molecules of any penicillin above indicated will unite with one molecule of the di amine, depending on the use of the monoor the di-salt.
- the diamine bases disclosed herein that form sparingly water-soluble or substantially water-insoluble penicillin salts are highly useful in that they can be used to isolate penicillin from a largely aqueous medium by reacting with this antibiotic and precipitating out as a penicillin salt. After isolation of the salt, one may easily cleave the salt in any known manner, as by treatment with an acid. This use not only permits isolation of the penicillin from an aqueous medium but is a means for purifying the penicillin from non-acidic impurities.
- the sparingly water-insoluble penicillin salts are stable in the dry state and may be kept for long periods of time without appreciable decomposition.
- the water-soluble salts of penicillin decompose quickly in a humid environment. It is possible, therefore, to convert the unstable penicillin salts to the sparingly water-soluble salts of the invention for purposes of long storage and then cleave the penicillin at any subsequent time, when and if desired.
- EXAMPLE 1 Preparation of N,N-dz'ethyl-ot-phenyl-ethylenediamine and salts thereof 60 grams styrene oxide and 45 grams ethylamine were dissolved in 200 cc. of absolute ethanol and held in a stoppered flask for 32 hours at room temperature. The solvent and excess amine were removed by concentration on the steam-bath. The residue was cooled, stirred with 100 cc. n-hexane; the precipitate, N-ethyl-p-hydroxy- 3 phenethylamine, was filtered, washed with hexane and dried. M. P. 80-81 C.
- EXAMPLE 3 Preparation of ot,ot'-diphenylethylenediamine and salts thereof Benzil (50 grams) (0.238 M) and hydroxylamine hydrochloride (45 grams) (0.65 M) are dissolved in 400 cc. of ethanol to which is added five drops of concentrated hydrochloric acid. This solution is heated on the steambath for two hours, then cooled and the dioxime filtered and dried. M. P. 237 C.
- Benzil dioxime (20 grams) (0.083 M) is added to 200 cc. of ethanol to which is added in small portions 70. grams of sodium. To prevent solidification additional ethanol is added to keep the mass fluid. After all the sodium is added, water is added until the solution is clear; and then concentrated hydrochloric acid is added until the solution is slightly acid. The ethanol is removed by vacuum distillation. The residue is chilled; concentrated aqueous sodium hydroxide is added to free the amine which is ether extracted. The ethereal solution is dried and then hydrogen chloride gas is passed into the solution which is filtered and the product, (1J1,- diphenyl ethylenediamine dihydrochloride dihydrate, dried. M. P. 248-9 C.
- EXAMPLE 4 Preparation of N,N-dimethyl-a,a'-diphelzylethylenediamine and salts thereof Benzil (21.0 grams) (0.1 M) is added to cold 100 cc. ethanol to which is added methylamine until the solution is clear. This solution is then subjected to catalytic hydrogenation using palladium on charcoal as a catalyst. After reduction has ceased, the solution is filtered and half the volume of ethanol removed by vacuum distillation. The residue is filtered; washed with cold ether and dried. M. P. 135-6 C. The free base is dissolved in ether and dry hydrogen chloride is passed into the solution to precipitate the diamine-dihydrochloride. M. P. 252-3 C.
- a,a'-Diphenyl-N,N-dimethylethylenediamine-dihydrochloride (1.62 grams) (0.005 M) is dissolved in 100 cc. of water to which is added potassium penicillin G (3.74 grams) (0.01 M) dissolved in 50 cc. of Water. The precipitate is filtered, water washed and dried. M. P. 177 C. Analysis: Calcd.: Nitrogen 9.2%; Found: Nitrogen 8.6%.
- the ether solution containing the benzal-Z-heptylamine (105.5 grams) (0.5 M) is added to 250 cc. of ether containing aluminum amalgam (27.0 grams). The mixture is allowed to react at room temperature and then refluxed on the steam-bath for live hours. Upon cooling and filtering the spent aluminum the ether is removed by vacuum. The oily residue is dissolved in methanol to which is added dropwise sulfuric acid to precipitate the amine-sulfate salt. Filter and dry. M. P. 256-7 C.
- EXAMPLE 8 Preparation of N,N'-dibenzyl-a,ot-diphenylethylenediamz'ne and salts thereof Benzalbenzylamine (87.5 grams) (0.5 M) is added to 500 cc. of dry ether containing aluminum amalgam (27.0 grams). The mixture is allowed to react at room temperature and then refluxed on the steam-bath for five hours. Upon cooling and filtering the spent aluminum the ether is removed by vacuum. The oily residue is dissolved in methanol to which is added dropwise sulfuric acid to precipitate the amine-sulfate salt. Filter and dry. M. P. 251 C.
- hydrobromide salt was filtered off and pressed dry (14 grams). The salt was redissolved in 200 cc. hot water and the pH adjusted to 8 with ammonium hydroxide. The free base precipitated; this was filtered off, washed with water, then dilute methanol, and dried. Recrystallized from aqueous dimethyl formamide. M. P. 1556 C. Analysis: Calcd.: Nitrogen 9.34; Found: Nitrogen 9.26.
- EXAMPLE 11 Preparation of N,N'-dz'methyl-a,a'-dibenzyl-ethylenediamine and salts thereof A reaction is carried out in similar manner to the procedure of Method C and Example 5, utilizing phenylacetaldehyde and methylamine, both dissolved in an ether solution. The product is then reduced with aluminum metal previously activated with mercuric chloride in ether solution. Following the reaction, the isolated base is then reacted with pencillin, or a salt is first formed by reaction with an acid and the acid-addition salt is reacted with a salt of penicillin to yield the corresponding ethylenediamine dipenicillin salt.
- the preceding method is quite flexible and provides a highly satisfactory method of making many substituted alkylene diamine salts including the penicillin salts.
- N,N'-dibenzylethylenediamine in high yields and of excellent purity, one merely reacts ethylenediamine with benzoyl chloride in the aforesaid manner and then reduces the benzoyl diamine compound to N, N'-dibenzylethylene diamine.
- Many other compounds of the ethylenediamine series may be prepared by the above disclosed procedures and further specific examples would merely be repetitive.
- penicillin salts of the invention are useful for therapeutic purposes and may be compounded in the same way as with other well-known penicillin salts. Thus, they may be used orally either in the form of a suspension in an aqueous vehicle, or in the form of a tablet compounded in the usual way with carriers, extenders, binders, etc.
- the salts may likewise be utilized in parenteral compositions containing either liyaluronidase or other spreading agents, or substances to slow-up the absorption of the salt, such as beeswax or aluminum mono-stearate or alumina gel.
- Suspending or carrier agents utilizable with the salts are such non-toxic synthetic hydrophilic agents as sodium carboxymethyl cellulose, polyvinylpyrrolidone, dextran, methyl cellulose, hydroxyethyl cellulose, sodium cellulose sulfate, etc.; or naturally occurring, non-toxic hydrophilic substances may be used such as various gums, for example, acacia or tragacanth, agar, pectin, gelatine, etc.
- the composition may be in the form of a dry admixture to be combined with liquid at the time of use, or may be in the form of a liquid suspension.
- Additional substances may likewise be present in the compositions.
- different penicillin salts with different degrees of water-solubility may be combined. These could involve either different alkylene diamine salts of penicillin or one or more of such salts combined with procaine penicillin or an alkali-metal salt of penicillin.
- other active therapeutic substances not necessarily penicillin salts may be combined with the alkylene diamine penicillin salts of the invention, as, for example, one or more therapeutically active sulfonamides.
Description
of the saturated type.
United States Patent O DIPH NYLETHYLElglEDIAMINE-PENICELIN ALT William F. Bruce, Havel-town, and Roy S. Hanslick and Meier E. Freed, Philadelphia, Pa., assignors to American Home Products Corporation, New York, N. Y., a corporation of Delaware No Drawing. Application June 2, 1953, Serial No. 359,212
4 Claims. (Cl. 260-2391) This invention relates to polybasic compounds, particularly to ethylenediamine derivatives and salts thereof and more particularly to penicillin salts of alpha-substituted ethylenediamines.
An object of the invention is to prepare salts of alkylene iamine derivatives. A further object is to prepare watersoluble salts of Ot-SlJbStitllted ethylenediamines. An important object of the invention involves theproduction of sparingly water-soluble to substantially water-insoluble salts of penicillin. A further important object of invention is to produce penicillin compositions for oral or parenteral use utilizing, as at least one active ingredient, ethylenediamine salts of penicillin. Other objects will become apparent from the general disclosure of the invention.
The compounds of the invention involve salts of ethylenediamine derivatives wherein the latter fall within the scope of the general formula a-N -oH- c mroH- -m l. i.
In the above formula, n is intended to represent a whole number from to 10 while R and R1 represent either hydrogen or aliphatic, alicyclic, aromatic or heterocyclic radicals, with or without substituents on a ring or alkyl chain, as taught by the Szabo et al. Patent No. 2,627,491, dated February 3, 1953. The radicals R2 and R3 are intended to represent aromatic radicals with'or without substituents, with R3 also capable of standing for hydrogen.
Where the radicals R and R1 represent an aliphatic radical, straightor branched-chain alkyl, alkene or alkyne radicals are contemplated.
When R and R1 represent alicyclic or heterocyclic radicals, 5- or 6-membered rings are contemplated and, insofaras the heterocyclic nucleus is concerned, these will be The ring elements in the hetero? cyclic nucleus may involve oxygen, sulfur or nitrogen atoms in addition to carbon. The aromatic radical for either R, R1, R or R3 may involve either mono-, dior tri-nuclear benzene rings with aryl, mono-arylalkyl, diarylalkyl and naphthyl radicals specifically deemed important.
Substitutents on a ring or alkyl chain in the above tormula may comprise either alkyl, alkoxy, cyano, halogen, oxo, hydroxy, nitro, acylamino, monoor dialkylamino groups with 3 or less of such substituents contemplated, particularly where they increase the solubility of the final product unduly. In forming salts from the ethylenediamine bases and particularly penicillin salts, the only substituents that must be excluded are strong acid groups, such as sulfonic acid radicals, and those having an oxidiz-- ing action as, for example, peroxides. With these two exceptions, no substituent has been found that interferes with the reaction to form penicillin salts.
In general, the greater the molecular weight or the more complex the substituent or substituents on the ethylenediamine molecule, the more watersinsoluble becomes the penicillin salt thereof. Since such salts are desirable for reasons as will: be more fully described below, the major hat the m r omple mo e u ar st u u e is a 9- sjni n r hs t e Pro du es, tor repar e c mmands th n lc hs, the sw s- 'jhsfh d washes Que P p i the sr hs' i t d. e v enq ia iihssf f. the imemiqm v t a t A QiBPQDnd c ntaining an alkylene oxide structpre is e cted; wi a Pr med Q s w dar m ie h reb min' g hebomphund nd changing. h h' st hr- -QX m n o p d BY ah l n iq step, a ha o: en a om r p s he. hYdIQXY d c d, fi a y, the
h o en ro p s s l r pl ced by mia tlia hY a t n he o ena ed. c m i cithe f'ui hf mm ia Q1- {1 p ima o s c ary n he me h i ,9 tra ted" the following reactions:
METHOD A METHOD B R20H(0H)-(CHr)nOH(0H)R; H-halogen R2 CH (CEZ)1A C II:RI h al. lial.
'T' H- BR He a? me E P ha]. hal. (5) R1--H OHa) CH Ra BNH; RZ ,OH-( ,OH;) -C1gt -R lie]. 7 h al. I RNH, 1 11" z a On the above reactions, n may stand for a number from 0 to 10. Reaction 4 may be carried out either with HCl or HBr, the latter being preferred. ForReaction 5,
' Bra is the preferred halide; and the product obtained may then be reacted with an amine as disclosed by Reaction 6. The radicals R, R1, Rz and R3 have the same meanings as previously merrtioned, with R1 being similar to R.
In accordanc wi refe red me hqd 0f nrhpathls the a,a'-disub'stituted ethylenedianiine bases, as aldehyde is copdensed with an amine to form a Schi'fis base with the release of water. TheSchifis base is then reduced using either aluminum or magnesium amalgam in ether as the m nute is hea ed a refluxin for some hqurs. he r actia ma h i ustr ted asfol ows:
3 METHOD In the above reactions, R and R2 are the same as indicated originally with R1 being similar to R, and Rs being similar to R2. It will be noted that the a,e'-substituents will be identical by this procedure. But by using a dilferent aldehyde to give a new Schifls base, the latter when mixed in equimolal proportions with the product of reaction 7 will yield on bimolecular reduction an ethylene-v diamine in which the a and a substituents are difierent.
Still another method for making the ethylenediamine bases permits the e d-radicals (R2 and R3) to be either similar or dissimilar to each other as in the case of Methods A and B. This method involves condensing a diketone with an amine which also forms a Schifis base with the release of water. The Schiifs base is then re duced using a hydrogenation catalyst. This procedure may be illustrated as follows:
Here, also, R, R1, R2 and R3 have the meanings disclosed originally with R and R1 representing similar radicals.
A special procedure for preparing m,u'-disubstitl1ted ethylenediamines where the amino groups are unsubstituted involves the reaction of a hydroxy-keto compound with phenylhydrazine to form an osazone. The latter is then hydrogenated catalytically to form the desired C- substituted ethylenediamine, the following reactions illus- In this reaction R2 and R3 have the originally assigned meanings.
A broad and general method for preparing ethylenediamines including those falling Within the scope of the invention involves reacting an ethylenediamine with an acyl halide to form a di-amido compound. In a second reaction, the di-amido compound is reduced with a reducing agent such as lithium aluminum hydride. The reactions may be illustrated more specifically as follows:
R-C O-NH-CH-(iJH-NH-C ORl 2 R a (Reducing In the reactions illustrated, R, R1, R2 and Rs have the meanings previously assigned, with R and R1 being similar radicals. This reaction is also flexible enough for preparing many of the compounds mentioned in the Szabo et a]. patent, previously identified. While the preferred reducing agent is lithium aluminum hydride, one may also use in this reaction lithium borohydride, sodium borohydride or potassium borohydride. The reduction is carried out in diethyl ether or dioxane under refluxing conditions. When the reaction is complete, the products are cooled and the agent decomposed with water. The solvent may then be removed by distillation and the product treated with concentrated alkali metal hydroxide. The desired diamine base may then be reacted with an acid to form the corresponding salt.
Salts of the ethylenediamine derivatives may be prepared from the free bases by dissolving the latter in a solvent, such as ether, to which is added the proper acid, depending on the particular salt desired. Another method for making a selected salt of the base is by reacting a salt of the base with the desired acid or a salt thereof.
Where penicillin salts of the ethylenediamines are desired,
the second method, involving the double decomposition of salts, is preferred since it avoids the possibility of inactivating the penicillin.
The salts formed may be either mono-salts or di-salts,
depending on the amounts of base and acid used. Thus, if one mol. equivalent each of acid and base were used, the mono-salt would be formed. On the other hand, if two mol. equivalents or an excess of acid are used with one mol. of the diamine, the di-salt would be formed. For making penicillin salts from the diamines, one would generally desire the double salt instead of the mono-salt since two mols. of penicillin would be combined when using the former whereas only one mol. of penicillin combines with the mono-salt.
Organic or inorganic acids may be used in forming salts of the ethylenediamines involved in this invention. The most common inorganic acids are hydrochloric, sulfuric, phosphoric, nitric or hydrobrornic acids; and, of these, the ones preferred are the acids which form substantially water-soluble salts. With regard to salts of organic acids, the aliphatic carboxylic acids are particularly preferred because, in general, they have also been found to form water-soluble salts.
Organic acids which are deemed useful are the lower aliphatic carboxylic acids of the mono-carboxylic, dicarboxylic, and tri-carboxylic classes. Lower alkyl, monohydroxy lower alkyl, and di-hydroxy lower alkyl carboxylic acids are deemed useful as well as chlorosubstituted compounds and unsaturated aliphatic acids. As specific examples of organic acids there may be mentioned the acids of 1 to 6 carbon atoms as formic, acetic, propionic, butyric, isovaleric, glycolic, lactic, gluconic, chloracetic, and crotonic acids as examples of the mono-. carboxylic type. found to be particularly useful are the acids of 3 to 6 carbon atoms as malonic, succinic, glutaric, adipic, malic,
tartaric, glutamic, maleic and fumaric acids. In the class of the tri-carboxylic acids, citric, isocitric, and aconitic acids are also deemed useful.
It has been found highly advantageous to prepare and use the water-soluble salts of the ethylenediamines when seeking to make penicillin salts of these bases. The reason for this lies in the fact that the penicillin salts of the diamines are substantially all waterinsoluble, or, at the most, only sparingly water-soluble. It is desirable to obtain the penicillin salts as a precipitated solid from a sub stantially aqueous medium. The desired salt may then be easily separated, as by filtration, and purified by washing. Thus, the selected ethylenediamine salt is dissolved in an aqueous medium and reacted with a water-soluble salt of penicillin. The desired penicillin salt, being either substantially water-insoluble or only sparingly water-soluble, precipitates from the aqueous medium and is separated therefrom. Where relatively water-soluble base saltsare used in preparing penicillin salts therefrom, less Examples of the di-carboxylic class.
liquid volume need be handled and, therefore, losses are likely to be less than if relatively insoluble salts were used.
In speaking of water-soluble, sparingly water-soluble and substantially water-insoluble salts, the generally accepted meaning is intended. However, in order to avoid any question as to meaning, it is preferred to consider a water-soluble salt to be one which will dissolve in water to the extent of at least about 5% by weight per unit of liquid volume at C. A sparingly water-soluble salt would be one whose solubility in water would range from just below this figure to about 1% by weight while a substantially water-insoluble salt would be one having a solubility less than about 1% by weight per unit of liquid volume at 30 C.
Any of the known penicillin salts may be combined with the poly-substituted diamines. Thus, one may use the alkali or alkaline earth metal salts of penicillin G, dihydro F, X, or penicillin K for combination with the selected diamine or salt thereof. However, the more preferred penicillin salts are the sodium or potassium salts of penicillin G. One or two molecules of any penicillin above indicated will unite with one molecule of the di amine, depending on the use of the monoor the di-salt.
The diamine bases disclosed herein that form sparingly water-soluble or substantially water-insoluble penicillin salts are highly useful in that they can be used to isolate penicillin from a largely aqueous medium by reacting with this antibiotic and precipitating out as a penicillin salt. After isolation of the salt, one may easily cleave the salt in any known manner, as by treatment with an acid. This use not only permits isolation of the penicillin from an aqueous medium but is a means for purifying the penicillin from non-acidic impurities.
Additionally, the sparingly water-insoluble penicillin salts are stable in the dry state and may be kept for long periods of time without appreciable decomposition. The water-soluble salts of penicillin, on the other hand, decompose quickly in a humid environment. It is possible, therefore, to convert the unstable penicillin salts to the sparingly water-soluble salts of the invention for purposes of long storage and then cleave the penicillin at any subsequent time, when and if desired.
As an additional discovery, many of these substantially insoluble or sparingly water-soluble salts of penicillin have been found valuable from a pharmacological aspect since they are relatively non-toxic and, when in contact with body fluids, slowly release penicillin for utilization in combat ng bacterial infections. A prolonged antibiotic edect can thus be achieved without difficulty. By the use of these new penicillin salts, one greatly reduces the number of injections required to sustain the desired blood level concentration of penicillin.
The examples given below will illustrate the invention in greater detail. It should be understood, however, that the following examples are merely for illustrative purposes and me not to be considered as limitative of the invention.
EXAMPLE 1 Preparation of N,N-dz'ethyl-ot-phenyl-ethylenediamine and salts thereof 60 grams styrene oxide and 45 grams ethylamine were dissolved in 200 cc. of absolute ethanol and held in a stoppered flask for 32 hours at room temperature. The solvent and excess amine were removed by concentration on the steam-bath. The residue was cooled, stirred with 100 cc. n-hexane; the precipitate, N-ethyl-p-hydroxy- 3 phenethylamine, was filtered, washed with hexane and dried. M. P. 80-81 C.
0.2 mole (33 grams) of the above compound was dissolved in 200 cc. cold HCCls. To this solution was added, with stirriing and cooling, 35 cc. SOClz (0.3 mole). The mixture was stirred for one hour with cooling (ice bath); a precipitate forms. The suspension was transferred to a flask fitted with. a reflux condenser, protected by a. CaClz tube and refluxed gently for one hour. Cool, filter, wash with chloroform, dry. The product, N-ethyLfl-chloro- B-phenethylamine-Hydrochloride, had a melting point of 1834 C. i i
0.15 mole (33 grams) N-ethyl-B-ch1oro-fl-phenethylamine Hydrochloride was suspended in 200 cc. refluxing isopropanol, stirred vigorously, while a solution of 310 grams ethylamine in 100 cc. isopropanol was dripped in over a 2-hour period. Refiuxed an additional 2 hours. The solvent was removed under vacuum, cooled. The solid residue was taken up in a minimum of 'hot ethanol and pH adjusted to 6 with alcoholic HCl. The'product, N,N'-diethyl-a-phenyl-ethylenediamine-Z HCl, was. ob.- tained after cooling. The product was filtered, dried and recrystallized from ethanol. M. P. 252-3" C.
3.8 grams N,N-diethyl-a-phenyl-ethylenediamine-2 HCl was dissolved in 10 cc. warm water 5'0 C.) To this was added 5.3 grams K penicillinate in 5 cc. water. Mixture chilled, supernatant decanted oif. The residue was pressed as dryas possible, then dried overnight at 0.1 mm. and recrystallized from acetone. M. P. 108-9? C.
EXAMPLE 2 Preparation of N-ethyl-B-amino-fl-phenethylamine and salts thereof 10 grams N-ethyl-fi-chloro-/3-phenethy1amine Hydrochloride was suspended in 75 cc. absolute ethanol containing 12 grams anhydrous ammonia. Sealed in pressure bottle and heated to -90 for 6 hours; cooled and filtered off ammonium chloride. The filtrate was concentrated to 40 cc., made acidic. with ethanolic HCl and concentrated to an oil identified as N-ethyl-ti-amino-t'iphenethylamine dihydrochloride.
The above compound was taken up in a minimum of water, made alkaline (40% NaOH) and ether extracted. The extract was dried over NaOH and filtered. The pH adjusted to 66.5 with glacial acetic acid and the ether removed under vacuum. The residue was dissolved in 5 cc. H2O. To this was added 15 grams K penicillin in 30 cc. H2O. Cooled. 100 cc. cold water added. A solid precipitated. This was separated, pressed dry, and vacuum dried. The dipenicillin salt of N-ethyl-fi-amino fi-phenethylamine was dissolved in acetone, bone.-b.lacked, filtered and solvent evaporated off under vacuum. M. P. -90 C.
EXAMPLE 3 Preparation of ot,ot'-diphenylethylenediamine and salts thereof Benzil (50 grams) (0.238 M) and hydroxylamine hydrochloride (45 grams) (0.65 M) are dissolved in 400 cc. of ethanol to which is added five drops of concentrated hydrochloric acid. This solution is heated on the steambath for two hours, then cooled and the dioxime filtered and dried. M. P. 237 C.
Benzil dioxime (20 grams) (0.083 M) is added to 200 cc. of ethanol to which is added in small portions 70. grams of sodium. To prevent solidification additional ethanol is added to keep the mass fluid. After all the sodium is added, water is added until the solution is clear; and then concentrated hydrochloric acid is added until the solution is slightly acid. The ethanol is removed by vacuum distillation. The residue is chilled; concentrated aqueous sodium hydroxide is added to free the amine which is ether extracted. The ethereal solution is dried and then hydrogen chloride gas is passed into the solution which is filtered and the product, (1J1,- diphenyl ethylenediamine dihydrochloride dihydrate, dried. M. P. 248-9 C.
a,u-Diphenylethylenediamine dihydrochloride dihydrate (3.21 grams) (0.01 M) 'is dissolved in 50 cc. of water to which is added potassium penicillin G (7.48 grams) (0.02 M) dissolved in 25 cc. of water. The precipitate is filtered, water washed and dried. M. P. 154 C.
7 Analysis: Calcd.: Nitrogen 9.55%; Found: Nitrogen 9.7%.
EXAMPLE 4 Preparation of N,N-dimethyl-a,a'-diphelzylethylenediamine and salts thereof Benzil (21.0 grams) (0.1 M) is added to cold 100 cc. ethanol to which is added methylamine until the solution is clear. This solution is then subjected to catalytic hydrogenation using palladium on charcoal as a catalyst. After reduction has ceased, the solution is filtered and half the volume of ethanol removed by vacuum distillation. The residue is filtered; washed with cold ether and dried. M. P. 135-6 C. The free base is dissolved in ether and dry hydrogen chloride is passed into the solution to precipitate the diamine-dihydrochloride. M. P. 252-3 C.
a,a'-Diphenyl-N,N-dimethylethylenediamine-dihydrochloride (1.62 grams) (0.005 M) is dissolved in 100 cc. of water to which is added potassium penicillin G (3.74 grams) (0.01 M) dissolved in 50 cc. of Water. The precipitate is filtered, water washed and dried. M. P. 177 C. Analysis: Calcd.: Nitrogen 9.2%; Found: Nitrogen 8.6%.
EXAMPLE 5 Preparation of N,N-di(2-heptyl)-a,m'-diphenylethylenediamine and salts thereof Benzaldehyde (53.0 grams) (0.5 M) is added with rapid stirring to 2-heptylamine (57.5 grams) (0.5 M). After a few seconds a reaction occurs. with evolution of heat and separation of water. The mixture is allowed to stand until cool, and then is added to 250 cc. of ether. The ether layer is removed leaving as residue 8.5 cc. of water.
The ether solution containing the benzal-Z-heptylamine (105.5 grams) (0.5 M) is added to 250 cc. of ether containing aluminum amalgam (27.0 grams). The mixture is allowed to react at room temperature and then refluxed on the steam-bath for live hours. Upon cooling and filtering the spent aluminum the ether is removed by vacuum. The oily residue is dissolved in methanol to which is added dropwise sulfuric acid to precipitate the amine-sulfate salt. Filter and dry. M. P. 256-7 C.
a,a-Diphenyl N,N-di(2-heptyl)ethylenediamine sulfate (5.1 grams) (0.01 M) is dissolved in 35 cc. of distilled water which is then added to potassium penicillin G (7.44 grams) (0.02 M) dissolved in 15 cc. of distilled water. The white precipitated salt of penicillin G is filtered, water washed and dried. Analysis: Sulfur: Theory 6.0%; Found 7.0%.
EXAMPLE 6 Preparation of N,N-di(n-decyl)-a,a'-diphenylethylenediamine and salts thereof a,a'-Diphenylethylenediamine (25 grams) (0.118 M) is added to toluene (80 cc.) containing n-decyl chloride (41.8 grams) (0.236 M) and refluxed on the steam-bath for four hours. The solution is cooled and filtered to remove the a,a'-diphenyl-ethylenediamine dihydrochloride. To the clear toluene solution is added hydrogen chloride gas to precipitate the di-n-decyl diphenylethylenediamine-dihydrochloride as a wax-like solid.
a,a-Diphenyl-N,N'-di-n-decylethylenediamine-dihydrochloride (1.4 grams) (0.0025 M) is dissolved in 15 cc. of water to which is added potassium penicillin G (1.87 grams) (0.005 M) dissolved in 5 cc. of water. The precipitate is filtered, water washed and dried. M. P. 118 C. Analysis: Calcd: Sulfur 5.5%; Found: Sulfur 5.7%.
EXAMPLE 7 Preparation of N,N-diphenyl-a,m'-diphenylethylenediamine and salts thereof Benzalaniline (80.0 grams) (0.44 M) is added to 500 cc. dry ether containing aluminum amalgam (27.0
grams). The mixture is allowed to react at room temperature and then refluxed on the steam-bath for five hours. Upon cooling and filtering oil the spent aluminum the ether is removed by vacuum. The oily residue is dissolved in methanol to which is added dropwise sulfuric acid to precipitate the amine-sulfate salt. Filter and dry. M. P. 215-216 C.
a, x-Diphenyl N,Ndiphenylethylenediamine sulfate (4.62 grams) (0.01 M) is dissolved in 40 cc. of distilled water which is then added to potassium penicillin G (7.44 grams) (0.02 M) dissolved in 10 cc. of distilled water. The white precipitated salt of penicillin G is filtered, water washed and dried. Anaylsis: Sulfur: Theory 6.2%; Found 6.56%.
EXAMPLE 8 Preparation of N,N'-dibenzyl-a,ot-diphenylethylenediamz'ne and salts thereof Benzalbenzylamine (87.5 grams) (0.5 M) is added to 500 cc. of dry ether containing aluminum amalgam (27.0 grams). The mixture is allowed to react at room temperature and then refluxed on the steam-bath for five hours. Upon cooling and filtering the spent aluminum the ether is removed by vacuum. The oily residue is dissolved in methanol to which is added dropwise sulfuric acid to precipitate the amine-sulfate salt. Filter and dry. M. P. 251 C.
a,a'-Diphenyl N,N- dibenzylethylenediamine sulfate (5.60 grams) (0.01 M) is dissolved in 15 cc. of distilled water which is then added to potassium penicillin G (7.44 grams) (0.02 M) dissolved in 10 cc. of distilled water. The white precipitated salt of penicillin G is filtered, water washed and dried. Analysis: Nitrogen: Theory 8.0%; Found 8.7%.
EXAMPLE 9 Preparation 0g N,N'-diethyl-oaa'-di(p-methoxyphenyl)- ethylenediamine and salts thereof was added dropwise, with stirring and gentle heating, to.
11 grams of clean, ether washed, aluminum filings, previously activated with 75 gram of mercuric chloride. After a 6 hour refluxing period the excess aluminum and a greenish mud were filtered oil. The filtrate was concentrated under vacuum to remove excess ethylamine. The residue was added to an ethereal solution of oxalic acid. The precipitate, yellow, was bone-blacked and recrystallized from isopropanol (aqueous). M. P. 204-5" C. (white). It was converted to the free base as follows: 2.3 grams of the oxalate was dissolved in 50 cc. of hot water and 5% ammonia added dropwise. Cool, stir. The free base separates as white crystals. M. P. 9192 C. The free base was dissolved in 20 cc. ether and the aqeuous filtrate extracted with two 20 cc. portions of ether. 0.5 cc. glacial acetic acid added. The ether was removed on the steam-bath and the residue taken up in 4 cc. of water. To this was added 2.6 grams of sodium penicillin in 3 cc. water. A solid product separated out, the aqueous phase decanted ofI and the residue vacuum dried over phosphorus pentoxide. M. P. -110 C.
EXAMPLE 10 Preparation of N,N'-diethyl-a,a-di(p-hydroxyphenyl)- ethylenediamine and salts thereof 12 grams N,N'-diethyl-u,a' di-p-methoxyphenyl-ethylenediamine dioxalate was suspended in cc. of 48% hydrobromit acid and refluxed for 4 hours. Cooled. The
hydrobromide salt was filtered off and pressed dry (14 grams). The salt was redissolved in 200 cc. hot water and the pH adjusted to 8 with ammonium hydroxide. The free base precipitated; this was filtered off, washed with water, then dilute methanol, and dried. Recrystallized from aqueous dimethyl formamide. M. P. 1556 C. Analysis: Calcd.: Nitrogen 9.34; Found: Nitrogen 9.26.
2 grams N,N'-diethyl-a,ot'-di(p-hydroxyphenyl)ethylenediamine was dissolved in a minimum of water acidified with 1 cc. acetic acid. To this was added 4.5 grams potassium penicillin. A solid product resulted. This was separated by decantation and dried under vacuum. The supernatant was chilled overnight. Additional crystals were obtained. The product was filtered and dried. M. P. 145-48 C.
EXAMPLE 11 Preparation of N,N'-dz'methyl-a,a'-dibenzyl-ethylenediamine and salts thereof A reaction is carried out in similar manner to the procedure of Method C and Example 5, utilizing phenylacetaldehyde and methylamine, both dissolved in an ether solution. The product is then reduced with aluminum metal previously activated with mercuric chloride in ether solution. Following the reaction, the isolated base is then reacted with pencillin, or a salt is first formed by reaction with an acid and the acid-addition salt is reacted with a salt of penicillin to yield the corresponding ethylenediamine dipenicillin salt.
EXAMPLE 12 Preparation of a-phenyl-ethylenediamine and salts thereof Phenyl glyoxime (16.4 grams) (0.1 M) is added portionwise to 250 cc. of dry ether containing lithium aluminum hydride (19.9 grams) (0.5 M) so that gentle refluxing results. After complete addition of the glyoxime the mass is refluxed on the steam-bath for four hours. Upon cooling, 25 cc. of water is added slowly to decompose the excess lithium aluminum hydride; then an excess of 30% aqueous sodium hydroxide to liberate the free diamine which is in the ether layer. The ether solution is dried over magnesium sulfate and a-phenylethylenediamine is finally precipitated as the oxalate. M. P. 149 C.
Mono-u-phenylethylenediamine-oxalate (2.25 grams) (0.01 M) is dissolved in 60 cc. of water to which is added potassium pencillin G (7.48 grams) (0.02 M) dissolved in 15 cc. of water. The gummy solid is allowed to stand for crystallization. The yield is almost quantitative. M. P. 112-3 C. Analysis: Sulfur: Calcd. 7.97%; Found 7.54%. Nitrogen: Calcd. 10.4%; Found 10.03%.
EXAMPLE 13 Preparation of N,N-difurfuryl-u,a-diphenyl-ethylenediamine and salts thereof u,a'-Diphenylethylenediamine (21.2 grams) is dissolved in trimethylamine and 2-furoyl chloride (27 grams) is added dropwise until the diamine is reacted, the reaction taking place at room temperature. After completion of the reaction, water is added, and the desired product, N,N-di-(2-furoyl)-a,ot'-diphenylethylenediamine hydrochloride, is precipitated. The free base is obtained by reacting the product with strong alkali, as, for example, sodium hydroxide solution.
Dry N,N'-di-(2-furoyl)-u,u'-diphenylethylenediamine grams) is dissolved in 150 cc. of anhydrous ether containing lithium aluminum hydride (3.8 grams) and then heated on a steam-bath to gentle reflux for 5 hours. The mixture is chilled and sufiicient water is added slowly to the mixture to decompose any lithium aluminum hydride and salts present. The ether is removed by vacuum and to the residue is added concentrated sodium hydroxide solution. The product is reacted with glacial acetic acid and the diacetate salt is isolated. The latter is then reacted with potassium penicillin G in an aqueous medium to form the dipenicillin salt of N,N'-(llf1llfl.ll'yl-u,m'-dlphenylethylenediamine.
As mentioned before, the preceding method is quite flexible and provides a highly satisfactory method of making many substituted alkylene diamine salts including the penicillin salts. Thus, if one desired to make N,N'-dibenzylethylenediamine in high yields and of excellent purity, one merely reacts ethylenediamine with benzoyl chloride in the aforesaid manner and then reduces the benzoyl diamine compound to N, N'-dibenzylethylene diamine. Many other compounds of the ethylenediamine series may be prepared by the above disclosed procedures and further specific examples would merely be repetitive.
The penicillin salts of the invention are useful for therapeutic purposes and may be compounded in the same way as with other well-known penicillin salts. Thus, they may be used orally either in the form of a suspension in an aqueous vehicle, or in the form of a tablet compounded in the usual way with carriers, extenders, binders, etc.
The salts may likewise be utilized in parenteral compositions containing either liyaluronidase or other spreading agents, or substances to slow-up the absorption of the salt, such as beeswax or aluminum mono-stearate or alumina gel. Suspending or carrier agents utilizable with the salts are such non-toxic synthetic hydrophilic agents as sodium carboxymethyl cellulose, polyvinylpyrrolidone, dextran, methyl cellulose, hydroxyethyl cellulose, sodium cellulose sulfate, etc.; or naturally occurring, non-toxic hydrophilic substances may be used such as various gums, for example, acacia or tragacanth, agar, pectin, gelatine, etc. The composition may be in the form of a dry admixture to be combined with liquid at the time of use, or may be in the form of a liquid suspension.
Additional substances may likewise be present in the compositions. Thus, where it is desired to obtain an immediate penicillin effect combined with a long-acting ef fect, different penicillin salts with different degrees of water-solubility may be combined. These could involve either different alkylene diamine salts of penicillin or one or more of such salts combined with procaine penicillin or an alkali-metal salt of penicillin. Likewise, other active therapeutic substances not necessarily penicillin salts may be combined with the alkylene diamine penicillin salts of the invention, as, for example, one or more therapeutically active sulfonamides.
Many modifications and changes within the skill of the art are contemplated without departing from the scope of the invention as defined in the appended claims.
We claim:
1. The penicillin salt of N,N-dimethy1-a,a'-diphenylethylenediamine.
2. The penicillin salt of a,a'-diphenyl-ethylenediamine.
3. The penicillin salt of N,N'-di(2-heptyl)-u,a'-diphenyl-ethylenediamine.
4. A penicillin salt of a compound having the formula References Cited in the file of this patent UNITED STATES PATENTS Granatek Dec. 11, 1951 Szabo et a1. Feb. 3, 1953
Claims (1)
- 4. A PENICILLIN SALT OF A COMPOUND HAVING THE FORMULA
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US359212A US2746959A (en) | 1953-06-02 | 1953-06-02 | Diphenylethylenediamine-penicillin salt |
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3013020A (en) * | 1958-01-24 | 1961-12-12 | Miles Lab | N,n'-bis-phenyl-alkylene-diamines |
US3223700A (en) * | 1960-06-11 | 1965-12-14 | Knoll Ag | Glycine amides |
US4159996A (en) * | 1977-10-31 | 1979-07-03 | Texaco Inc. | Preparation of alkane diamines |
US4888445A (en) * | 1984-12-13 | 1989-12-19 | L'oreal | New 2,4-dinitro- or 2-amino-4-nitro- or 2-nitro-4-amino-6-hydroxyalkylanilines, the process for preparation thereof and their use in dyeing keratinous fibres, and especially human hair |
US5521220A (en) * | 1991-11-12 | 1996-05-28 | Pfizer Inc. | Acyclic ethylenediamine derivatives |
WO2006067437A1 (en) * | 2004-12-23 | 2006-06-29 | Glaxo Group Limited | Oxygen containing heterocycles as glycine transporter inhibiting compounds |
US20080070973A1 (en) * | 2006-06-22 | 2008-03-20 | Anderton Clare L | Compounds having activity at the GlyT1 transporter |
US20080287547A1 (en) * | 2004-12-23 | 2008-11-20 | Daniel Marcus Bradley | Glycine Transport Inhibitors |
JP2009535301A (en) * | 2006-04-05 | 2009-10-01 | グラクソ グループ リミテッド | Compounds that inhibit glycine transporters and uses thereof |
CN105218380A (en) * | 2014-06-12 | 2016-01-06 | 连云港手性化学有限公司 | The preparation method of one (±)-1,2-diphenyl ethylene diamine |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2578536A (en) * | 1949-12-08 | 1951-12-11 | Bristol Lab Inc | Emetine penicillin |
US2627491A (en) * | 1950-07-15 | 1953-02-03 | Wyeth Corp | Penicillin salts of substituted alkylene diamines |
-
1953
- 1953-06-02 US US359212A patent/US2746959A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2578536A (en) * | 1949-12-08 | 1951-12-11 | Bristol Lab Inc | Emetine penicillin |
US2627491A (en) * | 1950-07-15 | 1953-02-03 | Wyeth Corp | Penicillin salts of substituted alkylene diamines |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3013020A (en) * | 1958-01-24 | 1961-12-12 | Miles Lab | N,n'-bis-phenyl-alkylene-diamines |
US3223700A (en) * | 1960-06-11 | 1965-12-14 | Knoll Ag | Glycine amides |
US4159996A (en) * | 1977-10-31 | 1979-07-03 | Texaco Inc. | Preparation of alkane diamines |
US4888445A (en) * | 1984-12-13 | 1989-12-19 | L'oreal | New 2,4-dinitro- or 2-amino-4-nitro- or 2-nitro-4-amino-6-hydroxyalkylanilines, the process for preparation thereof and their use in dyeing keratinous fibres, and especially human hair |
US5521220A (en) * | 1991-11-12 | 1996-05-28 | Pfizer Inc. | Acyclic ethylenediamine derivatives |
WO2006067437A1 (en) * | 2004-12-23 | 2006-06-29 | Glaxo Group Limited | Oxygen containing heterocycles as glycine transporter inhibiting compounds |
US20080287547A1 (en) * | 2004-12-23 | 2008-11-20 | Daniel Marcus Bradley | Glycine Transport Inhibitors |
US7745642B2 (en) | 2004-12-23 | 2010-06-29 | Glaxo Group Limited | Glycine transport inhibitors |
JP2009535301A (en) * | 2006-04-05 | 2009-10-01 | グラクソ グループ リミテッド | Compounds that inhibit glycine transporters and uses thereof |
US20080070973A1 (en) * | 2006-06-22 | 2008-03-20 | Anderton Clare L | Compounds having activity at the GlyT1 transporter |
CN105218380A (en) * | 2014-06-12 | 2016-01-06 | 连云港手性化学有限公司 | The preparation method of one (±)-1,2-diphenyl ethylene diamine |
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