DK167319B1 - Stabilt hydrat af et penicillinderivat og fremgangsmaade til fremstilling deraf - Google Patents
Stabilt hydrat af et penicillinderivat og fremgangsmaade til fremstilling deraf Download PDFInfo
- Publication number
- DK167319B1 DK167319B1 DK500887A DK500887A DK167319B1 DK 167319 B1 DK167319 B1 DK 167319B1 DK 500887 A DK500887 A DK 500887A DK 500887 A DK500887 A DK 500887A DK 167319 B1 DK167319 B1 DK 167319B1
- Authority
- DK
- Denmark
- Prior art keywords
- methyl
- asparaginylamoxicillin
- solution
- water
- trihydrate
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 10
- 150000002960 penicillins Chemical class 0.000 title description 2
- 150000004684 trihydrates Chemical class 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- -1 N-methyl-carbamoyl Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000012736 aqueous medium Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- HDICEEFBWQQCPM-UHFFFAOYSA-N O.CCCCCC(C)C(O)=O Chemical compound O.CCCCCC(C)C(O)=O HDICEEFBWQQCPM-UHFFFAOYSA-N 0.000 claims 2
- BHELIUBJHYAEDK-OAIUPTLZSA-N Aspoxicillin Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3[C@H](C(C)(C)S[C@@H]32)C(O)=O)=O)NC(=O)[C@H](N)CC(=O)NC)=CC=C(O)C=C1 BHELIUBJHYAEDK-OAIUPTLZSA-N 0.000 claims 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- ATPVSNJCPGPJGO-XUXOXWKISA-N 6-[[(1s)-2-[[(2s)-4-amino-2-(methylamino)-4-oxobutanoyl]amino]-1-(4-hydroxyphenyl)-2-oxoethyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound C1([C@H](NC2C(N3C(C(C)(C)SC32)C(O)=O)=O)C(=O)NC(=O)[C@H](CC(N)=O)NC)=CC=C(O)C=C1 ATPVSNJCPGPJGO-XUXOXWKISA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000001159 Fisher's combined probability test Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical class [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010979 pH adjustment Methods 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229940032007 methylethyl ketone Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- CFDQFHUYEPNDFU-UHFFFAOYSA-N 2-methylheptanoic acid trihydrate Chemical compound O.O.O.CCCCCC(C)C(O)=O CFDQFHUYEPNDFU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Natural products NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- QIOZLISABUUKJY-UHFFFAOYSA-N Thiobenzamide Chemical compound NC(=S)C1=CC=CC=C1 QIOZLISABUUKJY-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 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 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 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 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 235000019553 satiation Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 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
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- C07D499/21—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 with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
i DK 167319 B1
Den foreliggende opfindelse angår et stabilt hydrat af et penicillinderivat og en fremgangsmåde til fremstilling deraf. Nærmere betegnet angår den foreliggende opfindelse krystallinsk (2S, 5R, 6R)-6-{(2R)-2-[{2R)-2-amino-3-(N-methylcarbamoyl)propionamidoJ-2-(p-hydroxyphenyl)-5 acetamido}-3,3-diméthyl-7-oxo-4-thia-l-azabicyclo[3,2,0]heptan-2-carb-oxylsyretri hydrat (i det følgende betegnet krystallinsk tri hydrat af "N4-methyl-D-asparaginylamoxicillin") med formlen (R) (R) (R)(R) .Sv 10 CH NHCOCH -CH-CO-NH-CH-CO-NH--f \ /CH_ · 3H_0 3 2 I V J Å «2 ' O ol—N· .(S/ XcH3
OH COOH
15 N^-methyl-D-asparaginylamoxicillin er nyttigt som kemoterapeutisk middel, fordi det viser stærk antimikrobiel aktivitet mod både gram- 4 positive og gram-negative mikroorganismer. Det er kendt, at N -methyl-D- asparaginylamoxicillin kan fremstilles (i) ved enten at kondensere 6- 20 aminopeniciliansyre med D-2-(D-2-amino-3-N-methylcarbamoylpropionamido)- 2-p-hydroxyphenyleddikesyre eller (ii) ved at kondensere amoxicillin med D-2-amino-3-N-methylcarbamoylpropionsyre (US patentskrift nr.
4 4.053.609). Det er også kendt, at rent N -methyl-D-asparaginylamoxicillin kan opnås som amorft anhydrat ved at bringe en vandig opløsning 4 25 af råt N -methyl-D-asparaginylamoxicillin i kontakt med en ikke-polær makroporøs adsorptionsharpiks, eluere det adsorberede produkt og lyofi-lisere eluatet indeholdende det ønskede produkt (US patentskrift nr. 4.313.875). Det amorfe N4-methyl-D-asparaginylamoxicillinanhydrat opnået ved den kendte teknik opsuger imidlertid gradvist fugt fra den omgivende 30 atmosfære, og det er ikke stabilt, med mindre det opbevares beskyttet mod fugt og lys.
4
Det har nu vist sig, at N -methyl-D-asparaginylamoxicillin kan opnås i form af et krystallisk trihydrat. Det hidtil ukendte trihydrat af 4 N -methyl-D-asparaginylamoxicillin har bedre egenskaber med hensyn til 35 krystallinsk form og stabilitet. Navnlig har det vist sig, at det hidtil ukendte trihydrat har en veldefineret krystallisk struktur, og det har vist sig bemærkelsesværdigt stabilt ved opbevaring. Disse egenskaber gør trihydratet af N^-methyl-D-asparaginylamoxicillin værdifuldt til farma- DK 167319 B1 2 ceutisk anvendelse.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man ind- 4 stiller pH-værdien af en opløsning af N -methyl-D-asparaginylamoxicillin eller et salt deraf i et vandigt medium til 3-6, og udkrystal1 i serer det 5 ønskede tri hydrat.
N -methyl-D-asparaginylamoxicillin, som anvendes ved fremgangsmåden ifølge den foreliggende opfindelse, kan enten være et råt produkt fremstillet ved den i US patentskrift nr. 4.053.609 beskrevne fremgangsmåde eller et amorft anhydrat fremstillet ved den i US patentskrift nr.
10 4.313.875 beskrevne fremgangsmåde. Eksempler på salte af N^-methyl-D-asparaginylamoxicillin omfatter alkalimetalsalte (f.eks. natrium- eller kaliumsalte), jordal kalimetal salte (f.eks. calcium- eller magnesiumsalte), aminosyresalte (f.eks. L-lysin-, L-arginin-, L-histidin- eller L-ornithinsalte) eller salte med organiske baser (f.eks. triethylamin, 15 tributylamin eller N-methylmorfolin). Vand, vandige lavere alkanoler (f.eks. vandig methanol, vandig ethanol eller vandig propanol) eller vandige lavere alkanoner (f.eks. vandig acetone eller vandig methyl-ethyl keton) anvendes fortrinsvis som det vandige medium. Fra et industrielt synspunkt er vand det mest foretrukne medium.
20 Ved udøvelsen af fremgangsmåden ifølge opfindelsen indstilles op løsningen af N^-methyl-D-asparaginylamoxicillin eller et salt deraf i det vandige medium først til en pH på 3-6, fortrinsvis 3,5-5,5. Når 4 f.eks. den frie form af N -methyl-D-asparaginylamoxicillin anvendes, udføres pH-indsti11 ingen ved at sætte syre eller alkali til opløsningen 25 af forbindelsen. Når N^-methyl-D-asparaginylamoxicillin anvendes i form af et salt deraf, udføres pH-indstillingen ved at sætte syre til opløsningen af saltet. Eksempler på syrer, som kan anvendes til pH-indstil-ling, omfatter mineralsyrer, såsom saltsyre eller svovlsyre, eller organiske syrer, såsom citronsyre, og eksempler på alkali omfatter al kali-30 metal hydroxider, såsom natriumhydroxid eller kaliumhydroxid. Efter at 4 opløsningen af N -methyl-D-asparaginylamoxicillin eller et salt deraf er indstillet til den ønskede pH-værdi, udkrystalliseres det ønskede trihydrat fra opløsningen. Krystallisation af det ønskede trihydrat kan fortrinsvis udføres ved afkøling eller kondensering af opløsningen eller 35 ved tilsætning af et vandblandbart organisk opløsningsmiddel eller ved en kombination deraf. Når f.eks. krystallisationen udføres ved afkøling af opløsningen, foretrækkes det, at opløsningen, som forud er blevet opvarmet til ca. 30-70°C, afkøles til 0-10eC. Når krystallisation DK 167319 B1 3 udføres ved kondensering, foretrækkes det, at opløsningen af N^-methyl-D-asparaginylamoxicillin eller et salt deraf kondenseres indtil koncentrationen af forbindelsen er 10-45 vægt%, navnlig ca. 30-40 vægt%. Endvidere når krystallisation udføres ved tilsætning af et vandblandbart 5 organisk opløsningsmiddel, kan det vandblandbare organiske opløsnings- 4 middel med mellemrum eller kontinuerligt sættes til opløsningen af N -methyl-D-asparaginylamoxicillin eller dets salt. Eksempler på sådanne vandblandbare organiske opløsningsmidler omfatter lavere alkanoler, såsom methanol, ethanol eller propanol, og lavere al kanoner, såsom acetone 10 eller methyl ethyl keton. Det udfældede tri hydrat kan let separeres ved konventionel faststof-væske-separationsteknik, såsom filtrering eller centrifugering.
4
Som nævnt ovenfor optager N -methyl-D-asparaginylamoxicillin-trihydrat ifølge opfindelsen vanskeligt fugtighed fra den omgivende 15 atmosfære og er stabilt ved opbevaring. Tri hydratet er derfor bedre end det kendte amorfe anhydrat som grundsubstans for medicin. Endvidere er trihydratet ifølge opfindelsen let at håndtere, fordi massefylden og elektrisk ladning af trihydratet er mindre end ved det kendte amorfe anhydrat. Endvidere er trihydratet ifølge opfindelsen karakteriseret ved, 20 at det let kan fremstilles i industriel skala på grund af dets gode krystal1 i sati onsegenskaber.
Forsøg (Stabilitetstest) 25 Krystallisk N4-methyl-D-asparaginylamoxici11 intrihydrat ifølge op findelsen og amorft N^-methyl-D-asparaginylamoxici11 inanhydrat (fremstillet i overensstemmelse med den i US patentskrift nr. 4.313.875 beskrevne fremgangsmåde) henstilledes ved 40eC i forseglede rør i 5, 10, 15 eller 30 dage, og hver forbindelses stabilitet vurderedes ved at måle 30 indholdet af N4-methyl-D-asparaginylamoxicillin. Resultaterne er vist i tabel 1 nedenfor.
4
Indholdet af N -methyl-D-asparaginylamoxicillin måltes ved højtryksvæskekromatografi (HPLC) under de nedenfor anførte betingelser.
35 Kolonne: Octadecylsilan (4,6 mm øX 150 mm)
Mobil fase: phosphatpuffer-acetonitril (87:13)(pH:3,0)
Flowhastighed: 1,0 ml/minut
Kolonnetemperatur: 40*C
4 DK 167319 B1 4
Indhold af N -methyl-D-aspara-Resterende mængde (%) ginylamoxicillin efter henstand N4-methyl-D- = X 100 4 asparaginylamoxicillin Indhold af N -methyl-D-aspara- 5 ginylamoxicillin før henstand
Tabel 1 ,-1- i 10 I J Resterende mængde N -methyl-D-aspara- | I I ginylamoxicillin (%) | ITestforbindelse |-j I I Henstandsperioden før test- | I nr. I forbindelsen (dage) |
15 I I I
I I-1-1-r~"—I-1 I I På starttidspunkt | 5 | 10 | 15 | 30 | I-1-1—I-1-1-1 I i. I 100,0 |ioo,o|ioo,o|ioo,o| 99,5 | 20 i-1-1-1-1-1-1 I 2. I 100,0 I 91,o| 90,o| 88,51 85,5 | I_I_I_I_I_I-1 25 Testforbindelse 1. Krystallisk N4-methyl-D-asparaginylamoxicillin-trihydrat (forbindelsen ifølge opfindelsen).
30 2. Amorft anhydrat af N4-methyl-D-asparaginylamoxicillin (fremstillet i overensstemmelse med US patentskrift nr. 4.313.875).
Eksempel 1 35 Amorft N4-methyl-D-asparaginylamoxicillinanhydrat (10 g) opløstes ved 40eC i vand (50 ml). Opløsningen indstilledes til pH 4,0 med fortyndet saltsyre og omrørtes ved 30eC i en time og afkøledes derefter til 5°C. De resulterende udfældninger opsamledes ved filtrering, vaskedes DK 167319 Bl 5 med vand og tørredes, hvorved N^-methyl-D-asparaginy]amoxiciHintrihydrat (8 g) opnåedes som et hvidt krystallinsk faststof.
Vandindhold (Karl Fisher metode): 10,05% (svarer til 3 mol). Produktindhold (HPLC): 99,7%.
5 [a]p° + 179,5° (c=l,0, vand).
Infrarødt spektrum: vist i fig. 1.
Røntgen-pulverdiffraktionsmønster: fremgår af tabel 2 nedenfor (Energikilde; Cu:Ni, 40KV, 35mA, λ = 1,5405).
10 I tabel 2 er til sammenligning også vist røntgen-pulverdiffrak- 4 tionsmønsteret for amorft N -methyl-D-asparaginylamoxicillinanhydrat.
Tabel 2 DK 167319 B1 6 1-"-1-1 I Krystallisk N -methyl-D- | Amorft N4-methyl-D- | J asparaginylamoxicillin | asparaginylamoxicillin | 5 I tri hydrat | anhydrat | I-1-1 I "d" værdi Relativ | "d" værdi Relativ | I intensitet* | intensitet* | I-1-1 10 I 15,77 w I 5,94 vw | I 10,77 w I 5,50 vw j I 9,21 vw I 4,57 vw j
I 7,89 w I I
I 5,98 s I I
15 I 5,57 vs I I
I 5,34 w I j
I 4,98 vw I I
I 4,62 vs I j
I 4,39 w I I
20 I 4,23 m | j
I 3,97 m I I
I 3,77 vw I I
I 3,64 vw I I
I 3,54 w I I
25 I 3,48 w I I
I 3,37 w I I
I 3,25 m I I
I 3,13 vw I I
I 3,01 w I I
30 I 2,86 vw I I
I 2,81 vw I I
I 2,65 vw I I
I 2,60 vw I I
I 2,40 w I I
35 I-1-1 * De relative intensiteter vurderedes ved at sammenligne linieintensiteterne mod et sæt af standarder: vs=meget stærk, s=stærk, m=medium, w=svag, vw=meget svag DK 167319 B1 7
Eksempel 2
Amorft N^-methyl-D-asparaginylamoxicillinanhydrat (10 g) opløstes i vand (500 ml) [opløsningens pH-værdi var 4,3]. Opløsningen koncentreredes under reduceret tryk til 250 g, og ethanol (250 g) tilsattes. De 5 resulterende udfældninger opsamledes ved filtrering og tørredes, hvorved N^-methyl-D-asparaginylamoxicillintrihydrat (5 g) opnåedes som et hvidt krystallinsk faststof.
Vandindhold (Karl Fisher metode): 10,74% (svarer til 3 mol). Produktindhold (HPLC): 99,3%.
10 [<*]j-0 + 179,3° (c= 1,0, vand).
Eksempel 3
Vand (70 ml) sattes til amorft N^-methyl-D-asparaginylamoxicillin-anhydrat (22,2 g), og en vandig 20% natriumhydroxidopløsning (5,4 ml)
15 tilsattes dråbevist til opløsning af anhydratet. Aktivkul sattes til opløsningen, og blandingen filtreredes. Filtratet indstilledes til pH
3,5 med 20% saltsyre (ca. 5,5 ml). De resulterende udfældninger opsamle-des ved filtrering og tørredes, hvorved N -methyl-D-asparaginylamoxi-cillintrihydrat (17 g) opnåedes som et hvidt krystallinsk faststof.
20 Vandindhold (Karl Fisher metode): 10,21% (svarer til 3 mol).
Produktindhold (HPLC): 99,7%.
[a]p° + 179,9° (c= 1,0, vand).
Eksempel 4 25 Thiobenzamid (20,5 g) opløstes i ethanol (290 ml), og (2S, 5R, 6R)- 6-{(2R)-2-[(2R)-2-(o-ni trophenylsulfenyl)-amino-3-(N-methylcarbamoyl)-propionamido]-2-(p-hydroxyphenyl)-acetamido}-3,3-dimethyl-7-oxo-4-thia- l-azabicyclo[3,2,0]heptan-2-carboxylsyretrihydrat (32,21 g) sattes dertil. Blandingen omrørtes ved 15-20°C i 17 timer for at fjerne den amino-30 beskyttende gruppe (det vil sige o-nitrophenylsulfenylgruppen). Udfæld-ningerne (det vil sige N -methyl-D-asparaginylamoxicillin) opsamledes ved filtrering, tørredes og sattes til en suspension af aktivkul (3 g) i vand (50 ml). Suspensionen indstilledes til pH 5,5 med 1% saltsyre (ca.
3 ml) og omrørtes ved stuetemperatur i en time. Uopløselige materialer 35 frafiltreredes, og filtratet koncentreredes under reduceret tryk, indtil 4 koncentrationen af N -methyl-D-asparaginylamoxicillin var 40 vægt%. Den koncentrerede opløsning omrørtes ved 30°C i en time og afkøledes derefter til 5°C. De resulterende udfældninger opsamledes ved filtrering og DK 167319 B1 8 tørredes, hvorved N^-methyl-D-asparaginylamoxicillintrihydrat (12,5 g) opnåedes som et hvidt krystallinsk faststof.
Vandindhold (Karl Fisher metode): 10,1% (svarer til 3 mol). Produktindhold (HPLC): 99,7%.
5 [a]p° + 180,0° (c= 1,0, vand).
Claims (5)
1. Krystallinsk (2S, 5R, 6R)-6-{(2R)-2-[(2R)-2-amino-3-(N-methyl-carbamoy1)prop i onami do]-2-(p-hydroxypheny1)acetami do}-3,3-d i methy1 -7- 5 oxo-4-thi a-1-azabi cyclo [3,2,0]heptan-2-carboxylsyretri hydrat.
2. Fremgangsmåde til fremstilling af krystallinsk (2S, 5R, 6R)-6-{(2R)-2-[(2R)-2-amino-3-(N-methylcarbamoyl)propi onamido]-2-(p-hydroxy-phenyl)-acetamido}-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3,2,0]heptan- 10 2-carboxylsyretri hydrat,KENDETEGNET ved, at man indstiller pH-værdien af en opløsning af (2S, 5R, 6R)-6-{(2R)-2-[(2R)-2-amino-3-(N-methylcarb-amoyl)propionamido]-2-(p-hydroxyphenyl)acetamido}-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3,2,0]heptan-2-carboxylsyre eller et salt deraf i et vandigt medium til 3-6, og udkrystalliserer det ønskede trihydrat. 15
3. Fremgangsmåde ifølge krav 2, KENDETEGNET ved, at pH-værdien indstilles til 3,5-5,5.
4. Fremgangsmåde ifølge krav 2-3, KENDETEGNET ved, at det vandige 20 medium er vand, en vandig lavere alkanol eller en vandig lavere alkanon.
5. Fremgangsmåde ifølge krav 4, KENDETEGNET ved, at udkrystallisationen udføres ved afkøling eller kondensering af opløsningen eller ved tilsætning af et vandblandbart organisk opløsningsmiddel. 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61226423A JPS6379888A (ja) | 1986-09-24 | 1986-09-24 | ペニシリン誘導体の安定型水和物 |
| JP22642386 | 1986-09-24 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK500887D0 DK500887D0 (da) | 1987-09-23 |
| DK500887A DK500887A (da) | 1988-03-25 |
| DK167319B1 true DK167319B1 (da) | 1993-10-11 |
Family
ID=16844890
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK500887A DK167319B1 (da) | 1986-09-24 | 1987-09-23 | Stabilt hydrat af et penicillinderivat og fremgangsmaade til fremstilling deraf |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US4866170A (da) |
| EP (1) | EP0261823B1 (da) |
| JP (1) | JPS6379888A (da) |
| KR (1) | KR920003902B1 (da) |
| CN (1) | CN1021225C (da) |
| AT (2) | ATE59655T1 (da) |
| AU (1) | AU592467B2 (da) |
| CA (1) | CA1286285C (da) |
| DE (1) | DE3766921D1 (da) |
| DK (1) | DK167319B1 (da) |
| ES (1) | ES2026545T3 (da) |
| FI (1) | FI86853C (da) |
| GR (1) | GR3001274T3 (da) |
| HK (1) | HK42093A (da) |
| HU (1) | HU196810B (da) |
| IE (1) | IE60042B1 (da) |
| IL (1) | IL83786A (da) |
| MY (1) | MY102553A (da) |
| NO (1) | NO169717C (da) |
| PH (1) | PH23644A (da) |
| PT (1) | PT85773B (da) |
| SG (1) | SG15393G (da) |
| SU (1) | SU1517764A3 (da) |
| ZA (1) | ZA876739B (da) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5375123A (en) * | 1993-02-05 | 1994-12-20 | Telefonakitebolaget L. M. Ericsson | Allocation of channels using interference estimation |
| US6473602B1 (en) | 1996-10-28 | 2002-10-29 | Ericsson Inc. | Mobile assisted handoff in radiocommunication systems |
| PE20000879A1 (es) * | 1998-04-29 | 2000-09-23 | Dsm Nv | METODO PARA CRISTALIZAR UN ANTIBIOTICO ß-LACTAMICO |
| KR101879756B1 (ko) * | 2016-11-30 | 2018-08-17 | 주식회사 지앤지비 | 욕실용 난방기 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL6705789A (da) * | 1967-03-08 | 1968-09-09 | ||
| GB1241844A (en) * | 1968-08-23 | 1971-08-04 | Beecham Group Ltd | Penicillins |
| US4053609A (en) * | 1975-09-12 | 1977-10-11 | Tanabe Seiyaku Co., Ltd. | Penicillins and processes for preparing the same |
| JPS5640686A (en) * | 1979-09-11 | 1981-04-16 | Tanabe Seiyaku Co Ltd | Purification of penicillin derivative |
-
1986
- 1986-09-24 JP JP61226423A patent/JPS6379888A/ja active Granted
-
1987
- 1987-09-01 IE IE234687A patent/IE60042B1/en not_active IP Right Cessation
- 1987-09-03 ES ES198787307794T patent/ES2026545T3/es not_active Expired - Lifetime
- 1987-09-03 DE DE8787307794T patent/DE3766921D1/de not_active Expired - Lifetime
- 1987-09-03 AT AT87307794T patent/ATE59655T1/de not_active IP Right Cessation
- 1987-09-03 EP EP87307794A patent/EP0261823B1/en not_active Expired - Lifetime
- 1987-09-04 IL IL83786A patent/IL83786A/xx not_active IP Right Cessation
- 1987-09-09 ZA ZA876739A patent/ZA876739B/xx unknown
- 1987-09-11 PH PH35805A patent/PH23644A/en unknown
- 1987-09-12 CN CN87106308A patent/CN1021225C/zh not_active Expired - Fee Related
- 1987-09-18 US US07/098,364 patent/US4866170A/en not_active Expired - Fee Related
- 1987-09-22 AU AU78827/87A patent/AU592467B2/en not_active Ceased
- 1987-09-22 MY MYPI87001873A patent/MY102553A/en unknown
- 1987-09-23 CA CA000547616A patent/CA1286285C/en not_active Expired - Lifetime
- 1987-09-23 HU HU874281A patent/HU196810B/hu not_active IP Right Cessation
- 1987-09-23 DK DK500887A patent/DK167319B1/da not_active IP Right Cessation
- 1987-09-23 FI FI874152A patent/FI86853C/fi not_active IP Right Cessation
- 1987-09-23 SU SU874203390A patent/SU1517764A3/ru active
- 1987-09-23 PT PT85773A patent/PT85773B/pt not_active IP Right Cessation
- 1987-09-23 NO NO873969A patent/NO169717C/no not_active IP Right Cessation
- 1987-09-24 KR KR1019870010566A patent/KR920003902B1/ko not_active Expired
- 1987-10-15 AT AT0273187A patent/AT389311B/de not_active IP Right Cessation
-
1991
- 1991-01-03 GR GR90400968T patent/GR3001274T3/el unknown
-
1993
- 1993-02-11 SG SG153/93A patent/SG15393G/en unknown
- 1993-04-29 HK HK420/93A patent/HK42093A/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
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| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |