AP768A - Method for preparing streptogramines. - Google Patents
Method for preparing streptogramines. Download PDFInfo
- Publication number
- AP768A AP768A APAP/P/1997/001121A AP9701121A AP768A AP 768 A AP768 A AP 768A AP 9701121 A AP9701121 A AP 9701121A AP 768 A AP768 A AP 768A
- Authority
- AP
- ARIPO
- Prior art keywords
- radical
- periodate
- hydrogen atom
- ethyl
- medium
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 15
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002609 medium Substances 0.000 claims abstract description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- 239000012736 aqueous medium Substances 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 108010034396 Streptogramins Proteins 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 150000003254 radicals Chemical class 0.000 claims description 7
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 6
- 229940041030 streptogramins Drugs 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- -1 oxo radical Chemical class 0.000 claims description 4
- 230000017858 demethylation Effects 0.000 claims description 3
- 238000010520 demethylation reaction Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 6
- 230000001335 demethylating effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- YVMBAUWDIGJRNY-BESUKNQGSA-N 4o8o7q7iu4 Chemical compound C1C(=O)C[C@H](O)\C=C(/C)\C=C\CNC(=O)\C=C\[C@@H](C)[C@@H](C(C)C)OC(=O)C2=CCCN2C(=O)C2=COC1=N2.N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2CCC(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O YVMBAUWDIGJRNY-BESUKNQGSA-N 0.000 description 8
- 108010079780 Pristinamycin Proteins 0.000 description 8
- RLNUPSVMIYRZSM-UHFFFAOYSA-N Pristinamycin Natural products CC1OC(=O)C(C=2C=CC=CC=2)NC(=O)C2CC(=O)CCN2C(=O)C(CC=2C=CC(=CC=2)N(C)C)CCN(C)C(=O)C2CCCN2C(=O)C(CC)NC(=O)C1NC(=O)C1=NC=CC=C1O RLNUPSVMIYRZSM-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 229960003961 pristinamycin Drugs 0.000 description 8
- DAIKHDNSXMZDCU-OUDXUNEISA-N pristinamycin-IIA Natural products CC(C)[C@H]1OC(=O)C2=CCCN2C(=O)c3coc(CC(=O)C[C@H](O)C=C(C)C=CCNC(=O)C=C[C@@H]1C)n3 DAIKHDNSXMZDCU-OUDXUNEISA-N 0.000 description 8
- JOOMGSFOCRDAHL-XKCHLWDXSA-N pristinamycin-IIB Natural products CC(C)[C@@H]1OC(=O)[C@H]2CCCN2C(=O)c3coc(CC(=O)C[C@@H](O)C=C(C)C=CCNC(=O)C=C[C@H]1C)n3 JOOMGSFOCRDAHL-XKCHLWDXSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- PCOXSOQWQVRJCH-RIECGXCRSA-N efepristin Chemical compound N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(NC)=CC=2)C(=O)N2CCC(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O PCOXSOQWQVRJCH-RIECGXCRSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 5
- YGXCETJZBDTKRY-DZCVGBHJSA-N pristinamycin IA Chemical compound N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2CCC(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O YGXCETJZBDTKRY-DZCVGBHJSA-N 0.000 description 5
- BYRKDHSWMQLYJB-UHFFFAOYSA-N pristinamycin IC Chemical compound CN1C(=O)C2CCCN2C(=O)C(C)NC(=O)C(NC(=O)C=2C(=CC=CN=2)O)C(C)OC(=O)C(C=2C=CC=CC=2)NC(=O)C2CC(=O)CCN2C(=O)C1CC1=CC=C(N(C)C)C=C1 BYRKDHSWMQLYJB-UHFFFAOYSA-N 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- PCOXSOQWQVRJCH-UHFFFAOYSA-N vernamycin-Bbeta Natural products CC1OC(=O)C(C=2C=CC=CC=2)NC(=O)C2CC(=O)CCN2C(=O)C(CC=2C=CC(NC)=CC=2)N(C)C(=O)C2CCCN2C(=O)C(CC)NC(=O)C1NC(=O)C1=NC=CC=C1O PCOXSOQWQVRJCH-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- YGXCETJZBDTKRY-UHFFFAOYSA-N Pristinamycin Component I A Natural products CC1OC(=O)C(C=2C=CC=CC=2)NC(=O)C2CC(=O)CCN2C(=O)C(CC=2C=CC(=CC=2)N(C)C)N(C)C(=O)C2CCCN2C(=O)C(CC)NC(=O)C1NC(=O)C1=NC=CC=C1O YGXCETJZBDTKRY-UHFFFAOYSA-N 0.000 description 2
- 108010015795 Streptogramin B Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- PYVXLMQALOZKES-UHFFFAOYSA-M tetrabutylazanium;periodate Chemical compound [O-]I(=O)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC PYVXLMQALOZKES-UHFFFAOYSA-M 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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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)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
A method for preparing streptogramines of general formula (I), wherein Ri is methyl or ethyl, R2 is H and X and Y togemei form an oxo radical or Ri is ethyl. R2 and X are H and Y is Hor OH, or else R1 is ethyl. R2 is OH and X and Y together form an oxo radical, by demethylating a synergistin derivative of general formula (II). wherein RI. R2. X and Y are as defined abovc, by means of a treatment with a periodate in an acetic medium, follow by a treatment in an aqueous medium.
Description
PROCESS FOR
THE PREPARATION OF STREPTOGRAMINS
The present invention relates to a novel process for the preparation of streptogramins of general formula:
in which:
either the radical Rx Represents a methyl or ethyl group, the radical R2 Represents a hydrogen atom and X and Y together ftrm an oxo radical, i , or Rx represents an ethyl radical, R2 and X 10 represent a hydrogen atom and Y represents a hydrogen atoRa or a hydroxyl radical, or Rx represents an ethyl radical, R2 represents a hydroxyl radical and X and Y together form an oxo radical, from a synergistih derivative of general formula:
AP. ΰ ΟΊ6 8
in which the radicals Rx, R2, X and Y are as defined above .
Streptogramins are a known class of compounds comprising components of group B [to which the products of general formula (I) belong] which, when combined with components of group A, bring about a synergism of the antimicrobial action.
The product of general formula (I) for which Rx is ethyl and R2 is hydrogen is known under the name of pristinamycin IB. The product of general formula (I) for which Rx is methyl and R2 is hydrogen is known under the name of vernamycin Βδ. The product of general formula (II) for which Rx is ethyl and R2 is hydrogen is known under the name of pristinamycin IA. The product of general formula (II) for which Rx is methyl and R2 is hydrogen is known under the name of pristinamycin IC or vernamycin Βγ. The product of general formula (II) for which Rx is ethyl and R2 is hydroxyl is known under the name of pristinamycin ID.
General methods of demethylation were already
AP/P/ 9 7/01 121
AP.00768 known, for examplje such as the methods described in Tet. Lett., 18, 1567 (1977); J. Org. Chem., 49, 2795 (1984); J. C. S. jchem. Comm. , 905 (1989), Tet. Lett., 33, 6991 (1992); (however, these methods could not be adapted to fragilie products such as streptogramins, either because thje reaction did not take place or because the operating conditions were degrading towards these products. Yet other mtethods involved toxic reactants which wiere not totally removable from the final product, this being unacceptable from the pharmaceutical pojint of view.
It has jiow been found, and this forms the subject of the priesent invehtion, that the streptogramins of! general formula (I) could be obtained by demethylation Of the corresponding derivative of general formula (ll) by treatment with a periodate in acetic medium followed by a treatment in aqueous acidic medium or by a treatment with an agent capable of consuming the fortoaldehyde in situ.
The periodate used is advantageously tetran-butylammonium periodate or an alkaline periodate (sodium periodate!) . The reaction is carried out in a solvent such as as chlorinated solvent (for example dichloromethane, Chloroform, dichloroethane or trichloroethane) ,j an ester (for example ethyl acetate) , a nitrile (for example acetonitrile) or in tetrahydrofuran, !N-methylpyrrolidone or optionally a mixture of these isolvents, in the presence or absence
AP/P/ 9 7/01 121
AP . Ο Ο 7 6 8 of ethylene glycol. The reaction takes place at a temperature of between 2 0 and 40°C.
The subsequent treatment is a hydrolysis, in aqueous medium, which releases formaldehyde. It is possible to perform the process by treatment of the product obtained in a homogeneous aqueous medium to which is added a strong acid, or directly in an acidic or non-acidic two-phase medium; in particular, the process may be performed in a dichloromethane/water mixture. In this case, preferably, the pH of the aqueous medium will he weakly acidic; it is understood that the acidity of the medium will be provided, indiscriminately, by addition of a strong or weak acid.
The acids used may be« chosen in particular from trifluoroacetic acid, sulphuric acid, hydrochloric acid, methanesulphonic acid, p-toluenesulphonic acid or formic acid. The treatment in acidic medium is carried out at a temperature of between 0 and 40°C.
When the subsequent treatment is carried out, it is also possible further to add an agent capable of consuming the formaldehyde in situ, this agent is advantageously chosen from hydroxylamine, a bisulphite (for example sodium bisulphite) or hydrogen peroxide in aqueous medium. The process is preferably performed in a two-phase medium at a temperature of between 0 and 40°C> at a pH of between 1 and 7.
The products of general formula (I) thus obtained may be purified, where appropriate, by the
AP/P/ 9 7/01121
AP.00768 usual methods sucl} as crystallization, precipitation,
I flash chromatography or HPLC.
The products of general formula (I) in which
R3 represents an ejthyl radical, R2 and X represent a 5 hydrogen atom and )Y represents a hydrogen atom or a hydroxyl radical ajre novel products of the streptogramin family.
The examjples which follow, given without any limitation being implied, illustrate the process according to the invention.
Example 1
540 g of) crude pristinamycin I [pristinamycin !
IA 72.2 % (433 g),jpristinamycin IB 4.2 % (25 g), pristinamycin Ic 2).67 % (16 g) , pristinamycin ID 3.17 % (19 g) ] are placed) in solution in a mixture of 1460 cm3 of dichloromethane), 500 cm3 Of acetic acid and 40 cm3 of ethylene glycol, ijn a three-hecked flask. 97.5 g of tetra-n-butylammonjium perioddte are added, while maintaining the tejmperature at 30°C. After stirring for
3 hours at 30°C, tjhe reaction is stopped by addition, i
with stirring, of )2000 cm3 of demineralized water. The aqueous phase is sjeparated out by settling and the organic phase is hashed again with 2000 cm3 of demineralized watejr. The aqueous phase is separated out by settling and the organic phase is concentrated to a volutae of 800 cm3.) 1000 cm3 of methyl ethyl ketone are added to the concentrate and the mixture is concentrated undef· reduced pressure (1.5 kPa) to a
AP/P/ 9 7/01121
AP. ο ο 7 6 8 volume of 1300 cm3. Methyl ethyl ketone is added up to a total volume of 2400 cm3 and the mixture is cooled to 0°C. The precipitated solid is filtered off, washed with 3 times 250 cm3 of methyl ethyl ketone and then dried at 40°C under reduced pressure (1.5 kPa). 441 g of a white solid are thus obtained, which product is dissolved in 8800 cm3 of 0.25 N hydrochloric acid and stirred for 1 hour and then extracted with 3500 cm3 of dichloromethane, adjusting the pH of the aqueous phase to 4 with 30 % sodium hydroxide. The organic phase is separated out by settling, washed with 3500 cm3 of water and then concentrated to dryness under reduced pressure (50 kPa at 30°C) to a volume of about 1100 cm3. 2200 cm3 of ethanol are added to this solution and the evaporation under reduced pressure is continued down to 1800 cm3 . 3500 cm3 of ethanol are then added.
The crystals obtained are filtered off at 10°C, filtered off and then rinsed with 3 times 330 cm3 of cold ethanol, then dried at 40°C under reduced pressure (1.5 kPa). 360 g of pristinamycin IB are thus obtained in the form of white, 80.7 % pure crystals, i.e. containing 290.4 g of pristinamycin IB .
Moreover, 1.1 % of vernamycin Βδ was obtained, equivalent to a conversion yield of 41.2 %, and 2 % of pristinamycin of general formula (I) in which is ethyl and R2 is hydroxyl, equivalent to a conversion yield of 63 % (HPLC assay).
AP/P/97/0 1 1 2 1
AP. Ο Ο 7 6 β
Example 2 g of jpristinamycin I [pristinamycin IA
76.5 % (15.3 g) , piristinamycin IB 7 % (1.4 g) ] are placed in solution), in a three-necked flask, in a mixture of 2 8 cm3 tof 1,2-dichloroethane, 70 cm3 of acetic acid and 2 cm3 of ethylene glycol. 4.9 g of sodium periodate ajre added, while maintaining the temperature at 25°C. After stirring for 6 hours, the reaction is stoppejd by addition, with stirring, of
100 cm3 of deminerialized water. The aqueous phase is separated out by Settling arid the organic phase is washed again with(50 cm3 of demineralized water. The aqueous phase is Separated dut by settling and the organic phase is Concentrated to dryness under reduced pressure. The sol4d is takeri up in 400 cm3 of methyl isobutyl ketone arid the product is extracted with twice 32 0 cm3 and then β|θ cm3 of 0.2 N sulphuric acid. The aqueous phases arC combined and then extracted with 400 cm3 of dichloComethane. The organic phase is separated out by Settling, concentrated to dryness under reduced pressure (30 kPa) at 30°C and then dried under reduced pressure (150 Pa) at 40°C to give 12.5 g of a white solid Containing 72 % (9 g) of pristinamycin IB and 5.6 % (0.7!g) of pristinamycin IA. Conversion yield: 84.9 %. j Example 3
540 g ojf crude pristinamycin I (pristinamycin IA 433 g, pristinamycin IB 25 g, pristinamycin Ic 16 g,
AP/P/ 9 7/01 121
AP. Ο Ο 7 6 8 pristinamycin ID 19 g) are placed in solution, in a three-necked flask, in a mixture of 1460 cd? of dichioromethane, 50 0 cnJ of acetic acid and 40 cirJ of ethylene glycol. 97.5 g of tetra-n-butylammonium periodate are added, while maintaining the temperature at 30°C. After stirring for 3 hours at 30°C, the reaction is stopped by addition, with stirring, of 2000 cm3 of demineralized water containing 34.7 g of hydroxylamine hydrochloride. The aqueous phase is settled and then separated out. The organic phase is washed with 2000 cm3 of water. After settling and separation, the organic phase is concentrated to a syrup. 2500 cm3 of ethyl acetate are poured onto this concentrate and the solution is then concentrated to a final volume of 1300 cm3. The suspension is filtered at 5°C. The crystals are washed with 3 times 400 cm3 of fresh ethyl acetate and dried at 40 °C under 1500 Pa of residual pressure. 331 g of a white product giving a pristinamycin IB assay of 91 % are thus obtained.
Example 4
180 g of crude pristinamycin I (containing
111.1 g of pristinamycin IA and 35.6 g of pri rH namyri n IB) are placed in solution, in a three-necked flask, in a mixture of 444 cm3 of dichioromethane, 128 cm3 of acetic acid and 10 cm3 of ethylene glycol. 25.9 g of tetra-n-butylammonium periodate are added. After stirring for 4 hours at 32 °C, the reaction is stopped by addition, with stirring, of 1100 cm3 of tap water.
21
CD £
£
AP .00768
The two phases ajfe settled and separated. The organic phase is washed c.gain 4 times in succession with, on each occasion, 1400 cm3 of tap water. The pH of these four washes is readjusted downwards with 5 ml of normal hydrochloric acid to facilitate the settlings. These four washes, settlings and separations are carried out at 35°C. The organic phase is concentrated by a factor of about two. 60(j cm3 of ethyl acetate are gradually ι
poured onto this iconcentrate, the crystallization being 10 initiated after a[bout one-third has been added. After the addition, supplying with ethyl acetate is continued with concomitant (distillation, so as to keep a constant volume in the fla^sk, i.e. about 60 0 cm3. After distillation to constant volume of about 800 cm3, the 15 suspension is coaled to 0°C and filtered. The filter cake is washed with twice 125 cm3 of ethyl acetate at
0°C and dried unc.er reduced pressure (1.5 kPa) at 40°C j
to constant weight. 120 g of a light beige product containing 110 g of pristinamycin IB are obtained.
AP/P/ 9 7/01 121
Claims (6)
- Having now particularly described and ascertained tny/oursaid invention and in what manner the same is to be performed l/we declare that what l/we claim m — A prooees for the preparation of streptogramins of general formulas in which:either the radical Rx represents a methyl or ethyl group, the radical R2 represents a hydrogen atom and X and Y together form an oxo radical, or Ra represents an ethyl radical, Ra and X represent a hydrogen atom and Y represents a hydrogen atom or a hydroxyl radical, or Rx represents an ethyl radical, Ra represents a hydroxyl radical and X and Y together form an oxo radical, by demethylation of a synergistin derivative of generalAP/P/ 9 7/01 121 formula:AP.00768 in which the radicals R1Z R2, X and Y are as defined above, by treatment with a periodate in acetic medium followed by a treatment in aqueous medium.
- 2. Process according to claim 1,5 characterized in that the periodate is chosen from tetra-n-butylammo)nium “periodate or an alkaline periodate.
- 3. Process according to claim 2, characterized in [that the alkaline periodate is sodium10 periodate. '
- 4. Process according to claim 1, characterized in that the subsequent treatment is a hydrolysis, in aqueous medium, either in a homogeneous medium to which 4s added a strong acid, or in an acidic 15 or non-acidic twp-phase medium.
- 5. Process according to claim 1, that an agent capable of consuming the formaldehyde in £itu is added, this agent being chosen from hydroxylamine, a bisulphite or hydrogen peroxide,20 during the subsequent treatment.characterized inAP/P/ 9 7/01 121AP . 0 0 7 6 8
- 6. A streptogramin derivative, characterized in that it corresponds to the general formula:in which Rx represents an ethyl radical, R2 and X 5 represent a hydrogen atom and Y represents a hydrogen atom or a hydroxyl radical.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9504585A FR2733236B1 (en) | 1995-04-18 | 1995-04-18 | PROCESS FOR THE PREPARATION OF STREPTOGRAMINS |
| PCT/FR1996/000575 WO1996033213A1 (en) | 1995-04-18 | 1996-04-16 | Method for preparing streptogramines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9701121A0 AP9701121A0 (en) | 1997-10-31 |
| AP768A true AP768A (en) | 1999-09-29 |
Family
ID=9478183
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1997/001121A AP768A (en) | 1995-04-18 | 1996-04-16 | Method for preparing streptogramines. |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US5789537A (en) |
| EP (1) | EP0821697B1 (en) |
| JP (2) | JP3856342B2 (en) |
| KR (1) | KR19990007800A (en) |
| CN (1) | CN1181758A (en) |
| AP (1) | AP768A (en) |
| AR (1) | AR002291A1 (en) |
| AT (1) | ATE194991T1 (en) |
| AU (1) | AU708419B2 (en) |
| BR (1) | BR9604927A (en) |
| CA (1) | CA2215991A1 (en) |
| CZ (1) | CZ285798B6 (en) |
| DE (1) | DE69609499T2 (en) |
| DK (1) | DK0821697T3 (en) |
| EA (1) | EA000350B1 (en) |
| EG (1) | EG20782A (en) |
| ES (1) | ES2148759T3 (en) |
| FR (1) | FR2733236B1 (en) |
| GR (1) | GR3033873T3 (en) |
| HU (1) | HUP9802942A3 (en) |
| IL (1) | IL117968A (en) |
| IN (1) | IN185120B (en) |
| NO (1) | NO974747L (en) |
| NZ (1) | NZ307236A (en) |
| OA (1) | OA10525A (en) |
| PL (1) | PL322822A1 (en) |
| PT (1) | PT821697E (en) |
| SK (1) | SK140497A3 (en) |
| TR (1) | TR199701204T1 (en) |
| TW (1) | TW334437B (en) |
| WO (1) | WO1996033213A1 (en) |
| ZA (1) | ZA963102B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2796950B1 (en) * | 1999-07-27 | 2001-09-21 | Aventis Pharma Sa | STREPTOGRAMIN DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM |
| ES2204681T3 (en) * | 1999-07-27 | 2004-05-01 | Aventis Pharma S.A. | DERIVATIVES OF STREPTOGRAMINS, THEIR PREPARATION AND COMPOSITIONS THAT CONTAIN THEM. |
| FR2796949B1 (en) * | 1999-07-27 | 2001-09-21 | Aventis Pharma Sa | STREPTOGRAMIN DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM |
| KR20070027290A (en) * | 2005-09-06 | 2007-03-09 | 엘지이노텍 주식회사 | Light emitting element and manufacturing method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2689518A1 (en) * | 1992-04-01 | 1993-10-08 | Rhone Poulenc Rorer Sa | Microorganisms, method of preparation and use |
| EP0614910A1 (en) * | 1993-02-17 | 1994-09-14 | Aventis Pharma S.A. | Streptogramines in purified form, their preparation and pharmaceutical compositions comprising them |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2664894A1 (en) * | 1990-07-19 | 1992-01-24 | Rhone Poulenc Sante | NOVEL STREPTOGRAMIN DERIVATIVES AND THEIR PREPARATION. |
-
1995
- 1995-04-18 FR FR9504585A patent/FR2733236B1/en not_active Expired - Fee Related
-
1996
- 1996-04-16 AT AT96913594T patent/ATE194991T1/en not_active IP Right Cessation
- 1996-04-16 DE DE69609499T patent/DE69609499T2/en not_active Expired - Lifetime
- 1996-04-16 AP APAP/P/1997/001121A patent/AP768A/en active
- 1996-04-16 TR TR97/01204T patent/TR199701204T1/en unknown
- 1996-04-16 DK DK96913594T patent/DK0821697T3/en active
- 1996-04-16 NZ NZ307236A patent/NZ307236A/en unknown
- 1996-04-16 PL PL96322822A patent/PL322822A1/en unknown
- 1996-04-16 HU HU9802942A patent/HUP9802942A3/en unknown
- 1996-04-16 EG EG32896A patent/EG20782A/en active
- 1996-04-16 IN IN811DE1996 patent/IN185120B/en unknown
- 1996-04-16 EA EA199700325A patent/EA000350B1/en not_active IP Right Cessation
- 1996-04-16 JP JP53151096A patent/JP3856342B2/en not_active Expired - Fee Related
- 1996-04-16 ES ES96913594T patent/ES2148759T3/en not_active Expired - Lifetime
- 1996-04-16 CZ CZ973290A patent/CZ285798B6/en not_active IP Right Cessation
- 1996-04-16 CN CN96193360A patent/CN1181758A/en active Pending
- 1996-04-16 BR BR9604927A patent/BR9604927A/en not_active Application Discontinuation
- 1996-04-16 EP EP96913594A patent/EP0821697B1/en not_active Expired - Lifetime
- 1996-04-16 KR KR1019970707323A patent/KR19990007800A/en not_active Withdrawn
- 1996-04-16 CA CA002215991A patent/CA2215991A1/en not_active Abandoned
- 1996-04-16 WO PCT/FR1996/000575 patent/WO1996033213A1/en not_active Application Discontinuation
- 1996-04-16 US US08/930,135 patent/US5789537A/en not_active Expired - Lifetime
- 1996-04-16 SK SK1404-97A patent/SK140497A3/en unknown
- 1996-04-16 AU AU56528/96A patent/AU708419B2/en not_active Ceased
- 1996-04-16 PT PT96913594T patent/PT821697E/en unknown
- 1996-04-18 TW TW085104644A patent/TW334437B/en active
- 1996-04-18 IL IL11796896A patent/IL117968A/en active IP Right Grant
- 1996-04-18 ZA ZA963102A patent/ZA963102B/en unknown
- 1996-04-18 AR ARP960102238A patent/AR002291A1/en unknown
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1997
- 1997-10-14 NO NO974747A patent/NO974747L/en not_active Application Discontinuation
- 1997-10-17 OA OA70108A patent/OA10525A/en unknown
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2000
- 2000-07-27 GR GR20000400169T patent/GR3033873T3/en not_active IP Right Cessation
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2689518A1 (en) * | 1992-04-01 | 1993-10-08 | Rhone Poulenc Rorer Sa | Microorganisms, method of preparation and use |
| EP0614910A1 (en) * | 1993-02-17 | 1994-09-14 | Aventis Pharma S.A. | Streptogramines in purified form, their preparation and pharmaceutical compositions comprising them |
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