WO2005012322A1 - エリスロマイシンa 11,12−サイクリックカーボネートの製造方法 - Google Patents
エリスロマイシンa 11,12−サイクリックカーボネートの製造方法 Download PDFInfo
- Publication number
- WO2005012322A1 WO2005012322A1 PCT/JP2004/011150 JP2004011150W WO2005012322A1 WO 2005012322 A1 WO2005012322 A1 WO 2005012322A1 JP 2004011150 W JP2004011150 W JP 2004011150W WO 2005012322 A1 WO2005012322 A1 WO 2005012322A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- erythromycin
- carbonate
- cyclic carbonate
- reaction
- comparative example
- Prior art date
Links
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 title claims abstract description 43
- 229960003276 erythromycin Drugs 0.000 title claims abstract description 40
- 229930006677 Erythromycin A Natural products 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 11
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 15
- 239000000126 substance Substances 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 19
- 238000004519 manufacturing process Methods 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000005676 cyclic carbonates Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010057190 Respiratory tract infections Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960002626 clarithromycin Drugs 0.000 description 2
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Definitions
- the present invention relates to a method for producing erythromycin A 11, 12-cyclic carbonate.
- clarithromycin second generation macrolide antimicrobial agent typified by clarithromycin Ya Ajisuromaishin is appeared in the early 1990s E, due to its superior therapeutic effects are now widely clinical field as Osamu Ryoyaku respiratory infections Used in.
- Osamu Ryoyaku respiratory infections Used in.
- penicillin and erythromycin resistant bacteria has become a major therapeutic problem in the respiratory tract infection area, and the development of new macrolide antibiotics having strong activity against these resistant bacteria has been actively promoted. Have been.
- erythromycin A 11, 12-cyclic carbonate derivative, 3_ ⁇ _ (3-pyridyl) -acetyl-5-0-desosaminyl 9-dihydroerythronolide A 6,9; 11,12-dicylic Patent Document 1 discloses click carbonate as a compound having the above-mentioned resistant bacterium activity.
- Patent Document 2 discloses the reaction conditions (potassium carbonate in toluene solvent) at 40 ° C. for 6 days, and the yield is only 24%.
- Patent Document 3 a target product is obtained by performing a reaction at a boiling temperature using a large amount of potassium carbonate in a benzene solvent. Furthermore, in this reaction, due to the presence of a large amount of base and the high reaction temperature, the target product undergoes a decarboxylation reaction to produce 10,11-anhydroerythromycin A as a by-product, thereby reducing the yield. As a result, the isolation of the target product is complicated.
- Patent document 1 International publication W098 / 13373 pamphlet
- Patent document 2 International publication WO02 / 14339 pamphlet
- Patent Document 3 US Patent No. 3417077
- An object of the present invention is to provide a method for efficiently producing erythromycin A 11, 12-cyclic carbonate.
- the inventors of the present invention have conducted intensive studies and as a result, when a certain kind of base is used in combination with a certain kind of base in a certain kind of ether solvent, an efficient isolation operation is not required.
- the present inventors have found that erythromycin A 11, 12-cyclic carbonate can be produced, and have completed the present invention.
- the present invention provides a reaction formula
- erythromycin A (I-drug compound (1)) to be represented by the formula (1) is also different from the method for producing erythromycin A 11,12-cyclic carbonate (compound (II)).
- Erythromycin A 11, 12-cyclic characterized by reacting erythromycin A with ethylene carbonate and cesium carbonate in one or more solvents selected from getyl ether, diisopropyl ether and t-butyl methyl ether A method for producing a carbonate is provided.
- the production method of the present invention provides an efficient erythromycin A without the need for complicated isolation operations.
- Erythromycin A is dissolved in toluene, etc., the insoluble matter is removed by filtration, concentrated under reduced pressure, and the residue is dissolved in one or more solvents selected from getyl ether, diisopropyl ether and t-butyl methyl ether. Ethylene carbonate and cesium carbonate are dried and reacted, and the precipitated crystals are collected by filtration and washed to produce erythromycin A 11, 12-cyclic carbonate. As a solvent, getyl ether or diisopropyl ether is preferable.
- Erythromycin A (294 g, 0.40 mol) was dissolved in toluene (1470 mL), the insoluble material was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was dissolved in 2900 mL of diisopropyl ether, and 53.0 g (0.60 mol) of ethylene carbonate and 65.5 g (0.20 mol) of cesium carbonate were added. The mixture was stirred at room temperature for 20 hours. The precipitated crystals were collected by filtration and washed with 1500 mL of water. The obtained crystals were dried with hot air at 50 ° C. to obtain 206 g (yield: 68%) of erythromycin A 11, 12-cyclic carbonate.
- Erythromycin A (73.39 g, 0.10 mmol) was dissolved in 367 mL (5 mL / g) of toluene by heating, a trace amount of insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure. As a residue, 74.27 g of a colorless amorphous (containing a trace amount of Tonolen) was obtained. 743 mg (l. 00) of this amorphous
- the reaction was carried out in substantially the same manner as in Example 1 except that the reaction solvent was changed in various ways, and the formation of erythromycin A 11,12-cyclic carbonate was monitored by thin-layer chromatography (TLC).
- TLC thin-layer chromatography
- the production method of the present invention is an industrially useful method for producing erythromycin A 11,12-cyclic power carbonate.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003-206089 | 2003-08-05 | ||
JP2003206089 | 2003-08-05 |
Publications (1)
Publication Number | Publication Date |
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WO2005012322A1 true WO2005012322A1 (ja) | 2005-02-10 |
Family
ID=34113702
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2004/011150 WO2005012322A1 (ja) | 2003-08-05 | 2004-08-04 | エリスロマイシンa 11,12−サイクリックカーボネートの製造方法 |
Country Status (1)
Country | Link |
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WO (1) | WO2005012322A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102212094A (zh) * | 2011-03-14 | 2011-10-12 | 金泳霖 | 一种红霉素残余药渣的处理工艺 |
CN103102377A (zh) * | 2011-11-15 | 2013-05-15 | 塔科敏斯基制药厂波尔法合资公司 | 红霉素a环11,12-碳酸酯的新晶形、包含新晶形b的药物组合物及其应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993013116A1 (en) * | 1991-12-27 | 1993-07-08 | Taisho Pharmaceutical Co., Ltd. | 5-o-desosaminylerythronolide derivative |
WO2002014339A1 (fr) * | 2000-08-14 | 2002-02-21 | Taisho Pharmaceutical Co., Ltd. | Procede servant a preparer un derive d'erythromycine |
-
2004
- 2004-08-04 WO PCT/JP2004/011150 patent/WO2005012322A1/ja not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993013116A1 (en) * | 1991-12-27 | 1993-07-08 | Taisho Pharmaceutical Co., Ltd. | 5-o-desosaminylerythronolide derivative |
WO2002014339A1 (fr) * | 2000-08-14 | 2002-02-21 | Taisho Pharmaceutical Co., Ltd. | Procede servant a preparer un derive d'erythromycine |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102212094A (zh) * | 2011-03-14 | 2011-10-12 | 金泳霖 | 一种红霉素残余药渣的处理工艺 |
CN102212094B (zh) * | 2011-03-14 | 2013-08-21 | 金泳霖 | 一种红霉素残余药渣的处理工艺 |
CN103102377A (zh) * | 2011-11-15 | 2013-05-15 | 塔科敏斯基制药厂波尔法合资公司 | 红霉素a环11,12-碳酸酯的新晶形、包含新晶形b的药物组合物及其应用 |
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