Ignacio Melgar Asensio Patent
Advances in ocular drug delivery: Emphasis on the posterior segment. Ignacio Melgar Asensio. Patent blood vessels may persist, necessitating repeated treatments in most patients,. Search the world's information, including webpages, images, videos and more. Google has many special features to help you find exactly what you're looking for. Her research was focused on targeted drug delivery using alkyl-phospholipid bound to radio-iodine 131 (I-131) for cancer treatment. While at Cellectar, she filed 7 patent applications with her team, built up the GLP based laboratory and submitted INDs to the FDA.
Info
- Publication number
- US6642364B2 US6642364B2US10/180,127US18012702AUS6642364B2US 6642364 B2US6642364 B2US 6642364B2US 18012702 AUS18012702 AUS 18012702AUS 6642364 B2US6642364 B2US 6642364B2
- Authority
- US
- United States
- Prior art keywords
- erythromycin
- obtain
- US20030023053A1 (en
- Inventor
- Ignacio Melgar Asensio Patent Group
- Luis Ángel Diaz Tejo
- Julià Sempere Cebrián
- Ercros Industrial SA
- Original Assignee
- Priority to ES200101562priorityPriority to ESP200101562priority
- Application filed by Ercros Industrial SAfiledAssigned to ERCROS INDUSTRIAL, S.A.reassignmentERCROS INDUSTRIAL, S.A.Assignors: NOMEN RIBE, ROSA, SEMPERE CEBRIAN, JULIA, BORRELL BILBAO, JOSE IGNACIO, ASENSIO DOMINGUEZ, RAMON, CRUZADO RODRIGUEZ, MARIA DEL CARMEN, DIAZ TEJO, LUIS ANGEL
- Criticalpatent/US20030023053A1/en
- Criticalpatent/US6642364B2/en
- Critical
- Critical
- Critical
- C—CHEMISTRY; METALLURGY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
Previous Stage.—Synthesis of the Erythromycin A 9-oxime Hydrochloride 28 ml of methanol and 15 g of erythromycin A are introduced in the reactor under stirring. Next, 7.6 g of imidazole and 7.1 g of hydroxylamine hydrochloride are added. The mixture is heated to reflux and this is maintained for 8 h. The mixture is later cooled to 0° C. and the solid that appears is recovered by filtration. The solid obtained is suspended in 30 ml of water which is stirred for 15 minutes. The solid obtained is recovered by filtration and is vacuum dried at 50° C. for 12 h. 12.5 g of erythromycin A 9-oxime hydrochloride are obtained.
Stage a.—Synthesis of the Mixed Acetal
9.4 g of erythromycin A 9-oxime hydrochloride and 55 ml of CH2Cl2 are introduced in the reactor, and the stirring is turned on. 0.09 g of pyridine hydrobromide is introduced and the solution is maintained at 15° C. 8.4 g of diisopropoxycyclohexane are added. The stirring is maintained at 15-20° C. for 1.5 h. Once the reaction has ended, the solution is washed with 28 ml of 5% NaOH and with 28 ml of a saturated NaCl solution. Finally, 38 ml de CH2Cl2 is added to the organic phase and distilled until a volume of 48 ml of CH2Cl2 is obtained. Approximately 50 ml of erythromycin A 9-[O-isopropoxycyclohexyl]oxime solution in CH2Cl2 is obtained, ready to be used in the following stage.
Stage b.—Preparation of the Silylation Agent
20 g of hexamethyldisilazane and 15.8 g of imidazole are introduced in the reactor and the stirring is turned on. 0.01 ml of concentrated sulphuric acid is slowly added. It is heated to 130-140° C. and is maintained at this temperature for 2 h. The solution is cooled to 20-25° C. and 84 ml of CH2Cl2 is introduced and, then, 26 g of chlortrimethylsilane. A white suspension is formed that is ready to be used in the silylation reaction.
Stage c.—Silylation Reaction
The solution of mixed acetal in CH2Cl2 obtained in Stage a is cooled to −5-0° C. Once the temperature has been reached, the silylation agent solution obtained in Stage b is slowly introduced. The stirring is maintained at the same temperature for 60′. Once the reaction has ended, two washes are carried out with 19 ml of water and 19 ml of saturated NaCl solution. Finally, 25 ml of methylene chloride is added and is distilled until a final volume of 62 ml of erythromycin A 2′,4″-bis(trimethylsilyl)-9-[O-isopropoxycyclohexyl]oxime solution is obtained.
Stage d.—Methylation Reaction
56 ml of dimethylsulfoxide is introduced in the reactor containing the solution from Stage c. The solution is cooled to 0-5° C. Once the indicated temperature is reached, 2.8 g of methyl iodide and 1.1 g of 89% potassium hydroxide powder are added. The stirring is maintained at 0-5° C. for 3h. Once the reaction has finished, 1.6 g of triethylamine are added at 0-5° C., the temperature is allowed to rise to 20-25° C. and, once reached, stirring is maintained for 45 min. Next, the solution is washed with 56 ml of water and 44 ml of saturated sodium chloride solution. Finally, the methylene chloride organic phase is distilled until an oily solution is obtained. Next, 72 ml de methanol is introduced and 20 ml of solution is distilled to eliminate the methylene chloride. Thus, a methanol solution of erythromycin A 2′,4″-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxycyclohexyl]oxime is obtained.
Stage e.—Unprotection Reaction
52 ml of water is introduced in the reactor with the methanolic solution obtained in Stage d, and pH is adjusted to 3-3.5 with formic acid (85%). The solution is heated to 35-40° C. for 3-5 h. Once the reaction has finished, 52 ml of water is introduced. The clarithromycin oxime is obtained by adding NaOH to a pH of 9.5-10. The solid obtained is recovered by filtration.
Stage f.—Deoximation Reaction
The solid obtained in Stage e is dissolved in 38 ml of methanol. 38 ml of water and 3.8 g of sodium metabisulphite are added to the solution obtained. The pH is adjusted to 4.5-5 with formic acid (85%). It is heated to reflux for 2-4 h. Once the reaction is finished, it is cooled to 20-25° C. and 56 ml of water is introduced. At the same temperature, the pH is adjusted to 10 with sodium hydroxide until the crystallization of the clarithromycin is achieved, which is recovered by filtration. 6.3 g of clarithromycin are obtained, which is recrystallized from ethanol to obtain the final clarithromycin. It is vacuum dried at 90-95° C. for 24 h. In this manner, obtaining the clarithromycin crystal form II is guaranteed (according to the terminology used in the description of the patent documents WO 98/04573 and WO 98/04574), that is habitually used in commercial formulations.
Claims (4)
What is claimed is: 1. A process for producing clarithromycin comprising the steps of:(a) reacting erythromycin A 9-oxime hydrochloride with 1,1-diisopropoxycyclohexane in the presence of a catalytic amount of a pyridine salt, in methylene chloride as a solvent, so as to obtain a mixed acetal;(b) reacting hexamethyldisilazane and imidazole in the presence of sulfuric acid, and thereafter adding chlorotrimethysilane in methylene chloride as a solvent, so as to obtain a silylation agent;(c) reacting the resulting mixed acetal of step (a) with the resulting silylation agent of step (b) in methylene chloride as a solvent, so as to obtain erythromycin A 2′,4″-bis(trimethylsilyl)-9-[O-isopropoxycyclohexyl]oxime;(d) reacting the resulting erythromycin A 2′,4″-bis(trimethylsilyl)-9-[O-isopropoxycyclohexyl]oxime of step (c) with methyl iodide and potassium hydroxide in methylene chloride and dimethylsulfoxide as solvents, so as to obtain erythromycin A 2′,4″-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxycyclohexyl]oxime;(e) deprotecting the resulting erythromycin A 2′,4″-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxycyclohexyl]oxime obtained in step (d) in a solution of methanol, water and 85% formic acid, so as to obtain clarithromycin oxime; and(f) deoximating the resulting clarithromycin oxime of step (e) with aqueous sodium metabisulfite so as to obtain clarithromycin.2. The process ofclaim 1 , wherein steps (a), (b), (c) and (d) are carried out without isolating reaction intermediates.3. The process ofclaim 1 , wherein in step (a) said pyridine salt is pyridine hydrobromide.4. The process ofclaim 1 , wherein said pyridine salt is pyridine hydrobromide, which is employed at a molar ratio of about 0.04 to 0.05 to said erythromycin A 9-oxime hydrochloride.US10/180,1272001-07-052002-06-27Process to obtain clarithromycin Expired - Fee RelatedUS6642364B2 (en) Priority Applications (3)
Application Number Priority Date Filing Date Title ESP200101562 2001-07-05 US20030023053A1US20030023053A1 (en) 2003-01-30 US10/180,127Expired - Fee RelatedUS6642364B2 (en) 2001-07-05 2002-06-27 Process to obtain clarithromycin Country Status (2)
Country Link ES (1) ES2195727B1 (en) Cited By (5)
* Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US20050084541A1 (en) * 2003-10-17 2005-04-21 Indranil Nandi Antibiotic compositions US20080096831A1 (en) * 2003-11-06 2008-04-24 Sadatrezaei Mohsen Stabilized azithromycin composition US4990602A (en) * 1986-12-17 1991-02-05 Taisho Pharmaceutical Co., Ltd. Erythromycin A derivatives JP2782793B2 (en) * 1988-06-15 1998-08-06 大正製薬株式会社 Erythromycin a derivative and a method of manufacturing the same - 2001-07-05ESES200101562Apatent/ES2195727B1/ennot_activeExpired - Fee Related
- 2002-06-27USUS10/180,127patent/US6642364B2/ennot_activeExpired - Fee Related
- clarithromycin
- process
- 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 - Fee Related
- Application number
- US10/180,127
- Other versions
- Ramón Asensio Dominguez
- Luis Ángel Diaz Tejo
- Julià Sempere Cebrián
- Ercros Industrial SA
- Original Assignee
- Priority to ES200101562priorityPriority to ESP200101562priority
- Application filed by Ercros Industrial SAfiledAssigned to ERCROS INDUSTRIAL, S.A.reassignmentERCROS INDUSTRIAL, S.A.Assignors: NOMEN RIBE, ROSA, SEMPERE CEBRIAN, JULIA, BORRELL BILBAO, JOSE IGNACIO, ASENSIO DOMINGUEZ, RAMON, CRUZADO RODRIGUEZ, MARIA DEL CARMEN, DIAZ TEJO, LUIS ANGEL
- Criticalpatent/US20030023053A1/en
- Criticalpatent/US6642364B2/en
- Critical
- Critical
- Critical
- C—CHEMISTRY; METALLURGY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
Previous Stage.—Synthesis of the Erythromycin A 9-oxime Hydrochloride 28 ml of methanol and 15 g of erythromycin A are introduced in the reactor under stirring. Next, 7.6 g of imidazole and 7.1 g of hydroxylamine hydrochloride are added. The mixture is heated to reflux and this is maintained for 8 h. The mixture is later cooled to 0° C. and the solid that appears is recovered by filtration. The solid obtained is suspended in 30 ml of water which is stirred for 15 minutes. The solid obtained is recovered by filtration and is vacuum dried at 50° C. for 12 h. 12.5 g of erythromycin A 9-oxime hydrochloride are obtained.
Stage a.—Synthesis of the Mixed Acetal
9.4 g of erythromycin A 9-oxime hydrochloride and 55 ml of CH2Cl2 are introduced in the reactor, and the stirring is turned on. 0.09 g of pyridine hydrobromide is introduced and the solution is maintained at 15° C. 8.4 g of diisopropoxycyclohexane are added. The stirring is maintained at 15-20° C. for 1.5 h. Once the reaction has ended, the solution is washed with 28 ml of 5% NaOH and with 28 ml of a saturated NaCl solution. Finally, 38 ml de CH2Cl2 is added to the organic phase and distilled until a volume of 48 ml of CH2Cl2 is obtained. Approximately 50 ml of erythromycin A 9-[O-isopropoxycyclohexyl]oxime solution in CH2Cl2 is obtained, ready to be used in the following stage.
Stage b.—Preparation of the Silylation Agent
20 g of hexamethyldisilazane and 15.8 g of imidazole are introduced in the reactor and the stirring is turned on. 0.01 ml of concentrated sulphuric acid is slowly added. It is heated to 130-140° C. and is maintained at this temperature for 2 h. The solution is cooled to 20-25° C. and 84 ml of CH2Cl2 is introduced and, then, 26 g of chlortrimethylsilane. A white suspension is formed that is ready to be used in the silylation reaction.
Stage c.—Silylation Reaction
The solution of mixed acetal in CH2Cl2 obtained in Stage a is cooled to −5-0° C. Once the temperature has been reached, the silylation agent solution obtained in Stage b is slowly introduced. The stirring is maintained at the same temperature for 60′. Once the reaction has ended, two washes are carried out with 19 ml of water and 19 ml of saturated NaCl solution. Finally, 25 ml of methylene chloride is added and is distilled until a final volume of 62 ml of erythromycin A 2′,4″-bis(trimethylsilyl)-9-[O-isopropoxycyclohexyl]oxime solution is obtained.
Stage d.—Methylation Reaction
56 ml of dimethylsulfoxide is introduced in the reactor containing the solution from Stage c. The solution is cooled to 0-5° C. Once the indicated temperature is reached, 2.8 g of methyl iodide and 1.1 g of 89% potassium hydroxide powder are added. The stirring is maintained at 0-5° C. for 3h. Once the reaction has finished, 1.6 g of triethylamine are added at 0-5° C., the temperature is allowed to rise to 20-25° C. and, once reached, stirring is maintained for 45 min. Next, the solution is washed with 56 ml of water and 44 ml of saturated sodium chloride solution. Finally, the methylene chloride organic phase is distilled until an oily solution is obtained. Next, 72 ml de methanol is introduced and 20 ml of solution is distilled to eliminate the methylene chloride. Thus, a methanol solution of erythromycin A 2′,4″-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxycyclohexyl]oxime is obtained.
Stage e.—Unprotection Reaction
52 ml of water is introduced in the reactor with the methanolic solution obtained in Stage d, and pH is adjusted to 3-3.5 with formic acid (85%). The solution is heated to 35-40° C. for 3-5 h. Once the reaction has finished, 52 ml of water is introduced. The clarithromycin oxime is obtained by adding NaOH to a pH of 9.5-10. The solid obtained is recovered by filtration.
Stage f.—Deoximation Reaction
The solid obtained in Stage e is dissolved in 38 ml of methanol. 38 ml of water and 3.8 g of sodium metabisulphite are added to the solution obtained. The pH is adjusted to 4.5-5 with formic acid (85%). It is heated to reflux for 2-4 h. Once the reaction is finished, it is cooled to 20-25° C. and 56 ml of water is introduced. At the same temperature, the pH is adjusted to 10 with sodium hydroxide until the crystallization of the clarithromycin is achieved, which is recovered by filtration. 6.3 g of clarithromycin are obtained, which is recrystallized from ethanol to obtain the final clarithromycin. It is vacuum dried at 90-95° C. for 24 h. In this manner, obtaining the clarithromycin crystal form II is guaranteed (according to the terminology used in the description of the patent documents WO 98/04573 and WO 98/04574), that is habitually used in commercial formulations.
Claims (4)
What is claimed is: 1. A process for producing clarithromycin comprising the steps of:(a) reacting erythromycin A 9-oxime hydrochloride with 1,1-diisopropoxycyclohexane in the presence of a catalytic amount of a pyridine salt, in methylene chloride as a solvent, so as to obtain a mixed acetal;(b) reacting hexamethyldisilazane and imidazole in the presence of sulfuric acid, and thereafter adding chlorotrimethysilane in methylene chloride as a solvent, so as to obtain a silylation agent;(c) reacting the resulting mixed acetal of step (a) with the resulting silylation agent of step (b) in methylene chloride as a solvent, so as to obtain erythromycin A 2′,4″-bis(trimethylsilyl)-9-[O-isopropoxycyclohexyl]oxime;(d) reacting the resulting erythromycin A 2′,4″-bis(trimethylsilyl)-9-[O-isopropoxycyclohexyl]oxime of step (c) with methyl iodide and potassium hydroxide in methylene chloride and dimethylsulfoxide as solvents, so as to obtain erythromycin A 2′,4″-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxycyclohexyl]oxime;(e) deprotecting the resulting erythromycin A 2′,4″-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxycyclohexyl]oxime obtained in step (d) in a solution of methanol, water and 85% formic acid, so as to obtain clarithromycin oxime; and(f) deoximating the resulting clarithromycin oxime of step (e) with aqueous sodium metabisulfite so as to obtain clarithromycin.2. The process ofclaim 1 , wherein steps (a), (b), (c) and (d) are carried out without isolating reaction intermediates.3. The process ofclaim 1 , wherein in step (a) said pyridine salt is pyridine hydrobromide.4. The process ofclaim 1 , wherein said pyridine salt is pyridine hydrobromide, which is employed at a molar ratio of about 0.04 to 0.05 to said erythromycin A 9-oxime hydrochloride.US10/180,1272001-07-052002-06-27Process to obtain clarithromycin Expired - Fee RelatedUS6642364B2 (en) Priority Applications (3)
Application Number Priority Date Filing Date Title ESP200101562 2001-07-05 US20030023053A1US20030023053A1 (en) 2003-01-30 US10/180,127Expired - Fee RelatedUS6642364B2 (en) 2001-07-05 2002-06-27 Process to obtain clarithromycin Country Status (2)
Country Link ES (1) ES2195727B1 (en) Cited By (5)
* Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US20050084541A1 (en) * 2003-10-17 2005-04-21 Indranil Nandi Antibiotic compositions US20080096831A1 (en) * 2003-11-06 2008-04-24 Sadatrezaei Mohsen Stabilized azithromycin composition US4990602A (en) * 1986-12-17 1991-02-05 Taisho Pharmaceutical Co., Ltd. Erythromycin A derivatives JP2782793B2 (en) * 1988-06-15 1998-08-06 大正製薬株式会社 Erythromycin a derivative and a method of manufacturing the same - 2001-07-05ESES200101562Apatent/ES2195727B1/ennot_activeExpired - Fee Related
- 2002-06-27USUS10/180,127patent/US6642364B2/ennot_activeExpired - Fee Related
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Links
Classifications
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999028333A1 (en) * | 1997-12-01 | 1999-06-10 | Abbott Laboratories | Chemical synthesis of 6-o-alkyl erythromycin c |
Non-Patent Citations (1)
*| Title |
|---|
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050084540A1 (en) * | 2003-10-17 | 2005-04-21 | Indranil Nandi | Taste masking antibiotic composition |
| US8168228B2 (en) | 2003-10-17 | 2012-05-01 | Sandoz Ag | Antibiotic clarithromycin micropellet compositions |
| US20090054634A1 (en) * | 2007-08-09 | 2009-02-26 | Vinod Kumar Kansal | Process for the preparation of clarithromycin |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2195727A1 (en) | 2003-12-01 |
| US5770579A (en) | Erythromycin compounds |
| AU702588B2 (en) | Process for purifying and isolating 2'-deoxy-2',2'-diflu oronucleosides |
| RU2066324C1 (en) | Crystalline azithromycin dehydrate, and process for preparation thereof |
| EP1253153B1 (en) | Process for preparing 4"-substituted-9-deoxo-9a-aza-9a-homoerythromycin A derivatives |
| EP0891371B1 (en) | 9-oximesilyl erythromycin a derivatives |
| DE69832486T2 (en) | C-4 "-substitutierte macrolide derivatives |
| CN1168734C (en) | Novel erythromycin derivatives, method for preparing same, and use thereof as drug |
| CN1326865C (en) | 3'-N-oxide, 3'-N-dimethylamine, 9-oxime erythromycin A derivatives |
| JP4703924B2 (en) | Macrolide |
| HU0300418A2 (en) | A process clarithromycin type (II) for the preparation of crystalline Form |
| EP0827965B1 (en) | Synthesis of 9-deoxo- 9a-aza 11,12-deoxy- 9a-methyl-9a-homoerythromycin A 11,12- hydrogenorthoborate dihydrate |
| HU221803B1 (en) | The azithromycin O-benzyloxycarbonyl derivatives and acid addition salts |
| DE602005002475T2 (en) | A process for the preparation of Telithromycin |
Legal Events
Owner name: ERCROS INDUSTRIAL, S.A., SPAIN| Date | Code | Title | Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| REMI | Maintenance fee reminder mailed | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| STCH | Information on status: patent discontinuation | FP | Expired due to failure to pay maintenance fee | oxime LinksClassificationsPatent Citations (2)
Non-Patent Citations (1)*
 Cited By (6)
Also Published As
Legal EventsOwner name: ERCROS INDUSTRIAL, S.A., SPAIN
|