WO2006064299A1 - Industrial process of clarithromycin associated with controlled level of side products - Google Patents

Industrial process of clarithromycin associated with controlled level of side products Download PDF

Info

Publication number
WO2006064299A1
WO2006064299A1 PCT/IB2004/004075 IB2004004075W WO2006064299A1 WO 2006064299 A1 WO2006064299 A1 WO 2006064299A1 IB 2004004075 W IB2004004075 W IB 2004004075W WO 2006064299 A1 WO2006064299 A1 WO 2006064299A1
Authority
WO
WIPO (PCT)
Prior art keywords
clarithromycin
oxime
erythromycin
methyl
impurities
Prior art date
Application number
PCT/IB2004/004075
Other languages
French (fr)
Inventor
Siddiqui Mohammed Jaweed Mukarram
Shiva Prasad Singh
Aravind Yekanathsa Merwade
Anjum Reyaz Khan
Kumar Kamlesh Laxmi Singh
Original Assignee
Wockhardt Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Wockhardt Limited filed Critical Wockhardt Limited
Priority to PCT/IB2004/004075 priority Critical patent/WO2006064299A1/en
Publication of WO2006064299A1 publication Critical patent/WO2006064299A1/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D407/00Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings

Abstract

The present invention describes a process for preparing Clarithromycin having 6,11-0­dimethyl erythromycin-A in less than 1 % amount. The methylation process in the present invention provides Clarithromycin having free of Claritromycin-9-Oxime with less than 3 % total impurities. Clarithromycin thus obtained is in polymorphic form II.

Description

INDUSTRIAL PROCESS OF CLARITHROMYCIN ASSOCIATED WITH CONTROLLED LEVELS OF SH)E PRODUCTS
FIELD OF THE INVENTION
The present invention relates to a robust, economically feasible and environmentally friendly manufacturing process of Clarithromycin, Formula (I) with controlled levels of side products. A total of eight impurities are characterized in Clarithromycin finished product based on HPLC analysis. The Clarithromycin manufactured by following the present invention is having a total impurities, (known & unknown) to the level of less than 3.0 % by HPLC. Another aspect of the present invention relates to producing Clarithromycin Polymorph-II as revealed by XRD, the said polymorphic Form II is obtained by a mixture of halogenated and protic solvent.
Formula (I)
Figure imgf000002_0001
Clarithromycin
BACKGROUND OF THE INVENTION
Erythromycin A is known to be a useful macrolide antibiotic having a strong activity against Gram-positive bacteria, this compound has an undesirable property that it loses rapidly the antibacterial activity by the acid in stomach when administered orally, where- upon its blood concentration remains at a low level. 6-0-Alkyl derivatives of Erythromycin- A are well known as an useful antibacterial agents. 6-O-Methyl-Erythromycin-A (Clarithromycin) and a pharmaceutically acceptable salt is a potent macrolide antibiotic as reported in US Patent No. 4,331 ,803. Clarithromycin is stable in acidic medium and also remarkable in vivo activity and has a strong antibacterial property against Gram-positive bacteria compared to Erythromycin- A. This compound shows excellent effect for the treatment of infections by oral administration.
A number of synthetic processes have been reported for preparing 6-O-alkyl erythromycin. US Patent No. 4,331 ,803 discloses a method for the preparation of Clarithromycin by methylating 6-OH group of 2'-O-3'-N-benzyloxycarbonyl erythromycin
Formula (III)
Figure imgf000003_0001
21,3'-O-Protected Erythromycin
Methylation of 6-OH group of the 2',3'-benzyloxycarbonyl erythromycin was carried out using methyl iodide in the presence of a suitable base in a solvent. Clarithromycin was obtained from the compound after removing benzyloxycarbonyl group by hydrogenolysis and then subjecting to the reductive methylation in the presence of excess amount of farmaldehyde. Clarithromycin can also be synthesized by the methylation of 6-OH position of Erythromycin-A-9-Oxime
Formula (II)
Figure imgf000004_0001
Erythromycin-9-Oxime
Synthesis of Clarithromycin using 9-oxime or its derivatives are well reported in US Patent Nos. 5,274,085; 4,680,386; 4,668,776; 4,670,549 and 4,672,109. In case of Erythromycin-9-Oxime derivatives, the oxime is protected before methylation step with 2- alkenyl group (US Patent Nos. 4,670,549; 4,668,776) or benzyl group (US Patent Nos. 4,680,386 and 4,670,549). However, it has been reported (Ref. Journal of Antibiotics 46, No. 6, Page No. 647, year 1993) that when the Erythromycin-A-9-Oxime is protected by trimethylsilyl group, which is very unstable under basic condition pose potential impurities formation during methylation. There are some methods reported in US Patent Nos., e.g. , 4,680,386; 4,670,549 and US Patent No. 4,311,803 for the synthesis of Clarithromycin by using chlorobenzyloxycarbonyl group for protection at 2' and 3' function of of Erythromycin-A-9-Oxime derivatives.
For the protection of 2'-OH group (US Patent No. 4,311 ,803) requires large amounts of benzyl chloroformate which poses problems in handling because of its severe irritating and toxic properties. This protection step also leads to the formation of 3' -N- demethylation, which requires an additional re-methylation step. The de-protection of chlorobenzyloxy carbonyl group leads to the formation of undesired side products. In earlier reported processes, e.g. , US Patent No. 4,990,602; EP 0,272,110 Al where the methylation has been done on Erythromycin-A-9-Oxime derivatives by the protection of 2' and 4" hydroxyl groups using DMSO and THF as a solvent at 0° to 50C or at room temperature, smooth methylation takes place with less side product formation. However, by using the above methylation processes the formation of 6, 11-O-dimethyl erythromycin- A (Compound- A) is always more than 1.0 % in Clarithromycin. Hence, there is a need for an efficient methylation process for the production of Clarithromycin with lesser amount of 6,11-O-dimethyl erythromycin-A than reported previously.
SUMMARY OF THE INVENTION
The present invention discloses the robust manufacturing process for the production of Clarithromycin having less than 1.0 % of 6, 11-O-dimethyl erythromycin-A, a potential side product in Clarithromycin (Compound A). The manufacturing process of Clarithromycin effects from Erythromycin A. Erythromycin-A is reacted with hydroxylamine hydrochloride in presence of caustic solution and acetic acid to get Erythromycin-A-9-Oxime in 85 to 90 % yield. The Erythromycin-A-9-Oxime is treated with 2-methoxy propene and hexamethyl disilazane (HMDS) in dichloromethane to obtain 2',4"-disilyated-erythromycin-A-9-methoxypropyl oxime (CAM-III). A total of eight impurities have been characterized in the finished product with help of HPLC impurity profile.
In one embodiment CAM-III is treated with methyl iodide in presence of potassium hydroxide powder using DMSO-diethyl ether (1 : 1) solvent mixture at room temperature for 90 minutes to produce 2>,4"-disilylated-clarithromycin-9-methoxypropyl oxime (CAM- IV). Further CAM-IV, i.e. , methylated product is treated with 98 % formic acid in Isopropyl alcohol-Water mixture (1: 1) followed by treatment with sodium metabisulphite in Isopropyl alcohol-Water mixture (1 : 1) to get Clarithromycin. The process reported in the present invention provides oxime free Clarithromycin with total impurities less than 3.0 % having less than 1.0 % compound A. In the next embodiment a total of 8 impurities are also identified which are associated with the purified Clarithromycin.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a HPLC profile of the Clarithromycin and 6,11-Di-O-methyleryhtromycin A using 1 % standard preparation.
Figure 2 is a HPLC profile of impurities detected from the isolated Clarithromycin
DETAILED DESCRIPTION OF THE INVENTION
6-O-Methyl-erythromycin (Clarithromycin) being a potent inhibitor of gram positive bacteria, a systematic study for its large scale production with high purity is under taken. This resulted in controlled methylation of 6-OH group of 2', 4"-OH protected erythromycin. The present invention relates to the production of a better purity level of Clarithromycin (Formula I)
Formula (I)
Figure imgf000006_0001
In the first embodiment Clarithromycin obtained by this method is having less than 1.0 % of 6,11-O-dimethyl erythromycin-A, a potential side product. The present invention is directed towards the industrial process of Clarithromycin associated with controlled level of side products. A total of eight impurities have been characterized in the finished product by HPLC analysis.
According to one embodiment the present invention, Clarithromycin Form II is prepared according to the following synthetic reaction scheme:
(a) Reaction of Erythromycin-A with hydroxylamine hydrochloride (Erythtromycin-A-9- Oxime)
Hydroxylamine hydrochloride is treated with caustic flakes in aqueous isopropyl alcohol at 10° to 2O0C to generate the hydroxylamine base in solution followed by addition of Erythromycin A.
NhLOH HCI isopropyl Alcohol
Figure imgf000007_0002
Figure imgf000007_0001
Erythromycin - A Erythromycin - A - 9 - Oxime
The pH of the reaction mixture is adjusted between 6.5 to 7.0 by careful slow addition of glacial acetic acid. To the stirred reaction mixture Erythromycin -A is added and stirred for further 28 hours at 550C. After completion of reaction, the mixture is neutralized by adding aqueous ammonia and water and stirring is continued for 1 hour. Additional volume of water is added to the mixture to get the precipitate of Erythromycin- A-9-Oxime in 85 to 90 % yield.
(b) Protection of Oxime, T and 4"-OH functions of Erythromycin-A-9-Oxime
Erythromycin-A-9-Oxime obtained by the above process is treated with 2-methoxy propene and pyridine hydrochloride in dichlorome thane. The reaction mixture is stirred for 6 hours at 8° to 120C followed by the addition of hexamethyldisilazane (HMDS)
Figure imgf000008_0001
Stirring is continued for about 15 hours at an ambient temperature. After complete protection of oxime and 2' & 4" -OH functions of Erythromycin - A-9-oxime, the fully protected stuff is isolated by usual work up and filtration method. After vacuum drying CAM-III is obtained in more than 90 % yield. Melting Point = 125° - 1270C.
(c) Methylation of 6-OH group and subsequent deprotection of oxime, 2' & 4'-OH functions of CAM-III
2',4"-O-Bis(trimethylsilyl)-erythromycin-A-9-[O-(l-methoxymethyl ethyl)oxime] is treated with methyl iodide in presence of potassium hydroxide powder in a mixture of suitable solvent system to generate 2',4"-disilylated-Clarithromycin-9-methoxypropyl oxime (CAM-IV). CAM-IV on subsequent hydrolysis produces Clarithromycin-9-Oxime as shown below:
Figure imgf000008_0002
(CAM-IN) Clarithromycin-9-Oxime Suitable solvent system for this reaction include, but are not limited to a mixture of DMSO and diethyl ether. The volume ratio of diethyl ether in DMSO is between about 40 to about 60 % and preferably about 50 % . This reaction is carried out typically at temperatures between about 10° to 6O0C, preferably between about 15° to about 250C, with reaction times being between about 40 minutes to 2 hours, preferably between about 80 to 100 minutes.
The ratio of methyl iodide and potassium hydroxide powder is very critical, as otherwise it leads to many unwanted side products. After exhaustive experimentation it is observed that 1.75 mole of methyl iodide and 1.20 moles of potassium hydroxide affords final product with controlled impurities after giving one or two re-crystallizations. The advantage of the methylation process of the present invention using DMSO-Diethyl ether is that the ether layer gets separated after quenching the reaction mixture with 40% dimethylamine solution. The ether layer contains exclusively the methylated product and the DMSO layer contains impurities, which is taken for recovery of DMSO (solvent). Further CAM-IV, i.e., methylated product is treated with 98 % formic acid in 1 : 1 volume ratio of Isopropyl alcohol and water for 30 minutes at 25° to 350C to get Clarithromycin-9- Oxime.
(d) Conversion of Clarithromycin-9-Oxime to Clarithromycin
Clarithromycin-9-Oxime is further treated with sodium metabisulphite in Isopropyl alcohol- Water (1 : 1 , v/v) for 6 to 8 hours at 800C to produce Clarithromycin.
Formula (I)
Figure imgf000009_0001
Clarithromycιn-9-Oxιme Clarithromycin The deoximation of Clarithromycin-9-Oxime as reported in US Patent No. 6,617,436 to get essentially Oxime free Clarithromycin involves the deoximating step using two fold use of deoximating agent, i.e. , sodium metabisulphite which is large excess (i.e. 7.0 moles with respect to Clarithromycin-9-Oxime). The process reported in the present invention involves the use of sodium metabisulphite 1 to 3 moles preferably 2.50 moles with respect to Clarithromycin-9-Oxime to obtain Clarithromycin which is Oxime free (detected by HPLC).
The Clarithromycin obtained using the above process after purification using Isopropyl alcohol-Chloroform as solvent mixture has the following levels of the known (characterized) impurities with total impurities less than 3.0 % by HPLC analysis and Compound-A less than 1.0 % (quantitative amount in Clarithromycin Figure 1).
The content of 6,11-di-O-methyleryhtromycin A in isolated Clarithromycin is calculated using the formula,
Figure imgf000010_0001
x x Response factor x 100
As concentration of test solution
where AUM is peak area of 6,11-di-O-methylerythromycin-A (Compound A) in test solution, As is peak area of Clarithromycin in 1 % Standard preparation and Cs is concentration of Clarithromycin in 1 % Standard preparation.
Concentrations: Cone, of Clarithromycin = 20.16 ppm, cone, of Clarithromycin sample = 2008 ppm, Assay of Clarithromycin = 100 %, Response factor of 6,11-di-O- methylerythromycin A = 0.68. The 6,11-di-O-methyleryhtromycin A using the above formula is found 0.510 % in Clarithromycin (Figure 1).
These impurities has been identified by comparing each and every impurity by authentic samples using HPLC analysis. Similar retention times of these impurities with their corresponding standard samples confirmed their presence in the Clarithromycin. An HPLC method is developed for determination of impurities associated with the isolated Clarithromycin. The said impurities comprises (Figure 2), e.g. , Clarithromycin impurity I (3-O-decladinosyl-6-O-methylerythromycin-A, RT = 8.117), Erythromycin-A (E-base, RT = 11.542). Clarithromycin impurity J (Erythromycin A-9 (E)-Oxime, RT = 12.658), Z-Oxime-(6-O-Methylerythromycin A-9 (Z)-Oxime, RT = 15.592), 3'-N- DMMEO (S'-N-dimethyl-ό-O-methylerythromycin A-9 (E)-Oxime, RT = 17.600), Clarithromycin impurity C (6-O-Methylerythromycin A-9 (E)-Oxime, RT = 19.117), Clarithromycin impurity E (6, 11-di-O-methylerythromycin, RT = 29.500), 6-0-MEMMO {6-O-methylerythromycin A-9-N-[O-(l-methoxy-l-methyl-l-methyletyl)Oxime-RT = 42.775]} and for unknown impurities in Clarithromycin and is further validated for precision, accuracy, ruggedness, linearity and range.
Following is the list of impurities characterized with their levels analyzed in Clarithromycin by HPLC profile,
1. 6-O-Methyl erythromycin A-9-(Z)-Oxime (Result = Not Detected)
2. 6, 11-di-O-methyl erythromycin-A (Result = Not more than 1.0 %)
3. 6-O-Methylerythromycin-A-9 (E)-Oxime (Result = Not more than 0.5 %)
4. 3-O-decladinosyl-6-O-methyl erythromycin-A (Result = Not Detected)
5. Erythromycin-A-9 (E)-Oxime (Result = Not Detected)
6. Erythromycin A (E-base) (Result = Not more than 0.5 %)
7. 3'-N-demethyl-6-O-methyl erythromycin A-9- (E)-Oxime (Result = Not Detected)
8. 6-O-Methyl erythromycin-A-9-N [O-(l-methoxy-l-methylethyl) Oxime] (Result = Not more than 0.5 %)
9. Total impurities (Known + Unknown) (Result = Not more than 3.0%)
The isolated Clarithromycin having the above associated impurities are identified by their respective retention time using same solvents and gradient keeping other parameter constant. The Clarithromycin reported in the present invention after crystallizing in Isopropyl alcohol-Chloroform mixture has the characteristic XRD which is similar to XRD pattern polymorphic Form II, identical to reported in WO 98/04574.
Examples
The following examples illustrate the invention, but is not limiting thereof,
EXAMPLE 1
Erythromycin-A-9-Oxime
To a solution of 201 Ltr water in 561 Kg isopropyl alcohol is added 282 Kg (4057 mol) of hydroxyl amine hydrochloride under stirring and the reaction mixture is brought to 10 to 200C. Caustic flakes (162 Kg, 4050 mol) is added slowly to the reaction mixture by keeping temperature between 10° to 200C. After 15 minutes of completion of addition, pH of reaction mixture is adjusted to 6.5 to 7.0 by the slow addition of glacial acetic acid (96 Ltr, 100.8 Kg, 1678.6 mole). To the stirred reaction mass is added 300 Kg (408.8 mole) of Erythromycin-A base and reaction mixture is stirred at 55° C for 28 hours. After completion of the reaction, mixture is brought to ambient temperature and to it a mixture of ammonia solution (270 Kg) and water (600 Ltr) is added within 1 hour followed by 3000 Ltr of fresh water in next two hours and stirred the reaction mass for further 1 hour. White solid product obtained is centrifuged, wet cake is washed with water and dried at 6O0C for 12 hours to give 270 Kg of erythromycin-A Oxime. Melting point = 156° to 158°C.
EXAMPLE 2
2',4"-O-Bis(trimethylsilyl)-erythro?nycin-A-9[O-(l-methoxy-l-methyl ethyl)oxime
To a solution of 80 Kg (106.8 mole) of Erythromycin-A-9-Oxime in 400 Ltr of dichloromethane is added 38.50 Kg (534 mole) of 2-methoxy propene at 100C temperature 19.25 Kg (166.6 mole) of pyridine hydrochloride is added under stirring and the reaction mixture is stirred at 8 to 12° C for 6 hours then to it is added 19.30 Kg (119.5 mole) of HMDS and stirring is continued for 12 to 15 hours at 15° to 18°C temperature. After completion of reaction, 400 Ltr of saturated aqueous sodium carbonate solution is added and the mixture is stirred thoroughly at room temperature. Aqueous layer is further extracted with fresh DCM (100 Ltr). Both DCM extracts are mixed together and washed with water (200 Ltr) followed by brine solution (200 Ltr). The solvent is evaporated under reduced pressure. To the obtained crude solid mass is charged isopropyl alcohol (240 Ltr) and distilled out 80 Ltr of isopropyl alcohol. To the reaction mixture 160 Ltr of water is charged and stirring continued at room temperature for 1 hour. Solid crystalline product obtained is centrifuged and dried at 60° to 650C for 8 hours under vacuum to give 85 Kg of title compound. Melting point = 125° to 126°C. HPLC Purity = More than 90 % .
EXAMPLE 3
Clarithromycin-9- Oxime
To a solution of 80 Kg (82.98 mole) of 2',4"-O-bis(trimethylsilyl)-erythromycin-A- 9-[O-(l-methoxy methyl ethyl)Oxime] in 1200 Ltr of a mixture of dimethyl sulfoxide and diethylether (1 : 1) are added methyl iodide (20.62 Kg, 145.2 mole) and 6.48 Kg (98.35 mole) of 85 % potassium hydroxide powder and the reaction mixture is stirred for 90 minutes at room temperature. To the reaction mass is added 53 Kg of 40 % dimethylamine solution and stirring is continued for 1 hour diethylether layer is separated and DMSO layer is further extracted with fresh diethylether (200 Ltr). Combined ether layer is washed with water and concentrated in vacuum. To the obtained semi solid mass 330 Ltr of isopropyl alcohol is charged and then distilled out 165 Ltr of isopropyl alcohol. To the obtained slurry 165 Ltr of water and 21.71 Kg formic acid (99%) are added and the mixture is stirred at room temperature for 30 minutes. 622 Ltr of water is added to the reaction mixture and pH is adjusted between 10.5 and 11.5 with 25 % aqueous sodium hydroxide solution. Solid compound obtained is centrifuged and wet cake is kept as such for further reaction on the basis of moisture content. Wet weight = 95 Kg, Moisture Content = 33 %, Dried weight = 62 Kg
EXAMPLE 4
6-O-Methyl erythromycin- A (Clarithromycin)
62 Kg of 6-O-Methyl erythromycin-9-Oxime is charged into a mixture of 434 Ltr of isopropyl alcohol and water (1: 1) and to it is added 38.80 Kg of sodium metabisulphite (203 mole) and then the mixture is heated to reflux for 6 to 8 hours. To the reaction mixture is charged water (620 Ltr) at ambient temperature and then the mixture is adjusted to pH about 10.5 to 11.5 by adding 25% aqueous sodium hydroxide solution and stirred for further 1 hour. White solid crude product is centrifuged, washed with water (300 Ltr), dried at 65° to 750C for 8 hours to give 40 Kg of crude Clarithromycin which on re- crystallization with chloroform isopropyl alcohol mixture provided 20 Kg of Clarithromycin (Form II).

Claims

We Claim:
1 Clarithromycin having 6, 11-Di-O-methyleryhtromycin A in less than 1 % .
2 A process for manufacturing Clarithromycin having 6, 11-Di-O-methyleryhtromycin A in less than 1 % , comprising:
(a) contacting 2',4"-O-Bis(trimethylsilyl)eryhthromycin-A-9-[O-(l- methoxymethylethyl)oxime] with methyl iodide in a solvent mixture for a sufficient time in presence of a base, and
(b) isolating the Clarithromycin containing 6, 11-Di-O-methyleryhtromycin A less than 1 % .
3 The process of claim 2, wherein solvents are organic solvent.
4 The process of claim 3, wherein solvents are mixtures of N, N-dimethy sulfoxide and diethyl ether.
5 The process of claim 3-4, wherein volume ratio of diethyl ether in N, N- dimethylsulfoxide is between about 40 to about 60 % .
6 The process of claim 5, wherein more preferably volume ratio of diethyl ether in N, N- dimethylsulfoxide is 50 % .
7 The process of claim 2, wherein the contacting step is conducted at temperature between about 10° to 60° C.
8 The process of claim 7, wherein more preferably temperature is between about 15° to 250 C.
9 The process of claim 2, wherein the contact time is between about 40 minutes to 2 hours.
10 The process of claim 2, wherein base is aliphatic.
11 The process of claim 11 , wherein base is potassium hydroxide.
12 The process of claim 2, wherein molar ratio of methyl iodide and potassiumn hydroxide is between about 1 : 0.5 mole.
13 The process of claim 12, wherein more preferably the molar ratio is 1.75 to 1.2.
14 A process of claim 2, wherein the isolated Clarithromycin contains 8 impurities in less than 3 %.
15 Clarithromycin produced according the claim 2, has the following characterized impurities: I. 6-O-Methyl erythromycin A-9-(Z)-Oxime
II . 6, 11 -di-O-methyl ery thromycin-A
III. 6-O-Methyl erythromycin-A-9 (E)-Oxime
IV. 3-O-decladinosyl-6-O-methyl erythromycin-A
V. Erythromycin-A-9 (E)-Oxime
VI. Erythromycin Erythromycin A (E-base)
VII. 3'-N-demethyl-6-O-methyl erythromycin A-9- (E)-Oxime
VIII. 6-O-Methyl erythromycin-A-9-N [O-(l-methoxy-l-methylethyl) Oxime]
The Clarithromycin produced according to claim2 conforms polymorphic form 2.
Clarithromycin essentially free of Clarithromycin-9-Oxime.
PCT/IB2004/004075 2004-12-13 2004-12-13 Industrial process of clarithromycin associated with controlled level of side products WO2006064299A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2004/004075 WO2006064299A1 (en) 2004-12-13 2004-12-13 Industrial process of clarithromycin associated with controlled level of side products

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2004/004075 WO2006064299A1 (en) 2004-12-13 2004-12-13 Industrial process of clarithromycin associated with controlled level of side products

Publications (1)

Publication Number Publication Date
WO2006064299A1 true WO2006064299A1 (en) 2006-06-22

Family

ID=36587580

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/004075 WO2006064299A1 (en) 2004-12-13 2004-12-13 Industrial process of clarithromycin associated with controlled level of side products

Country Status (1)

Country Link
WO (1) WO2006064299A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103897002A (en) * 2012-12-31 2014-07-02 菏泽市方明制药有限公司 Method for preparing erythrocin A9-oxime from rough erythromycin thiocyanate
CN106749462A (en) * 2016-11-11 2017-05-31 杭州新桂实业有限公司 A kind of efficient green CLA intermediate synthesis technique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4670549A (en) * 1985-03-18 1987-06-02 Taisho Pharmaceutical Co., Ltd. Method for selective methylation of erythromycin a derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4670549A (en) * 1985-03-18 1987-06-02 Taisho Pharmaceutical Co., Ltd. Method for selective methylation of erythromycin a derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103897002A (en) * 2012-12-31 2014-07-02 菏泽市方明制药有限公司 Method for preparing erythrocin A9-oxime from rough erythromycin thiocyanate
CN106749462A (en) * 2016-11-11 2017-05-31 杭州新桂实业有限公司 A kind of efficient green CLA intermediate synthesis technique

Similar Documents

Publication Publication Date Title
EP0487411B1 (en) Erythromycin derivatives, their preparation, intermediates obtained and their application as medicaments
RU2066324C1 (en) Crystalline azithromycin dehydrate, and process for preparation thereof
JP4750755B2 (en) Novel erythromycin derivatives, their production and use as pharmaceuticals
CA2102457C (en) Erythromycin derivatives, process for the preparation thereof, and use thereof as medicaments
AU2011255464C1 (en) Processes for preparing macrolides and ketolides and intermediates therefor
JP4104463B2 (en) Process for preparing 4 "-substituted-9-deoxo-9A-aza-9A-homoerythromycin derivatives
KR0166096B1 (en) 6-o-methylerythromycin-a derivative
DE60019976T2 (en) METHOD FOR PRODUCING 6-O-ALKENYL-SUBSITUTED ERYTHROMYCIN DERIVATIVES
JP3140703B2 (en) Novel erythromycins, their preparation and use as pharmaceuticals
US6576749B2 (en) C-4″-substituted macrolide derivatives
AP1189A (en) C-4"-substituted macrolide derivatives.
DK2125850T3 (en) MACROCYCLIC POLYMORPHS, COMPOSITIONS INCLUDING SUCH POLYMORPHS, PROCEDURES FOR PREPARING AND USING THEREOF
RU2045533C1 (en) O-methyl derivatives of azithromycin a showing antibacterial activity, azithromycins as intermediate compounds for synthesis of o-methyl derivatives of azithromycin a and a method of synthesis of o-methyl derivatives of azithromycin a
EP0891371B1 (en) 9-oximesilyl erythromycin a derivatives
EP1189915B1 (en) Process for the production of azithromycin
EP1152765B1 (en) Ethanolate of azithromycin, process for manufacture, and pharmaceutical compositions thereof
US6451990B1 (en) Azithromycin preparation in its noncryst alline and crystalline dihydrate forms
KR100319358B1 (en) Novel erythromycin derivatives, preparation method thereof and use thereof as medicament
US6740642B2 (en) Macrolides with antibacterial activity
EP0180415B1 (en) A 6-0-methylerythromycin A derivative
DE69913413T2 (en) 2-Fluoro 3-de (2,6-dideoxy 3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl oxy) 6-1-methyl 3-oxo erythromycin, its process for its preparation and its use in synthesis of drugs
EP1280535B1 (en) Processes for preparing clarithromycin polymorphs
US7101858B2 (en) Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same
HU193886B (en) Process for preparing epimer azahomoerythromycin a derivatives
AP952A (en) Novel erthromycin derivatives, method for preparing same, and use thereof as drugs.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 04806328

Country of ref document: EP

Kind code of ref document: A1