CN104829662B - A kind of preparation method of azithromycin about material - Google Patents
A kind of preparation method of azithromycin about material Download PDFInfo
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- CN104829662B CN104829662B CN201510143560.7A CN201510143560A CN104829662B CN 104829662 B CN104829662 B CN 104829662B CN 201510143560 A CN201510143560 A CN 201510143560A CN 104829662 B CN104829662 B CN 104829662B
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- azithromycin
- azithromycins
- demethyls
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The present invention relates to a kind of preparation method of azithromycin about the ˊ N formoxyl azithromycins of 3 ˊ N demethyls of material 3, belong to pharmaceutical technology field.The synthetic method by 3 ˊ N demethyls azithromycins and Ethyl formate in the presence of organic solvent and base catalyst after chemical reaction and carry out, with high income, the features such as purity is high.The present invention provides scientific basis for relevant material source and raising product quality in research azithromycin, is that azithromycin is laid a good foundation about the foundation in substance data storehouse, also provides important evidence for the quality control and drug safety of China's azithromycin.
Description
Technical field
The present invention relates to a kind of preparation method of Drug-related, and in particular to the relevant ˊ-N- of material 3 of azithromycin
The preparation method of the ˊ-N- formoxyl azithromycins of demethyl -3, belongs to pharmaceutical technology field.
Background technology
Azithromycin is 15 yuan of azilide class antibiotic of first listing, is existed first within 1991 by Pfizer
The U.S. is listed, and is referred to as " cookle " in twentieth century antibiotic medicine.Azithromycin has a broad antifungal spectrum, antibacterial action is strong
Greatly, clinic is widely used in acpuei pharyngitis caused by micrococcus scarlatinae, acute tonsillitis；Nasosinusitis caused by sensitive bacterial,
Tympanitis, acute bronchitis, AECB；Streptococcus pneumonia, haemophilus influenzae and pneumonia branch are former
Pneumonia caused by body；Urethritis and cervicitis caused by chlamydia trachomatis and non-a variety of resistance NEISSERIA GONORRHOEAEs；Sensitive bacterial draws
The treatment for the skin soft-tissue infection risen；One of best-selling antibiotic product on China's medical market is turned at present.
Its chemical name of azithromycin is (2R, 3R, 4R, 5R, 8R, 10R, 11S, 12S, 13R, 14R) -13- [(2,6- bis-
Deoxidation -3-C- methyl-α-L- cores-own pyranose) oxygen] -2- ethyl -3,4,10- trihydroxies -3,5,6,8,10,12,14- seven
Methyl isophthalic acid 1- [[3,4,6- tri- deoxidation -3- (dimethylamino)-β-D- wood-own pyranose] oxygen] -1- oxa- -6- chlorine heterocycle 15
The ketone of alkane -15, with structural formula shown in formula I：
It has now been found that azithromycin drug in relevant material have 16 kinds, structural formula of compound see the table below.
In above-mentioned relevant material,《European Pharmacopoeia》、《American Pharmacopeia》With《British Pharmacopoeia》Azithromycin standard in respectively
It is required that 16 kinds, 13 kinds and 16 kinds impurity of control.《Chinese Pharmacopoeia》Required in 2010 editions azithromycin drug standards control for 5
Kind, it is Erythromycin A iminoether respectively, 3 ˊ-N- demethyls azithromycins remove cladinose azithromycin, azithromycin with 3-O-
Impurity Gx and azithromycin B.Compared to American-European pharmacopeia, require that the amount of impurities of control is less in China's azithromycin standard, it is unfavorable
In the security for ensureing clinical application, it is necessary to further improve.And in order to it is tightened up control azithromycin in relevant material,
The higher single relevant materials compounds of purity will necessarily be used in drug quality detection as in reference substance, therefore azithromycin
About preparing just as relatively more urgent technical problem for material.
Relevant ˊ-N- formoxyl the Zitromax of 3 ˊ-N- demethyls of material -3 of azithromycin is disclosed in patent US2007043214
Element and preparation method thereof, this method is using 3 ˊ-N- demethyls azithromycins as raw material, and arboxylic acid acid anhydride is formylation reagent,
K2CO3Diethyl ether solution in, carry out formylation reaction obtain impurity crude product, then using acetone as refining solvent, drip cooling tie again
Crystalline substance is made twice.This method has following defect：A, arboxylic acid acid anhydride used need fresh prepare to synthesize, and add the step of reaction
Rapid and operation difficulty；B, operating process complexity are cumbersome, and severe reaction conditions are, it is necessary to when strict controlling reaction temperature is with reacting
Between, operation difficulty and production cost are added, is unsuitable for practical application；C, yield are relatively low, and only 24%；D, the solvent second used
Ether is volatile poisonous and gas of irritant smell, and easy firing blast brings great danger to operator.
The content of the invention
The technical problems to be solved by the invention are that the defect for overcoming prior art provides relevant thing in a kind of azithromycin
The preparation method of the ˊ-N- formoxyl azithromycins of 3 ˊ-N- demethyls of matter -3.This method process conditions are simple, reaction condition relaxes,
Product separation and purification is simple, with the characteristics of simple and efficient to handle, cost is low, target product yield is high, purity is high, suitable for industry
Metaplasia is produced.
Technical problem of the present invention is realized by following technical scheme.
A kind of preparation of azithromycin as shown in Formula II about the ˊ-N- formoxyl azithromycins of 3 ˊ-N- demethyls of material -3
Method, comprises the following steps：
A. in organic solvent, using 3 ˊ-N- demethyls azithromycins as initiation material, under base catalyst effect, with
Ethyl formate carries out heating reflux reaction, and lamellae monitoring reaction to terminal, adds the purified water with organic solvent equivalent and filled
Divide stirring, stand, obtain white solid；
White solid obtained by step a is added refining solvent by b, is heated to reflux clarifying dissolving, is filtered, and filtrate is cooled to 5-
10 DEG C, stirring and crystallizing, fractional crystallization is dried to obtain the ˊ-N- formoxyl azithromycins of 3 ˊ-N- demethyls -3 of high-purity.
Above-mentioned preparation method, organic solvent described in step a is selected from tetrahydrofuran, dichloromethane, DMF, DMAC；It is preferred that two
Chloromethanes；The weight g of the volume ml of the organic solvent and 3 ˊ-N- demethyl azithromycins ratio is 8-10:1；3 ˊ-the N-
The mol ratio of demethyl azithromycin and Ethyl formate is 1:1.3.
Above-mentioned preparation method, base catalyst described in step a is selected from triethylamine, pyridine, diisopropyl ethyl amine, hydrogen-oxygen
Change sodium or potassium hydroxide；It is preferred that triethylamine；The mol ratio of the 3 ˊ-N- demethyls azithromycins and base catalyst is 1:0.3.
Above-mentioned preparation method, refining solvent described in step b is lower alcohol and water using volume ratio as 1:The mixing of 1 composition is molten
Agent, the lower alcohol is methanol, ethanol or isopropanol；It is preferred that methanol；The volume ml of the refining solvent and 3 ˊ-N- demethyl Ahs
The weight g of miramycin ratio is 3-5:1.
Separation in the step b, can be any solid-liquids well known to those skilled in the art such as press filtration, suction filtration, centrifugation
Separation method.
The present invention determines analysis by carrying out NMR, MS and HPLC to target product, and contrasting data result confirms its knot
Structure.
Beneficial effects of the present invention：
The azithromycin that the present invention is provided is about the preparation method of material, and simply, reaction condition relaxes process conditions, product
Separation and purification is simple, with simple and efficient to handle, cost is low, high income the characteristics of, can be with more convenient suitable for industrialized production
Efficiently obtain the relevant material of large number of azithromycin, and obtained relevant product substance purity is high, reach 99% with
On, the qualitative and quantitative analysis during azithromycin is produced can be applied to as reference substance, is conducive to strengthening to it about material
Control, so as to lift the quality standard and quality level of azithromycin, preferably provide guarantee for people's masses'safety medication.
Brief description of the drawings
The HPLC figures of Fig. 1 present invention ˊ-N- formoxyl azithromycins of 3 ˊ-N- demethyls -3.
The NMR hydrogen spectrograms of Fig. 2 present invention ˊ-N- formoxyl azithromycins of 3 ˊ-N- demethyls -3.
The NMR carbon spectrograms of Fig. 3 present invention ˊ-N- formoxyl azithromycins of 3 ˊ-N- demethyls -3.
Embodiment
The present invention is described in further detail below by embodiment, but is only intended to help and understands this hair
It is bright, professional and technical personnel in the field is realized or using the present invention, any limitation is not constituted to the present invention.
The raw materials used present invention is 3 ˊ-N- demethyl azithromycins, what it can be reported using patent CN103319553
Prepared by method, it would however also be possible to employ prior art other method is prepared.
The preparation of the ˊ-N- formoxyl azithromycins of 13 ˊ-N- demethyls of embodiment -3
3 ˊ-N- demethyls azithromycins (20g, 0.027mol) are taken, are dissolved with 200mL dichloromethane, triethylamine is added
(0.81g, 0.008mol) is catalyzed, and adds Ethyl formate (2.6g, 0.035mol), and heating carries out back flow reaction, and TLC monitorings are anti-
Should, reaction adds 200ml purified waters after terminating, and is sufficiently stirred for, and stands, filtering, dry white crude solid.It is solid to crude product
Mixed solvent (methanol and the water volume ratio 1 of 100ml first alcohol and waters are added in body:1), it is heated to reflux clarifying dissolving, filters, filter
Liquid is cooled to 5-10 DEG C, and stirring and crystallizing 2h, filtering obtains the relevant ˊ-N- formoxyl Archies of 3 ˊ-N- demethyls of material -3 of azithromycin
Mycin, 19.05g, yield 92.5%, HPLC purity 99.9% are weighed as after drying.
The preparation of the ˊ-N- formoxyl azithromycins of 23 ˊ-N- demethyls of embodiment -3
3 ˊ-N- demethyls azithromycins (30g, 0.041mol) are taken, are dissolved with 240mLDMF, addition pyridine (0.95g,
0.012mol) it is catalyzed, adds Ethyl formate (3.93g, 0.053mol), heating carries out back flow reaction, and TLC monitorings are reacted, instead
240ml purified waters are added after should terminating, are sufficiently stirred for, are stood, filtering, dry white crude solid.Into crude solid
Add mixed solvent (methanol and the water volume ratio 1 of 150ml first alcohol and waters:1), it is heated to reflux clarifying dissolving, filters, filtrate drop
Temperature is to 5-10 DEG C, and stirring and crystallizing 3h, filtering obtains the relevant ˊ-N- formoxyl azithromycins of 3 ˊ-N- demethyls of material -3 of azithromycin,
28.2g, yield 90.1%, HPLC purity 99.7% are weighed as after drying.
The preparation of the ˊ-N- formoxyl azithromycins of 33 ˊ-N- demethyls of embodiment -3
3 ˊ-N- demethyls azithromycins (15g, 0.02mol) are taken, are dissolved with 140mL tetrahydrofurans, sodium hydroxide is added
(0.24g, 0.006mol) is catalyzed, and adds Ethyl formate (1.93g, 0.026mol), and heating carries out back flow reaction, TLC monitorings
Reaction, reaction adds 140ml purified waters after terminating, and is sufficiently stirred for, and stands, filtering, dry white crude solid.To crude product
Mixed solvent (methanol and the water volume ratio 1 of 45ml first alcohol and waters are added in solid:1), it is heated to reflux clarifying dissolving, filters,
Filtrate is cooled to 5-10 DEG C, and stirring and crystallizing 1.5h, filtering obtains the relevant ˊ-N- formoxyls of 3 ˊ-N- demethyls of material -3 of azithromycin
Azithromycin, 13.85g, yield 90.8%, HPLC purity 99.8% are weighed as after drying.
The preparation of the ˊ-N- formoxyl azithromycins of 43 ˊ-N- demethyls of embodiment -3
3 ˊ-N- demethyls azithromycins (18g, 0.024mol) are taken, are dissolved with 180mLDMAC, potassium hydroxide is added
(0.39g, 0.007mol) is catalyzed, and adds Ethyl formate (2.30g, 0.031mol), and heating carries out back flow reaction, TLC monitorings
Reaction, reaction adds 180ml purified waters after terminating, and is sufficiently stirred for, and stands, filtering, dry white crude solid.To crude product
Mixed solvent (ethanol and the water volume ratio 1 of 80ml second alcohol and waters are added in solid:1), it is heated to reflux clarifying dissolving, filters,
Filtrate is cooled to 5-10 DEG C, and stirring and crystallizing 2h, filtering obtains the relevant ˊ-N- formoxyl Ahs of 3 ˊ-N- demethyls of material -3 of azithromycin
Miramycin, 16.66g, yield 91.0%, HPLC purity 99.6% are weighed as after drying.
The preparation of the ˊ-N- formoxyl azithromycins of 53 ˊ-N- demethyls of embodiment -3
3 ˊ-N- demethyls azithromycins (24g, 0.033mol) are taken, are dissolved with 200mL dichloromethane, diisopropyl is added
Ethylamine (1.29g, 0.01mol) is catalyzed, and adds Ethyl formate (3.18g, 0.043mol), and heating carries out back flow reaction, TLC
Monitoring reaction, reaction adds 200ml purified waters after terminating, and is sufficiently stirred for, and stands, filtering, dry white crude solid.To
Mixed solvent (isopropanol and the water volume ratio 1 of 100ml isopropyl alcohol and waters are added in crude solid:1), it is heated to reflux making dissolving clear
Clearly, filter, filtrate is cooled to 5-10 DEG C, and stirring and crystallizing 3h, filtering obtains the relevant ˊ-N- of 3 ˊ-N- demethyls of material -3 of azithromycin
Formoxyl azithromycin, 22.73g, yield 90.3%, HPLC purity 99.7% are weighed as after drying.
1 pair of present invention gained 3 ˊ-N- demethyls -3 ˊ-N- formoxyls azithromycin of testing example carries out structural identification
(1), MS is analyzed
It is consistent with theoretical molecular that mass spectrometric data is shown in Table 1. measured values (M+1).
The mass spectrometric data of table 1
| Sample | Theoretical molecular | Measured value (M+1) |
| Embodiment 1 | 762.97 | 763.0 |
| Embodiment 2 | 762.97 | 763.0 |
| Embodiment 3 | 762.97 | 762.8 |
| Embodiment 4 | 762.97 | 762.9 |
| Embodiment 5 | 762.97 | 763.1 |
(2), HPLC is analyzed
(1) chromatographic condition chromatographic column：Waters XbridgeTm shield RP 18 (5 μm) (L=0.25m, φ=
4.6mm), mobile phase：The solution of mobile phase A phosphoric acid,diluted or diluted sodium hydroxide solution regulation 1.8g/l ADSPs
PH value is to 8.9.Mobile phase B methanol：Acetonitrile (250:750) the two is mobile phase；Flow velocity：1.0ml/ minutes, column temperature：60 DEG C, inspection
Survey device：210nm, sampling volume：50μL.
(2) solution is appropriate with the ˊ-N- formoxyls azithromycin of 3 ˊ-N- demethyls -3 of the invention is produced, plus mixed solvent
Simultaneously the solution containing 8mg in every 1ml is made in constant volume dilution to (acetonitrile and methanol) ultrasonic dissolution, and precision measures 50 μ L injection liquid phase colors
Spectrometer, records chromatogram, the results are shown in Table 2.
The HPLC methods of table 2 detect each result about material
| Sample | Relative retention time | Relative time in pharmacopeia | Purity |
| Embodiment 1 | 0.51 | 0.48 | 99.9% |
| Embodiment 2 | 0.50 | 0.48 | 99.7% |
| Embodiment 3 | 0.48 | 0.48 | 99.8% |
| Embodiment 4 | 0.49 | 0.48 | 99.6% |
| Embodiment 5 | 0.48 | 0.48 | 99.7% |
It the above is only the preferred embodiment of the present invention, be not intended to limit the invention, come for those skilled in the art
Say, under the premise without departing from the principles of the invention, some improvement that can also make, retouching, equivalent substitution should be included in this
Within the protection domain of invention.
Claims (3)
1. a kind of azithromycin is about the preparation method of material, the relevant material is the ˊ-N- formoxyl Ahs of 3 ˊ-N- demethyls -3
Miramycin, it is as shown in Formula II, it is characterised in that the preparation method comprises the following steps：
A. in organic solvent, using 3 ˊ-N- demethyls azithromycins as initiation material, under base catalyst effect, with formic acid
Ethyl ester carries out heating reflux reaction, and lamellae monitoring reaction to terminal, adds the purified water with organic solvent equivalent and fully stirred
Mix, stand, obtain white solid；
White solid obtained by step a is added refining solvent by b, is heated to reflux clarifying dissolving, is filtered, and filtrate is cooled to 5-10
DEG C, stirring and crystallizing, fractional crystallization is dried to obtain the ˊ-N- formoxyl azithromycins of 3 ˊ-N- demethyls -3 of high-purity；
Wherein, the organic solvent is selected from tetrahydrofuran, dichloromethane, DMF, DMAC；The volume ml and 3 ˊ of the organic solvent-
The weight g of N- demethyl azithromycins ratio is 8-10:1；The mol ratio of the 3 ˊ-N- demethyls azithromycins and Ethyl formate
For 1:1.3；The base catalyst is selected from triethylamine, pyridine, diisopropyl ethyl amine, sodium hydroxide or potassium hydroxide；Described 3
The mol ratio of ˊ-N- demethyls azithromycins and base catalyst is 1:0.3；The refining solvent is lower alcohol and water with volume
Than for 1:The mixed solvent of 1 composition, the lower alcohol is methanol, ethanol or isopropanol；The volume ml and 3 ˊ of the refining solvent-
The weight g of N- demethyl azithromycins ratio is 3-5:1.
2. azithromycin according to claim 1 is about the preparation method of material, it is characterised in that the organic solvent is
Dichloromethane；The base catalyst is triethylamine；The refining solvent is methanol and water using volume ratio as 1:The mixing of 1 composition
Solvent.
3. azithromycin according to claim 1 is about the preparation method of material, it is characterised in that the preparation method includes
Following steps：
A. 3 ˊ-N- demethyl azithromycin 20g, 0.027mol are taken, are dissolved with 200mL dichloromethane, addition triethylamine 0.81g,
0.008mol is catalyzed, and adds Ethyl formate 2.6g, 0.035mol, and heating carries out back flow reaction, TLC monitoring reactions, reaction knot
200ml purified waters are added after beam, are sufficiently stirred for, are stood, filtering, dry white crude solid；
B. 100ml methanol is added into crude solid obtained by step a with water with volume ratio 1:1 composition mixed solvent, is heated to reflux
Dissolving is clarified, is filtered, filtrate is cooled to 5-10 DEG C, and stirring and crystallizing 2h, filtering obtains the relevant ˊ-N- of material 3 of azithromycin and goes first
ˊ-N- formoxyl the azithromycins of base -3,19.05g, yield 92.5%, HPLC purity 99.9% are weighed as after drying.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1190959A (en) * | 1995-08-03 | 1998-08-19 | 贝林格尔·英格海姆公司 | Method of preparing norbenzomorphane as an intermediate in the preparation of pharmaceutically useful benzomorphane derivatives, in particular (-)-(1R, 5S, 2'R')-3'-hydroxy-2-(2-methoxypropyl)-5,..... |
| WO2004092736A2 (en) * | 2003-04-17 | 2004-10-28 | Sandoz Ag | Derivatives of azithromycin |
| CN102399231A (en) * | 2010-09-13 | 2012-04-04 | 上海北卡医药技术有限公司 | Galanthamine preparation method |
-
2015
- 2015-03-30 CN CN201510143560.7A patent/CN104829662B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1190959A (en) * | 1995-08-03 | 1998-08-19 | 贝林格尔·英格海姆公司 | Method of preparing norbenzomorphane as an intermediate in the preparation of pharmaceutically useful benzomorphane derivatives, in particular (-)-(1R, 5S, 2'R')-3'-hydroxy-2-(2-methoxypropyl)-5,..... |
| WO2004092736A2 (en) * | 2003-04-17 | 2004-10-28 | Sandoz Ag | Derivatives of azithromycin |
| CN102399231A (en) * | 2010-09-13 | 2012-04-04 | 上海北卡医药技术有限公司 | Galanthamine preparation method |
Non-Patent Citations (2)
| Title |
|---|
| A New Synthetic Route to Polyaza-crown Macrocycles Through the Per(N-formyl)polyaza-crowns;Jerald S. Bradshaw,等;《J. Heterocyclic Chem.》;19921130;第29卷;第1429-1432页 * |
| Improvement in synthesis of 3’-N-demethylazithromycin and its derivatives;Fu Yan-jie,等;《Journal of Beijing Institute of Technology》;20131231;第22卷(第1期);第130-134页 * |
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