CN1660872A - Antibiotic 2-hydroxy ester in new type macrolide group, preparation and preparing method - Google Patents
Antibiotic 2-hydroxy ester in new type macrolide group, preparation and preparing method Download PDFInfo
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- CN1660872A CN1660872A CN 200510005411 CN200510005411A CN1660872A CN 1660872 A CN1660872 A CN 1660872A CN 200510005411 CN200510005411 CN 200510005411 CN 200510005411 A CN200510005411 A CN 200510005411A CN 1660872 A CN1660872 A CN 1660872A
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- macrolide antibiotic
- ethylsuccinate
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Abstract
A macrolitye of of antibiotics 2'-substituted hydroxyester, such as erythromycin ethylsuccinate, azimycin ethyllsuccinate, etc can be used to prepare the medicines in various forms.
Description
Technical field the present invention relates to pharmaceutical new novel macrolide antibiotic 2`-position hydroxy ester and its preparation and preparation method thereof.
The background technology macrolide antibiotics is the most frequently used clinically anti-infective, and to the particularly infection of chlamydia, mycoplasma, legionella initiation of infection that multiple sensitive strain causes, the treatment works well.Novel macrolide antibiotic commonly used at present has Roxithromycin (Roxithromycin), Azythromycin (Azithromycin), clarithromycin (Clarithromycin), rokitamycin (Rokitamycin), dirithromycin (Dirithromycin), Flurithromycin (Flurithromycin) etc., it is exactly the taste hardship that there is a common problem in these novel macrolide antibiotics, usually adopt the preparation means to be difficult to correct and overcome bitter taste, thereby the oral preparations of making is because taste is too bitter, patient particularly children is difficult to accept, and has limited application thus.In order to improve the medication compliance of oral novel macrolide antibiotic, it is very necessary to develop the novel macrolide antibiotic derivative that new no bitter taste or bitter taste alleviate.
In macrolide antibiotics, erythromycin be clinical application the earliest, the most general kind, erythromycin is extremely bitter to sour instability and taste, for many years by transformation to the erythromycin structure, particularly make erythromycin 2`-position hydroxyl become ester as making Erythromycin (erythromycin ethylsuccinate, Erythromycin Ethylsuccinate), stearic acid 2`-erythromycin propyl ester (erythromycin estolate, Erythromycin Estolate) etc., not only improved the stability of erythromycin to acid, and alleviated the bitter taste of erythromycin effectively, make it can make multiple formulation and use for oral particularly children.With reference to the experience that the erythromycin structure is successfully transformed, novel macrolide antibiotic such as Roxithromycin, Azythromycin, clarithromycin, rokitamycin, dirithromycin, Flurithromycin are carried out structure of modification, made a series of new novel macrolide antibiotic 2`-position hydroxy esters.
Summary of the invention the present invention is intended to overcome particularly children's problem of being difficult to accept of the oral preparations patient of having gone on the market novel macrolide antibiotic taste hardship, having made, by novel macrolide antibiotic is carried out structure of modification, prepare a series of new novel macrolide antibiotic 2`-position hydroxy esters, alleviated the problem of novel macrolide antibiotic taste hardship effectively.
The new novel macrolide antibiotic 2`-position hydroxy ester that the present invention makes, hydrolysis and discharge the original shape macrolide antibiotics and play anti-microbial effect in vivo.Because taste is not bitter or bitter taste alleviates, can be made into tablet, dispersible tablet, enteric coated tablet, buccal tablet, capsule, dry suspensoid, suspensoid, powder, granule, syrup, the solution of pro ore, can be made into suppository (rectum and vaginal application) and lotion again, also can be made into freeze-dried powder and intravenous infusion for intravenously administrable for topical application.
The new novel macrolide antibiotic 2`-position hydroxy ester of the present invention can be explained with following general formula,
R-CO-CH
2-R
1·R
2 n
R is a novel macrolide antibiotic in the general formula, specifically is Roxithromycin, Azythromycin, clarithromycin, rokitamycin, dirithromycin, Flurithromycin; R in the general formula
1Be preferably CH
3CH
2OCOCH
2-, also can be H, CH
3-, CH
3CH
2-, CH
3-(CH
2)
9-, CH
3-(CH
2)
15-, CH
3CH
2CH
2OCOCH
2-, (CH
3)
2CHOCOCH
2-, CH
3(CH
2)
3OCOCH
2-, (CH
3)
2CHCH
2OCOCH
2-; R in the general formula
2Can be hydrochloric acid, sulfuric acid, phosphoric acid, acetate, the acid of tangerine rafter, oxysuccinic acid, toxilic acid, lactic acid, fumaric acid, lactobionic acid, amygdalic acid, stearic acid, lauric acid, taurine, aspartic acid, L-glutamic acid, n=0～2; Acyl group in the general formula becomes ester with the 2`-position hydroxyl of novel macrolide antibiotic.
The novel macrolide antibiotic 2`-position hydroxy ester that the present invention is new can adopt following general formula and preparation method preparation,
R+R
1-CH
2COCl→R-OCCH
2-R
1
R represents novel macrolide antibiotic in the general formula, specifically is Roxithromycin, Azythromycin, clarithromycin, rokitamycin, dirithromycin, Flurithromycin; R in the general formula
1Be preferably CH
3CH
2OCOCH
2-, also can be H, CH
3-, CH
3CH
2-, CH
3-(CH
2)
9-, CH
3-(CH
2)
15-, CH
3CH
2CH
2OCOCH
2-, (CH
3)
2CHOCOCH
2-, CH
3(CH
2)
3OCOCH
2-, (CH
3)
2CHCH
2OCOCH
2-; Acyl group in the general formula becomes ester with the 2`-position hydroxyl of novel macrolide antibiotic.
The preparation method: with the heating of carboxylic acid and sulfur oxychloride or reflux and make acyl chlorides, again under alkalescence with the novel macrolide antibiotic condensation, through aftertreatment be drying to obtain new novel macrolide antibiotic 2`-position hydroxy ester.Acyl chlorides and novel macrolide antibiotic proportioning are 1: 3mol, be preferably 1: 1.5mol.Reaction can be tetrahydrofuran (THF), n-butyl ether, acetone, butanone-2, pentanone-2, Virahol, ethyl acetate with solvent, is preferably tetrahydrofuran (THF).The sour used alkali that neutralization reaction generates can be sodium bicarbonate, yellow soda ash, saleratus, salt of wormwood, sodium hydroxide, potassium hydroxide, and consumption is 0.5～1.5% (mol ratio) of raw materials used acyl chlorides.10～50 ℃ of temperature of reaction, be preferably 35 ℃.Reaction times 1～5h, be preferably 2～3h.
A series of new novel macrolide antibiotic 2`-position hydroxy esters have been prepared by above-mentioned general formula and preparation method.
Add R in the general formula
2The acid of representative also can be made into new novel macrolide antibiotic 2`-position hydroxy ester series salt.
A series of new novel macrolide antibiotic 2`-position hydroxy esters have been prepared by above-mentioned general formula and method, being the new novel macrolide antibiotic 2`-position hydroxy ester of representative with 2`-(ethyl succsinic acid) macrolide antibiotics ester particularly, specifically is Roxithromycin 2'-(Ethylsuccinate) (Roxithromycin 2-` (Ethylsuccinate)), Azithromycin 2'-(Ethylsuccinate) (Azithromycin2-` (Ethylsuccinate)), Clarithromycin 2'-(Ethylsuccinate) (Clarithromycin 2-` (Ethylsuccinate)), Rokitamycin 2'-(Ethylsuccinate) (Rokitamycin 2-` (Ethylsuccinate)), Dirithromycin 2'-(Ethylsuccinate) (Dirithromycin2-` (Ethylsuccinate)), Flurithromycin 2'-(Ethylsuccinate) (Flurithromycin 2-` (Ethylsuccinate)).
The novel macrolide antibiotic 2`-position hydroxy ester that the present invention is new, can be made into tablet, dispersible tablet, enteric coated tablet, buccal tablet, capsule, dry suspensoid, suspensoid, powder, granule, syrup, the solution of pro ore, for the suppository (rectum and vaginal application) and the lotion of topical application, also can be made into freeze-dried powder and intravenous infusion for intravenously administrable.
The tablet and the dispersible tablet of the novel macrolide antibiotic 2`-position hydroxy ester that the present invention is new, every contains new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g, best 0.1g～0.5g in the prescription, also contains tamanori, thinner, disintegrating agent, tensio-active agent and lubricant in the prescription.Tamanori, thinner, disintegrating agent, tensio-active agent and lubricant can be 30 POVIDONE K 30 BP/USP 30, hypromellose, carmethose, Microcrystalline Cellulose, hydroxypropylcellulose, carboxymethylstach sodium, pregelatinized Starch, starch, sodium lauryl sulphate, polyethylene glycol 6000, micropowder silica gel, talcum powder, Magnesium Stearate, and these auxiliary materials can multiplely mix use in varing proportions.Tamanori, thinner, the total add-on of disintegrating agent are 5～50%, best 10～45% of recipe quantity; Tensio-active agent, the total add-on of lubricant are 0.5～5%, best 1～4.5% of recipe quantity, good to guarantee tablet material fluidity in the course of processing, tablet compressibility, good moldability, the tablet appearance that makes, hardness, friability, disintegration, dispersed homogeneous degree and drug dissolution are qualified.Fine powder with new novel macrolide antibiotic 2`-position hydroxy ester and thinner, disintegrating agent during preparation mixes, produce wet granular with an amount of tamanori, in 60 ℃ of air seasonings, whole grain, it is even to add tensio-active agent and mix lubricant, according to the content of the new novel macrolide antibiotic 2`-position hydroxy ester of difference, select for use the punch die compressing tablet of different size promptly to get the tablet and the dispersible tablet of novel macrolide antibiotic 2`-position hydroxy ester newly.
The capsule of the novel macrolide antibiotic 2`-position hydroxy ester that the present invention is new, every contains new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g, best 0.1g～0.5g in the prescription, also contains thinner, glidant in the prescription.Thinner, glidant are some pharmaceutical excipients commonly used such as starch, pregelatinized Starch, dextrin, lactose, sucrose, glucose, hypromellose, hydroxypropylcellulose, polyethylene glycol 6000, micropowder silica gel, talcum powder, Magnesium Stearate, these auxiliary materials can multiplely mix use in varing proportions, total consumption be recipe quantity 10～60%, be preferably 15～55%, guaranteeing that capsule material fluidity in the course of processing is good, the product loading amount is accurate, and the drug dissolution height.Fine powder with new novel macrolide antibiotic 2`-position hydroxy ester and thinner, glidant during preparation mixes, according to the content of the new novel macrolide antibiotic 2`-position hydroxy ester of difference, select for use the capsule of different size to load the capsule that promptly gets novel macrolide antibiotic 2`-position hydroxy ester newly.
The dry suspensoid of the novel macrolide antibiotic 2`-position hydroxy ester that the present invention is new, every bag contains new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g, best 0.1g～0.5g in the prescription, also contains thickening material, suspending agent, fragrant correctives in the prescription.Thickening material, suspending agent are specially hydroxypropylcellulose, hypromellose, carmethose, polyoxyethylene glycol, polyvinyl alcohol, alginates, pectin, gum arabic, colloid silica, xanthan gum, 30 POVIDONE K 30 BP/USP 30 etc., can be separately, also can mix use in varing proportions, total consumption be recipe quantity 0.5～4%, best 1%～3%, can the homodisperse suspendible after being added in the water to guarantee dry suspensoid.Fragrant correctives can be sucrose, glucose, N.F,USP MANNITOL, lactose, glycyrrhetate, Steviosin, aspartame, soluble saccharin, xitix, Citric Acid, synthetic and natural perfume, can be separately, also can mix use in varing proportions, total consumption is 60～98%, best 75～95% of a recipe quantity, so that the dry suspensoid that makes is fragrant and sweet good to eat, patient takes like a shot.Can the new novel macrolide antibiotic 2`-position hydroxy ester and the auxiliary material that contain moisture is dry in advance during preparation, be ground into the above fine powder of 100 orders, after mixing by the dilution method of progressively increasing step by step then, pack packing on request, every bag of 1～5g promptly gets the dry suspensoid of novel macrolide antibiotic 2`-position hydroxy ester newly.
The granule of the novel macrolide antibiotic 2`-position hydroxy ester that the present invention is new, every bag contains new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g, best 0.1g～0.5g in the prescription, also contains thinner, tamanori, fragrant correctives in the prescription.Thinner is specially hydroxypropylcellulose, carmethose, polyoxyethylene glycol, polyvinyl alcohol, starch, pregelatinized Starch, sucrose, glucose, N.F,USP MANNITOL, lactose, can be separately, also can mix use in varing proportions, total consumption is 50～95%, best 75～90% of a recipe quantity.Tamanori is specially starch paste, 30 POVIDONE K 30 BP/USP 30, hypromellose, syrup, can be separately, also can mix use in varing proportions, and total consumption is 3～15%, best 5～10% of a recipe quantity.The fragrance correctives can be glycyrrhetate, Steviosin, aspartame, soluble saccharin, xitix, Citric Acid, synthetic and natural perfume, can be separately, also can mix use in varing proportions, and total consumption is 1～10%, best 3～7% of a recipe quantity.New novel macrolide antibiotic 2`-position hydroxy ester and ingredient powder can be broken into the above fine powder of 100 orders during preparation, after mixing by the dilution method of progressively increasing step by step then, make softwood with an amount of tamanori, the system wet granular, drying adds fragrant correctives, whole grain and mix after, pack packing on request, every bag of 1～5g promptly gets the granule of novel macrolide antibiotic 2`-position hydroxy ester newly.
The suppository of the novel macrolide antibiotic 2`-position hydroxy ester that the present invention is new, every contains new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g, best 0.1g～0.5g in the prescription, also contains matrix in the prescription.Matrix specifically can be semi-synthetic fatty acid ester, mixed fatty glycerides, theobroma oil, polyethylene glycol 6000, and these auxiliary materials can multiplely mix use in varing proportions, and total consumption is 10～97%, best 50～95% of a recipe quantity.After during preparation substrate mixture being heated to 70 ℃ of thawings, the cooling back adds new novel macrolide antibiotic 2`-position hydroxy ester fine powder slightly, mix, be poured in the suppository mould of the different size of selecting for use according to the new novel macrolide antibiotic 2`-position hydroxy ester content of difference that scribbles whiteruss and shape, scrape after the cooling and overflow part, molding goes out the suppository that bolt promptly gets novel macrolide antibiotic 2`-position hydroxy ester newly.
The lotion of the novel macrolide antibiotic 2`-position hydroxy ester that the present invention is new, every 100ml contains new novel macrolide antibiotic 2`-position hydroxy ester 0.1g～10g, best 0.5g～8g in the prescription, also contain solvating agent, stablizer in the prescription, solvating agent and stablizer specifically can be purified water, propylene glycol, glycerine, poly(oxyethylene glycol) 400, tween 80, Zonon D, these auxiliary materials can multiplely mix use in varing proportions, and total consumption is 50～99%, best 60～97% of a recipe quantity.During preparation new novel macrolide antibiotic 2`-position hydroxy ester fine powder is joined in the mixed solution of solvating agents such as purified water, glycerine, propylene glycol and stablizer, heat makes material dissolution a little, filter, can promptly gets the lotion of novel macrolide antibiotic 2`-position hydroxy ester newly in bottle.
Embodiment the present invention can be with following exemplary embodiments, particularly be that the embodiment of representative is illustrated with new novel macrolide antibiotic 2`-(ethyl succsinic acid) ester.
Embodiment 1, Clarithromycin 2'-(Ethylsuccinate):
Preparation method: in the mixing solutions of 60ml tetrahydrofuran (THF), 90ml 20% yellow soda ash, add clarithromycin 15g (0.02mol), stirring is cooled to below 20 ℃, slowly be added dropwise to the tetrahydrofuran solution of 5g (0.03mol) Ethyl Succinyl Chloride, behind the reaction 3h, add an amount of yellow soda ash and regulate pH to 7.0～9.0, littlely be heated to 30 ℃, stir 30min, tell organic layer after leaving standstill, use anhydrous sodium sulfate drying, filter, cooling also adds an amount of purified water and makes and separate out crystallization, filter washing, vacuum-drying, get Clarithromycin 2'-(Ethylsuccinate), yield is more than 90%.
Other embodiment: adopt and a kind of same method of embodiment, but replace clarithromycin among the embodiment 1 respectively with Roxithromycin, Azythromycin, rokitamycin, dirithromycin, Flurithromycin, can prepare Roxithromycin 2'-(Ethylsuccinate), Azithromycin 2'-(Ethylsuccinate), Rokitamycin 2'-(Ethylsuccinate), Dirithromycin 2'-(Ethylsuccinate), Flurithromycin 2'-(Ethylsuccinate) respectively.
Embodiment 2, the Clarithromycin 2'-(Ethylsuccinate) tablet:
Prescription: Clarithromycin 2'-(Ethylsuccinate) 300g
Hydroxypropylcellulose 20g
Microcrystalline Cellulose 20g
Pregelatinized Starch 20g
Lactose 30g
The 3% hypromellose aqueous solution is an amount of
Sodium lauryl sulphate 2g
Micropowder silica gel 4g
Magnesium Stearate 2g
Make 1000
Preparation method: take by weighing 80～100 purpose Clarithromycin 2'-(Ethylsuccinate)s, hydroxypropylcellulose, Microcrystalline Cellulose, pregelatinized Starch, lactose and sodium lauryl sulphate, mix, it is an amount of to add the 3% hypromellose aqueous solution, make suitable softwood, granulate with 16 order nylon wires, wet granular evenly spreads out in drying tray, in 60 ℃ of quick air seasonings down, and control moisture 1～2%.Add micropowder silica gel and Magnesium Stearate in dried particle, mixing is with the whole grain of 14 order nylon wires, control pressure 4～5kg/cm behind the mixing
2Compressing tablet promptly gets the Clarithromycin 2'-(Ethylsuccinate) sheet.
Other embodiment: adopt and 2 kinds of same methods of embodiment, but replace Clarithromycin 2'-(Ethylsuccinate) among the embodiment 2 respectively with Roxithromycin 2'-(Ethylsuccinate), Azithromycin 2'-(Ethylsuccinate), Rokitamycin 2'-(Ethylsuccinate), Dirithromycin 2'-(Ethylsuccinate), Flurithromycin 2'-(Ethylsuccinate), can prepare Roxithromycin 2'-(Ethylsuccinate) sheet, Azithromycin 2'-(Ethylsuccinate) sheet, Rokitamycin 2'-(Ethylsuccinate) sheet, Dirithromycin 2'-(Ethylsuccinate) sheet, Flurithromycin 2'-(Ethylsuccinate) sheet respectively.
Embodiment 3, the Roxithromycin 2'-(Ethylsuccinate) dispersible tablet:
Prescription: Roxithromycin 2'-(Ethylsuccinate) 175g
Carboxymethylstach sodium 14g
Hydroxypropylcellulose 14g
Microcrystalline Cellulose 14g
Pregelatinized Starch 49g
Sodium lauryl sulphate 2.8g
10% 30 POVIDONE K 30 BP/USP, 30 ethanol liquid are an amount of
Polyethylene glycol 6000 5.6g
Micropowder silica gel 4.2g
Magnesium Stearate 1.4g
Make 1000
Preparation method: take by weighing 80～100 purpose Roxithromycin 2'-(Ethylsuccinate)s, carboxymethylstach sodium, hydroxypropylcellulose, Microcrystalline Cellulose, pregelatinized Starch and sodium lauryl sulphate, mix, add 10% 30 POVIDONE K 30 BP/USP, 30 ethanol liquid and make suitable softwood.Granulate with 16 order nylon wires, wet granular evenly spreads out in drying tray, in 60 ℃ of quick air seasonings, and control moisture 1～2%.Add polyethylene glycol 6000, micropowder silica gel and Magnesium Stearate in dried particle, mixing is with the whole grain of 14 order nylon wires, control pressure 4～5kg/cm behind the mixing
2Compressing tablet promptly gets the Roxithromycin 2'-(Ethylsuccinate) dispersible tablet.
Other embodiment: adopt and 3 kinds of same methods of embodiment, but replace Roxithromycin 2'-(Ethylsuccinate) among the embodiment 3 respectively with Azithromycin 2'-(Ethylsuccinate), Clarithromycin 2'-(Ethylsuccinate), Rokitamycin 2'-(Ethylsuccinate), Dirithromycin 2'-(Ethylsuccinate), Flurithromycin 2'-(Ethylsuccinate), can prepare Azithromycin 2'-(Ethylsuccinate) dispersible tablet, Clarithromycin 2'-(Ethylsuccinate) dispersible tablet, Rokitamycin 2'-(Ethylsuccinate) dispersible tablet, Dirithromycin 2'-(Ethylsuccinate) dispersible tablet, Flurithromycin 2'-(Ethylsuccinate) dispersible tablet respectively.
Embodiment 4, the Azithromycin 2'-(Ethylsuccinate) capsule:
Prescription and preparation method: take by weighing 80～100 purpose Azithromycin 2'-(Ethylsuccinate) 300g, hydroxypropylcellulose 15g, lactose 25g, polyethylene glycol 6000 20g, micropowder silica gel 10g, mix, can promptly gets the Azithromycin 2'-(Ethylsuccinate) capsule in capsule.
Other embodiment: adopt and 4 kinds of same methods of embodiment, but replace Azithromycin 2'-(Ethylsuccinate) among the embodiment 4 respectively with Roxithromycin 2'-(Ethylsuccinate), Clarithromycin 2'-(Ethylsuccinate), Rokitamycin 2'-(Ethylsuccinate), Dirithromycin 2'-(Ethylsuccinate), Flurithromycin 2'-(Ethylsuccinate), can prepare Roxithromycin 2'-(Ethylsuccinate) capsule, Clarithromycin 2'-(Ethylsuccinate) capsule, Rokitamycin 2'-(Ethylsuccinate) capsule, Dirithromycin 2'-(Ethylsuccinate) capsule, Flurithromycin 2'-(Ethylsuccinate) capsule respectively.
Embodiment 5, the Clarithromycin 2'-(Ethylsuccinate) dry suspensoid:
Prescription: Clarithromycin 2'-(Ethylsuccinate) 300g
Hydroxypropylcellulose 20g
Xanthan gum 10g
Micropowder silica gel 10g
Spices 20g
Lactose 500g
Sucrose 1140g
Make 1000 bags
The preparation method: take by weighing 80～100 purpose Clarithromycin 2'-(Ethylsuccinate)s, hydroxypropylcellulose, xanthan gum, micropowder silica gel, spices, lactose and cane sugar powder, mix by the dilution method of progressively increasing step by step, the pack packing promptly gets the Clarithromycin 2'-(Ethylsuccinate) dry suspensoid.
Other embodiment: adopt and 5 kinds of same methods of embodiment, but replace Clarithromycin 2'-(Ethylsuccinate) among the embodiment 5 respectively with Roxithromycin 2'-(Ethylsuccinate), Azithromycin 2'-(Ethylsuccinate), Rokitamycin 2'-(Ethylsuccinate), Dirithromycin 2'-(Ethylsuccinate), Flurithromycin 2'-(Ethylsuccinate), can prepare Roxithromycin 2'-(Ethylsuccinate) dry suspensoid, Azithromycin 2'-(Ethylsuccinate) dry suspensoid, Rokitamycin 2'-(Ethylsuccinate) dry suspensoid, Dirithromycin 2'-(Ethylsuccinate) dry suspensoid, Flurithromycin 2'-(Ethylsuccinate) dry suspensoid respectively.
Embodiment 6, the Clarithromycin 2'-(Ethylsuccinate) granule:
Prescription: Clarithromycin 2'-(Ethylsuccinate) 300g
Hydroxypropylcellulose 20g
Starch 50g
Micropowder silica gel 10g
Spices 20g
Lactose 500g
Sucrose 600g
10% starch paste is an amount of
Make 1000 bags of 1500g
Preparation method: take by weighing 80～100 purpose Clarithromycin 2'-(Ethylsuccinate)s, hydroxypropylcellulose, starch, micropowder silica gel, lactose and cane sugar powder, mix by the dilution method of progressively increasing step by step, make suitable softwood in right amount with 10% starch paste, granulate with 16 order nylon wires, wet granular evenly spreads out in drying tray, in 60 ℃ of quick air seasonings, control moisture 1～2%.In dried particle, add spices, mixing, with the whole grain of 14 order nylon wires, the pack packing promptly gets the Clarithromycin 2'-(Ethylsuccinate) granule.
Other embodiment: adopt and 6 kinds of same methods of embodiment, but replace Clarithromycin 2'-(Ethylsuccinate) among the embodiment 6 respectively with Roxithromycin 2'-(Ethylsuccinate), Azithromycin 2'-(Ethylsuccinate), Rokitamycin 2'-(Ethylsuccinate), Dirithromycin 2'-(Ethylsuccinate), Flurithromycin 2'-(Ethylsuccinate), can prepare Roxithromycin 2'-(Ethylsuccinate) granule, Azithromycin 2'-(Ethylsuccinate) granule, Rokitamycin 2'-(Ethylsuccinate) granule, Dirithromycin 2'-(Ethylsuccinate) granule, Flurithromycin 2'-(Ethylsuccinate) granule respectively.
Embodiment 7, Roxithromycin 2'-(Ethylsuccinate) suppository:
Prescription and preparation method: after mixture heating up to the 70 ℃ thawing with semi-synthetic fatty acid ester 350g and polyethylene glycol 6000 50g, add 200g Roxithromycin 2'-(Ethylsuccinate) fine powder, mix, be poured in the duckbill suppository mould that scribbles whiteruss, scrape after the cooling and overflow part, molding goes out bolt and promptly gets Roxithromycin 2'-(Ethylsuccinate) suppository.
Other embodiment: adopt and 7 kinds of same methods of embodiment, but with Azithromycin 2'-(Ethylsuccinate), Clarithromycin 2'-(Ethylsuccinate), Rokitamycin 2'-(Ethylsuccinate), Dirithromycin 2'-(Ethylsuccinate), Flurithromycin 2'-(Ethylsuccinate).Replace the Roxithromycin 2'-(Ethylsuccinate) among the embodiment 7 respectively, can prepare Azithromycin 2'-(Ethylsuccinate) bolt, Clarithromycin 2'-(Ethylsuccinate) bolt, Rokitamycin 2'-(Ethylsuccinate) bolt, Dirithromycin 2'-(Ethylsuccinate) bolt, Flurithromycin 2'-(Ethylsuccinate) bolt respectively.
Embodiment 8, the Roxithromycin 2'-(Ethylsuccinate) lotion:
Prescription and preparation method: 200ml propylene glycol, 200ml glycerine, 50ml poly(oxyethylene glycol) 400,10g tween 80,5g Zonon D are added in the 500ml purified water, stir and make to dissolve and mix, be heated to 50 ℃, add 8g Roxithromycin 2'-(Ethylsuccinate) fine powder, stir 1h in 50 ℃ and make abundant dissolving, filter, add purified water and make into 1000ml, be sub-packed in and promptly get the Roxithromycin 2'-(Ethylsuccinate) lotion in the 100ml bottle.
Other embodiment: adopt and 8 kinds of same methods of embodiment, but replace Roxithromycin 2'-(Ethylsuccinate) among the embodiment 8 respectively with Azithromycin 2'-(Ethylsuccinate), Clarithromycin 2'-(Ethylsuccinate), Rokitamycin 2'-(Ethylsuccinate), Dirithromycin 2'-(Ethylsuccinate), Flurithromycin 2'-(Ethylsuccinate), can prepare Azithromycin 2'-(Ethylsuccinate) lotion, Clarithromycin 2'-(Ethylsuccinate) lotion, Rokitamycin 2'-(Ethylsuccinate) lotion, Dirithromycin 2'-(Ethylsuccinate) lotion, Flurithromycin 2'-(Ethylsuccinate) lotion respectively.
Claims (11)
1, new novel macrolide antibiotic 2-position hydroxy ester and its preparation and preparation method thereof.
2, the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 1 has following general formula,
R-CO-CH
2-R
1·R
2 n
R is a novel macrolide antibiotic in the general formula, specifically is Roxithromycin, Azythromycin, clarithromycin, rokitamycin, dirithromycin, Flurithromycin; R in the general formula
1Be preferably CH
3CH
2OCOCH
2-, also can be H, CH
3-, CH
3CH
2-, CH
3-(CH
2)
9-, CH
3-(CH
2)
15-, CH
3CH
2CH
2OCOCH
2-, (CH
3)
2CHOCOCH
2-, CH
3(CH
2)
3OCOCH
2-, (CH
3)
2CHCH
2OCOCH
2-; R in the general formula
2Can be hydrochloric acid, sulfuric acid, phosphoric acid, acetate, the acid of tangerine rafter, oxysuccinic acid, toxilic acid, lactic acid, fumaric acid, lactobionic acid, amygdalic acid, stearic acid, lauric acid, taurine, aspartic acid, L-glutamic acid, n=0～2; Acyl group in the general formula becomes ester with the 2`-position hydroxyl of novel macrolide antibiotic.
3, claim 1 can adopt following general formula and preparation method preparation to the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 2,
R+R
1-CH
2COCl→R-OCCH
2-R
1
R represents novel macrolide antibiotic in the general formula, specifically is Roxithromycin, Azythromycin, clarithromycin, rokitamycin, dirithromycin, Flurithromycin; R in the general formula
1Be preferably CH
3CH
2OCOCH
2-, also can be H, CH
3-, CH
3CH
2-, CH
3-(CH
2)
9-, CH
3-(CH
2)
15-, CH
3CH
2CH
2OCOCH
2-, (CH
3)
2CHOCOCH
2-, CH
3(CH
2)
3OCOCH
2-, (CH
3)
2CHCH
2OCOCH
2-; Acyl group in the general formula becomes ester with the 2`-position hydroxyl of novel macrolide antibiotic.
The preparation method: with the heating of carboxylic acid and sulfur oxychloride or reflux and make acyl chlorides, again under alkalescence with the novel macrolide antibiotic condensation, after aftertreatment and drying, promptly get novel macrolide antibiotic 2`-position hydroxy ester newly.Acyl chlorides and novel macrolide antibiotic proportioning are 1: 3 (mol ratio), are preferably 1: 2 (mol ratio).Reaction can be tetrahydrofuran (THF), n-butyl ether, acetone, butanone-2, pentanone-2, Virahol, ethyl acetate with solvent, is preferably tetrahydrofuran (THF).The sour used alkali that neutralization reaction generates can be sodium bicarbonate, yellow soda ash, saleratus, salt of wormwood, sodium hydroxide, potassium hydroxide, and consumption is 0.5～1.5% (mol ratio) of raw materials used acyl chlorides.10～50 ℃ of temperature of reaction, be preferably 35 ℃.Reaction times 1～5h, be preferably 2～3h.
A series of new novel macrolide antibiotic 2`-position hydroxy esters have been prepared respectively by above-mentioned general formula and preparation method.
Add R in the described general formula of claim 2
2The acid of representative also can be made into new novel macrolide antibiotic 2`-position hydroxy ester series salt.
4, claim 1, new novel macrolide antibiotic 2`-position hydroxy ester described in claim 2 and claim 3 general formula, being the new novel macrolide antibiotic 2`-position hydroxy ester of representative with 2`-(ethyl succsinic acid) novel macrolide antibiotic ester particularly, specifically is Roxithromycin 2'-(Ethylsuccinate) (Roxithromycin 2-` (Ethylsuccinate)), Azithromycin 2'-(Ethylsuccinate) (Azithromycin 2-` (Ethylsuccinate)), Clarithromycin 2'-(Ethylsuccinate) (Clarithromycin2-` (Ethylsuccinate)), Rokitamycin 2'-(Ethylsuccinate) (Rokitamycin 2-` (Ethylsuccinate)), Dirithromycin 2'-(Ethylsuccinate) (Dirithromycin 2-` (Ethylsuccinate)), Flurithromycin 2'-(Ethylsuccinate) (Flurithromycin2-` (Ethylsuccinate)).
5, the preparation of the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 1, specifically be meant in claim 2 general formula and the preparation of the concrete kind of the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 4, Roxithromycin 2'-(Ethylsuccinate) particularly, Azithromycin 2'-(Ethylsuccinate), Clarithromycin 2'-(Ethylsuccinate), Rokitamycin 2'-(Ethylsuccinate), Dirithromycin 2'-(Ethylsuccinate), the preparation of Flurithromycin 2'-(Ethylsuccinate), formulation comprises the tablet of pro ore, dispersible tablet, enteric coated tablet, buccal tablet, capsule, dry suspensoid, suspensoid, powder, granule, syrup, solution, for the suppository (rectum and vaginal application) and the lotion of topical application, for the freeze-dried powder and the intravenous infusion of intravenously administrable.
6, claim 1 to the preparation of the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 5 comprises tablet and dispersible tablet, every contains the described new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g of claim 2, best 0.1g～0.5g in tablet and the dispersible tablet prescription, also contains tamanori, thinner, disintegrating agent, tensio-active agent and lubricant in the prescription.Tamanori, thinner, disintegrating agent, tensio-active agent and lubricant can be 30 POVIDONE K 30 BP/USP 30, hypromellose, carmethose, Microcrystalline Cellulose, hydroxypropylcellulose, carboxymethylstach sodium, pregelatinized Starch, starch, sodium lauryl sulphate, polyethylene glycol 6000, micropowder silica gel, talcum powder, Magnesium Stearate, and these auxiliary materials can multiplely mix use in varing proportions.Tamanori, thinner, the total add-on of disintegrating agent are 5～50%, best 10～45% of recipe quantity; Tensio-active agent, the total add-on of lubricant are 0.5～5%, best 1～4.5% of recipe quantity.Fine powder with new novel macrolide antibiotic 2`-position hydroxy ester and thinner, disintegrating agent during preparation mixes, produce wet granular with an amount of tamanori, in 60 ℃ of air seasonings, whole grain, it is even to add tensio-active agent and mix lubricant, and the punch die compressing tablet of selecting different size for use according to the content of the new novel macrolide antibiotic 2`-position hydroxy ester of difference promptly.
7, claim 1 to the preparation of the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 5 comprises capsule, every contains the described new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g of claim 2, best 0.1g～0.5g in the capsule prescription, also contains thinner, glidant in the prescription.Thinner, glidant are some pharmaceutical excipients commonly used such as starch, pregelatinized Starch, dextrin, lactose, sucrose, glucose, hypromellose, hydroxypropylcellulose, polyethylene glycol 6000, micropowder silica gel, talcum powder, Magnesium Stearate, these auxiliary materials can be multiple mix in varing proportions and use, total consumption be recipe quantity 10～60%, be preferably 15～55%.Fine powder with new novel macrolide antibiotic 2`-position hydroxy ester and thinner, glidant during preparation mixes, and fills in as required in the capsule of different size promptly.
8, claim 1 to the preparation of the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 5 comprises dry suspensoid, every bag contains the described new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g of claim 2, best 0.1g～0.5g in the dry suspensoid prescription, also contains thickening material, suspending agent, fragrant correctives in the prescription.Thickening material, suspending agent are specially hydroxypropylcellulose, hypromellose, carmethose, polyoxyethylene glycol, polyvinyl alcohol, alginates, pectin, gum arabic, colloid silica, xanthan gum, 30 POVIDONE K 30 BP/USP 30 etc., can be separately, also can mix use in varing proportions, total consumption be recipe quantity 0.5～4%, best 1%～3%, can the homodisperse suspendible after being added in the water to guarantee dry suspensoid.Fragrant correctives can be sucrose, glucose, N.F,USP MANNITOL, lactose, glycyrrhetate, Steviosin, aspartame, soluble saccharin, xitix, Citric Acid, synthetic and natural perfume, can be separately, also can mix use in varing proportions, total consumption is 60～98%, best 75～95% of a recipe quantity, so that the dry suspensoid that makes is fragrant and sweet good to eat, patient takes like a shot.Can the new novel macrolide antibiotic 2`-position hydroxy ester and the auxiliary material that contain moisture is dry in advance during preparation, be ground into the above fine powder of 100 orders, after mixing by the dilution method of progressively increasing step by step then, can pack packing on request, every bag of 1～5g.
9, claim 1 to the preparation of the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 5 comprises granule, every bag contains the described new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g of claim 2, best 0.1g～0.5g in the granule prescription, also contains thinner, tamanori, fragrant correctives in the prescription.Thinner is specially hydroxypropylcellulose, carmethose, polyoxyethylene glycol, polyvinyl alcohol, starch, pregelatinized Starch, sucrose, glucose, N.F,USP MANNITOL, lactose, can be separately, also can mix use in varing proportions, total consumption is 50～95%, best 75～90% of a recipe quantity.Tamanori is specially starch paste, 30 POVIDONE K 30 BP/USP 30, hypromellose, syrup, can be separately, also can mix use in varing proportions, and total consumption is 3～15%, best 5～10% of a recipe quantity.The fragrance correctives can be glycyrrhetate, Steviosin, aspartame, soluble saccharin, xitix, Citric Acid, synthetic and natural perfume, can be separately, also can mix use in varing proportions, and total consumption is 1～10%, best 3～7% of a recipe quantity.New novel macrolide antibiotic 2`-position hydroxy ester and ingredient powder can be broken into the above fine powder of 100 orders during preparation, after mixing by the dilution method of progressively increasing step by step then, make softwood with an amount of tamanori, the system wet granular, drying adds fragrant correctives, whole grain and mix after, can pack packing on request, every bag of 1～5g.
10, claim 1 to the preparation of the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 5 comprises suppository, every contains the described new novel macrolide antibiotic 2`-position hydroxy ester 0.05g～0.55g of claim 2, best 0.1g～0.5g in the suppository prescription, also contains matrix in the prescription.Matrix specifically can be semi-synthetic fatty acid ester, mixed fatty glycerides, theobroma oil, polyethylene glycol 6000, and these auxiliary materials can multiplely mix use in varing proportions, and total consumption is 10～97%, best 50～95% of a recipe quantity.After during preparation substrate mixture being heated to 70 ℃ of thawings, the cooling back adds new novel macrolide antibiotic 2`-position hydroxy ester fine powder slightly, mix, be poured in the suppository mould of the different size of selecting for use according to the new novel macrolide antibiotic 2`-position hydroxy ester content of difference that scribbles whiteruss, scrape after the cooling and overflow part, molding goes out bolt promptly.
11, claim 1 to the preparation of the described new novel macrolide antibiotic 2`-position hydroxy ester of claim 5 comprises lotion, every 100ml contains the described new novel macrolide antibiotic 2`-position hydroxy ester 0.1g～10g of claim 2 in the lotion prescription, best 0.5g～8g, also contain solvating agent in the prescription, stablizer, solvating agent and stablizer specifically can be purified water, propylene glycol, glycerine, poly(oxyethylene glycol) 400, tween 80, Zonon D, these auxiliary materials can multiplely mix use in varing proportions, and total consumption is 50～99% of a recipe quantity, best 60～97%.During preparation new novel macrolide antibiotic 2`-position hydroxy ester fine powder joined in the mixed solution of solvating agent such as purified water, glycerine, propylene glycol and stablizer, heat makes material dissolution a little, filter, can in bottle promptly.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038700B (en) * | 2009-10-14 | 2012-09-12 | 海南澳美华制药有限公司 | Bitter-taste-masking erythromycin-cydocarbonate-containing oral composition |
| CN106632553A (en) * | 2016-12-27 | 2017-05-10 | 黄石世星药业有限责任公司 | Preparation method of erythromycin ethylsuccinate |
| CN111358754A (en) * | 2020-03-13 | 2020-07-03 | 广州白云山汉方现代药业有限公司 | Long-circulating emulsion of macrolide antibiotics and preparation method thereof |
| CN112022820A (en) * | 2020-09-04 | 2020-12-04 | 迪沙药业集团有限公司 | Erythromycin ethylsuccinate tablet composition and preparation method thereof |
| WO2024092149A1 (en) * | 2022-10-26 | 2024-05-02 | University Of Notre Dame Du Lac | Urea-linked 2-aminoimidazole dimer potentiators |
-
2005
- 2005-01-02 CN CN 200510005411 patent/CN1660872A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038700B (en) * | 2009-10-14 | 2012-09-12 | 海南澳美华制药有限公司 | Bitter-taste-masking erythromycin-cydocarbonate-containing oral composition |
| CN106632553A (en) * | 2016-12-27 | 2017-05-10 | 黄石世星药业有限责任公司 | Preparation method of erythromycin ethylsuccinate |
| CN111358754A (en) * | 2020-03-13 | 2020-07-03 | 广州白云山汉方现代药业有限公司 | Long-circulating emulsion of macrolide antibiotics and preparation method thereof |
| CN112022820A (en) * | 2020-09-04 | 2020-12-04 | 迪沙药业集团有限公司 | Erythromycin ethylsuccinate tablet composition and preparation method thereof |
| WO2024092149A1 (en) * | 2022-10-26 | 2024-05-02 | University Of Notre Dame Du Lac | Urea-linked 2-aminoimidazole dimer potentiators |
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