CN102250173A - Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin - Google Patents
Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin Download PDFInfo
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Abstract
The invention provides a preparation method of a compound of formula III The preparation method is characterized in that: the preparation method comprises the following step: a hydroxy group at the sixth position of a compound of formula II is subjected to a methylation reaction in a mixed solvent of 2-methyltetrahydrofuran and other polar and inertia solvents under the effect of alkali and a methylating reagent to obtain the compound of the formula III; wherein R1 is an oxime hydroxy protecting group, and R2 is a hydroxy protecting group. In the invention, defects of low output, low purity, difficult recovery of solvents, large pollution, high cost and the like of present selective methylation methods of the compound of formula II are overcome, and preparation methods of the compound of the formula III and clarithromycin which are simple, economic, environment friendly, and easy to industrially produce, are provided The preparation methods of the present invention allow 2-methyltetrahydrofuran and other polar and inertia solvents to be fully separated when reactions are finished, the dosage of solvents to be saved, and the compound of the formula III and clarithromycin with high yield and high purity to be prepared.
Description
Technical field
The present invention relates to the synthetic field of medicine, relate in particular to the preparation method of a kind of 6-O-erythromycin A derivative and clarithromycin.
Background technology
6-O-erythromycin A (having another name called clarithromycin) is a kind of semi-synthetic novel macrolide antibiotic of Erythromycin A, and it is strong that it has an anti-microbial activity, the bioavailability height, and the advantage of the wide and long half time of tissue distribution has potential applicability in clinical practice very widely.
U.S. Pat 4,331 discloses clarithromycin in 803 first.After this, also reported the multiple different method for preparing clarithromycin in the document.Wherein, the most conventional method may further comprise the steps: (a) 9 oxime hydroxyls of protection; (b) protection 2 ' and 4 " the position hydroxyl; (c) methylate 6 hydroxyl; (d) remove 2 ', 4 " and 9 protecting group.The committed step of synthetic clarithromycin is the selective methylation on 6 hydroxyls in (c) step.
R wherein
1Be alkyl, it is substituted or is not substituted; The aryl substituent methyl; Or substituted alkoxy; R
2Be TMS, carbobenzoxy-(Cbz), allyloxycarbonyl or other alkyl protecting group.
U.S. Pat 4,990,602 disclose use as dimethyl sulfoxide (DMSO), N, and the mixture isopolarity inert solvent that one or more in dinethylformamide and the hexamethyl phosphoric triamide and tetrahydrofuran (THF) are formed carries out selective methylation at 6.In its method example, under 0~20 ℃, react and can react completely in 2 hours, use dimethylamine solution to stop using hexane extraction again after the methylation.The shortcoming of this method is that tetrahydrofuran (THF) always is evenly distributed in dimethyl sulfoxide (DMSO) water layer and hexane layer, so extremely difficult recovery set usefulness, and cost is higher.The productive rate of this reaction is generally between 82~95%, but mixed solvent is miscible and all water-soluble, so separation difficulty causes the solvent cost height, and can't be in industrial production.In addition, this patent also discloses use silylating reagent and Lewis acid to formula I compound 2 ' and 4 " the position hydroxyl carries out the method for selective silicon alkanisation; and as using trimethylchlorosilane and triethylamine; trimethylchlorosilane and trimethyl silicon based imidazole; hexamethyldisilazane and ammonia chloride, or hexamethyldisilazane and pyridine hydrochloride etc. react.The purity that this kind method makes is generally 80~98%, if will obtain high purity as 98% product, will use the higher silylating reagent of price, as trimethylchlorosilane or trimethyl silicon based imidazole, causes production cost high and be not suitable for suitability for industrialized production.
U.S. Pat 5,719,272 disclose a kind of method of methylation, wherein use the mixed solvent of methyl tertiary butyl ether and polar aprotic solvent.
U. S. application patent US2003/0023053 and US2004/0010128A have described a kind of method of methylation respectively, the mixed solvent that wherein uses methylene dichloride or toluene and polar aprotic solvent to form.
Above-mentioned methylation method all has the low main drawback of purity mostly, in view of this, needs a kind of simple, economy of development, environmental protection and is easy to 6 hydroxyl selective methylation action methods of the erythromycin A derivant of suitability for industrialized production.
The defective of above-mentioned Silicane Method is: lewis acidic consumption is very big, is 150~300% of formula I compound mole number, and suitability for industrialized production can cause the three wastes too much, and big multi-method all has the main drawback that purity is low or cost is high.
Summary of the invention
Technical problem to be solved by this invention has been to overcome existing 6 hydroxyl selective methylation methods suc as formula the erythromycin A derivant shown in the II and has yielded poorly, purity is low, solvent is difficult to reclaim, pollute big, defectives such as cost height, provide a kind of simple, economical, environmental protection and be easy to the 6-O-erythromycin A derivative shown in formula III of suitability for industrialized production and the preparation method of clarithromycin, this method can fully be separated the 2-methyltetrahydrofuran with other polar aprotic solvent after reaction finishes, save the consumption of solvent, and can make high yield, highly purified formula III compound and clarithromycin.
The invention provides a kind of preparation method of the 6-O-erythromycin A derivative shown in formula III, it comprises the steps: in the mixed solvent of 2-methyltetrahydrofuran and other polar aprotic solvent, under the effect of alkali and methylating reagent, 6 hydroxyls to formula II compound carry out methylation reaction, get the formula III compound; Wherein, R
1Be oxime hydroxyl protecting group, R
2Be hydroxyl protecting group.
Adopt the mixed solvent of other polar aprotic solvent and 2-methyltetrahydrofuran among the present invention, in the time of can after methylation reaction finishes, extracting, the 2-methyltetrahydrofuran is separated with the water layer that contains polar aprotic solvent, thereby be convenient to the recycling of solvent.
Wherein, described oxime hydroxyl protecting group is the protecting group that is used to protect the oxime hydroxyl conventional in this area, is preferably to replace or unsubstituted C
1~C
12, preferable C
1~C
6Alkyl, C
6~C
10Aryl substituent methyl or replacement C
1~C
12, preferable C
1~C
6Alkoxyl group;
Described replacement C
1~C
12, preferable C
1~C
6Substituting group in the alkyl is C
1~C
6Alkyl, the halogen phenyl and the C that replace
1~C
6In the alkoxyl group one or more; Described C
1~C
6Alkyl preferable be alkane and/or aromatic hydrocarbons, one or more that better is in phenyl, methyl, ethyl, sec.-propyl and the cyclohexyl; Described C
1~C
6Alkoxyl group is one or more in methoxyl group, oxyethyl group and the isopropoxy;
Described replacement C
1~C
12, preferable C
1~C
6Substituting group in the alkoxyl group is one or more in phenyl, halogen substituted phenyl, methyl, ethyl, sec.-propyl and the cyclohexyl.
What oxime hydroxyl protecting group of the present invention was better is trityl, benzyl, 2-benzyl chloride base, 1-methoxyl group-1-methylethyl, 1-oxyethyl group-1-methylethyl, 1-methoxyl group-1-cyclohexyl, 1-oxyethyl group-1-cyclohexyl or 1-isopropoxy-1-cyclohexyl, and best is 1-isopropoxy-1-cyclohexyl.
Wherein, described hydroxyl protecting group is the group commonly used that is used to protect hydroxyl in this area, and preferable is TMS, carbobenzoxy-(Cbz) or allyloxycarbonyl.
In the present invention's one preferred implementation, R in the described formula II compound
1Be 1-isopropoxy-1-cyclohexyl, R
2Be TMS, its structural formula is as follows:
Wherein, the volume ratio of 2-methyltetrahydrofuran and other polar aprotic solvent can be selected according to this area ordinary method, and preferable is 1: 0.5~1: 5, and better is 1: 1.
Wherein, described other polar aprotic solvent be conventionally in this type of methylation reaction of this area use, not with formula II compound polar solvent that react, except that the 2-methyltetrahydrofuran, that preferable is N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), 1, in 2-glycol dimethyl ether and the hexamethyl phosphoric triamide etc. one or more, better is dimethyl sulfoxide (DMSO).
Wherein, described methylating reagent is a conventional methylating reagent commonly known in the art, as in methyl chloride, monobromethane, methyl iodide, methyl-sulfate, methyl tosylate and the methyl methylsulfonate etc. one or more.The consumption of described methylating reagent can be selected according to this area ordinary method, 1~10 times of formula II compound molar weight that preferable is, and better is 1~2 times.
Wherein, described alkali is the conventional alkali that uses in this type of methylation reaction of this area, preferable is mineral alkali, one or more that better is in metal hydroxides, metal hydride and the metal carbonated, one or more that best is in potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride KH, salt of wormwood and the yellow soda ash.The consumption of described alkali can be selected according to this area ordinary method, 1~10 times of formula II compound molar weight that preferable is, and better is 1~2 times.
Methylation reaction of the present invention can carry out under mild conditions, and concrete reaction conditions can be selected according to this area general knowledge, and what temperature of reaction was preferable is 0~60 ℃, and better is 5~20 ℃.In the preferred range of reaction temperature of the present invention, can reduce unwanted by product.Till the reaction times of described methylation reaction ran out of by the high performance liquid chromatography detecting reactant, preferable was 0.5~4 hour, and better is 2 hours.
After methylation reaction of the present invention finishes, the following method of preferable employing is carried out aftertreatment: use the dimethylamine agueous solution diluted reaction mixture, 2-methyltetrahydrofuran layer is separated with the water layer that contains other polar aprotic solvent, separate the formula III compound with the distillatory method, thereby realize a large amount of recyclings solvent.
The present invention also provides a kind of preparation method of clarithromycin, it comprises the steps: that (1) is in the mixed solvent of 2-methyltetrahydrofuran and other polar aprotic solvent, under the effect of alkali and methylating reagent, 6 hydroxyls to formula II compound carry out methylation reaction, get the formula III compound; (2) with formula III compound 2 ', 4 " hydroxyl protecting group deprotection on the position, the oxime hydroxyl protecting group on 9 is hydrolyzed into carbonyl, clarithromycin; Wherein, R
1And R
2With aforementioned.
Wherein, the method for described step (1) and optimum condition are with aforesaid methylation reaction, and step (2) can adopt the deprotection based method of conventional use in this type of reaction of this area to carry out.
In the present invention's one preferred implementation, described formula II compound is made by following method: in the solvent, under the effect of asccharin compounds, formula I compound and silylating reagent carry out 2 ' and 4 " position hydroxyl Silanization reaction, get final product; Wherein, R
1With aforementioned; R
2Be the trimethylammonium alkyl.
What wherein, described asccharin compounds was preferable is asccharin and/or the trimethyl silicon based asccharin of N-; What the consumption of described asccharin compounds was preferable is catalytic amount, and better is 0.1~10% of formula I compound molar weight, and best is 0.5~5%.Asccharin compounds among the present invention plays lewis acidic effect in existing this type of reaction equally, but its consumption compare with the Lewis acid of routine and decline to a great extent, be catalytic amount only, reaction cost is declined to a great extent.
Wherein, described silylating reagent is the conventional silylating reagent that uses in this area, as long as it can be with formula I compound 2 ' and 4 " silicolization; that preferable is hexamethyldisilazane, trimethyl silicon based imidazole, N; N-two (trimethyl silicon based) ethanamide and N, one or more in N '-two (trimethyl silicon based) urea.The consumption of described silylating reagent can be selected according to this area general knowledge, 1~10 times of formula I compound molar weight that preferable is.
Wherein, described solvent is for the conventional solvent that uses in this type of reaction of the present invention, as methylene dichloride, 1,2-ethylene dichloride, acetonitrile, N, in dinethylformamide, N,N-dimethylacetamide, methyl tertiary butyl ether and the ethyl acetate one or more, preferred methylene dichloride.The consumption of described solvent can be selected according to this area general knowledge, and preferable is 5~30ml/g formula I compound.
Wherein, described Silanization reaction can carry out under mild conditions, and what temperature of reaction was preferable is 0~100 ℃, and better is 15~40 ℃.In this preferred range of reaction temperature, can reduce unwanted by product.Till the reaction times of described Silanization reaction ran out of by the high performance liquid chromatography detecting reactant, preferable was 12~48 hours, and better is 24 hours.
After Silanization reaction of the present invention finishes, the following method of preferable employing is carried out aftertreatment: use the saturated sodium bicarbonate aqueous solution diluted reaction mixture, solvent layer is separated with water layer, and with distillatory method separate type II compound, thereby realization is to a large amount of recyclings of solvent.
Among the present invention, but above-mentioned optimum condition arbitrary combination on the basis that meets this area general knowledge promptly gets the preferred embodiments of the invention.
Raw material of the present invention and reagent are all commercially available to be got.
Positive progressive effect of the present invention is:
(1) methylation reaction of the present invention can carry out under mild conditions, helps industrial production and environment protection, and the mixed solvent of use is easy to separate, and can recycle in a large number.
(2) methylation reaction of the present invention can obtain high yield, highly purified formula III compound and clarithromycin.
(3) the formula III compound clarithromycin that makes with the present invention can access the clarithromycin of high yield, highly selective.
(4) preparation method of formula III compound of the present invention is not subjected to the restriction of formula II classes of compounds, can be applicable to the methylation reaction of all kinds of formula II compounds, and use range is extensive, especially for R
1Be 1-isopropoxy-1-cyclohexyl, R
2Be the formula II compound of TMS, effect is better.
(5) in the present invention one preferred embodiment, described formula II compound is made by preferable methods, utilize the asccharin compounds to substitute conventional other Lewis acids that use in the prior art in this method, greatly reduce consumption, and the productive rate of energy freeze mode II compound and not decline of purity, can significantly reduce reaction cost.
Embodiment
Below in conjunction with embodiment technical scheme of the present invention is described further, but the present invention is not limited.
Table 1
Embodiment 1
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based) Erythromycin A 9-O-(1-oxyethyl group-1-methylethyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 10 ℃, add 1.4 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.9 and restrain methyl iodide (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A 9-O-(1-oxyethyl group-1-methylethyl) oxime (the formula III compound sees Table 1), purity is 85%.
Embodiment 2
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(1-oxyethyl group-1-cyclohexyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 15 ℃, add 1.3 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.7 and restrain methyl iodide (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A 9-O-(1-oxyethyl group-1-cyclohexyl) oxime (the formula III compound sees Table 1), purity is 90%.
Embodiment 3
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 10 ℃, add 1.3 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.7 and restrain methyl iodide (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A9-O-(1-isopropoxy-1-cyclohexyl) oxime (the formula III compound sees Table 1), purity is 92%.
Embodiment 4
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 15 ℃, add 1.3 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.7 and restrain methyl iodide (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (the formula III compound sees Table 1), purity is 93%.
Embodiment 5
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 20 ℃, add 1.3 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.7 and restrain methyl iodide (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A9-O-(1-isopropoxy-1-cyclohexyl) oxime (the formula III compound sees Table 1), purity is 95%.
Embodiment 6
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 15 ℃, add 1.3 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 1.8 and restrain monobromethanes (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (the formula III compound sees Table 1), purity is 90%.
Embodiment 7
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime, and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 15 ℃, add 1.3 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.5 and restrain methyl-sulfates (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, and separated organic layer and washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes and promptly gets 10 grams 2 ', 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime, purity is 91%.
Embodiment 8
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-trityl oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 500 milliliters of hexamethyl phosphoric triamide again, be cooled to 0 ℃, add 2 gram sodium hydrides (formula II compound molar weight 10 times) and 17 gram methyl tosylates (formula II compound molar weight 10 times), react after 2 hours adding dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A 9-O-(trityl) oxime (the formula III compound sees Table 1), purity is 92%.
Embodiment 9
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-benzyl oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of N again, dinethylformamide in 60 ℃, adds 1.4 gram salt of wormwood (formula II compound molar weight 1 times) and 1.1 and restrains methyl methylsulfonates (formula II compound molar weight 1 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes and promptly gets 10 grams 2 ', 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A 9-O-benzyl oxime (formula III compound; see Table 1), purity is 91%.
Embodiment 10
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(2-benzyl chloride base) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 50 milliliter 1 again, the 2-glycol dimethyl ether is cooled to 5 ℃, adds 1.3 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.5 and restrains methyl-sulfates (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes and promptly gets 10 grams 2 ', 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A9-O-(2-benzyl chloride base) oxime (formula III compound; see Table 1), purity is 91%.
Embodiment 11
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based) Erythromycin A 9-O-(1-methoxyl group-1-methylethyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 10 ℃, add 1.4 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.9 and restrain methyl iodide (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A 9-O-(1-oxyethyl group-1-methylethyl) oxime (the formula III compound sees Table 1), purity is 82%.
Embodiment 12
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(1-methoxyl group-1-cyclohexyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 15 ℃, add 1.3 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.7 and restrain methyl iodide (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (trimethyl silicon based)-6-O-erythromycin A 9-O-(1-methoxyl group-1-cyclohexyl) oxime (the formula III compound sees Table 1), purity is 89%.
Embodiment 13
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (carbobenzoxy-(Cbz))-Erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 10 ℃, add 1.2 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.5 and restrain methyl iodide (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (carbobenzoxy-(Cbz))-6-O-erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (the formula III compound sees Table 1), purity is 90%.
Embodiment 14
In 250 milliliters of four-hole reaction flasks of agitator and thermometer are housed, add 10 grams 2 '; 4 "-O-two (allyloxycarbonyl)-Erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (formula II compound, see Table 1), and then add 100 milliliters of 2-methyltetrahydrofurans, stirring makes its dissolving, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 10 ℃, add 1.3 gram potassium hydroxide (content 〉=82%) (formula II compound molar weight 2 times) and 2.7 and restrain methyl iodide (formula II compound molar weight 2 times), react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steaming desolventizes and promptly gets 10 grams 2 '; 4 "-O-two (allyloxycarbonyl)-6-O-erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (the formula III compound sees Table 1), purity is 90%.
Embodiment 15 preparation clarithromycins
Formula III compound among the embodiment 3 10 gram is dissolved in 100 milliliters of ethanol/waters (1: 1), adds 4 gram sodium bisulfites and 1 gram, 98% formic acid, and with reaction mixture refluxed 3 hours.Then, reaction mixture is adjusted to 10 with the dilution of 50 ml waters and with sodium hydroxide solution with the pH value, stirred reaction mixture is 1 hour under the ice-water bath, and filtering precipitate, washing and alcohol crystal obtain 6 gram clarithromycins, and its purity is 98%.
Embodiment 16 preparation formula II compounds
Agitator is being housed, add 10 clarithromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime in 250 milliliters of four-hole reaction flasks of prolong and thermometer, and then add 100 milliliters of methylene dichloride, stirring makes its dissolving, under 40 ℃ of backflows, add 4.5 gram hexamethyldisilazanes and the trimethyl silicon based asccharin of 0.07 gram N-(formula I compound molar weight 2%), react after 24 hours, add 50 milliliters of saturated sodium bicarbonate aqueous solutions, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying filters, and steams to desolventize promptly to get 11.4 grams 2 '; 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime, it is 98% that HPLC detects purity.
Embodiment 17 preparation clarithromycins
(1) preparation formula II compound
In being housed, 250 milliliters of four-hole reaction flasks of agitator and thermometer add 10 clarithromycin A9-O-(1-isopropoxy-1-cyclohexyl) oxime, and then add 100 milliliters of methylene dichloride, stirring makes its dissolving, under 25 ℃, add 4.5 gram hexamethyldisilazanes and 0.05 gram asccharin (formula I compound molar weight 2%), react after 24 hours, add 50 milliliters of saturated sodium bicarbonate aqueous solutions, stirred 30 minutes, separate organic layer and washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes and promptly gets 11.0 grams 2 ', 4 "-O-two (trimethyl silicon based)-Erythromycin A 9-O-(1-isopropoxy-1-cyclohexyl) oxime (formula II compound; see Table 1), it is 98% that HPLC detects purity.
(2) preparation formula III compound
Formula II compound 10 grams are dissolved in 100 milliliters of tetrahydrofuran (THF)s, add 100 milliliters of dimethyl sulfoxide (DMSO) again, be cooled to 10 ℃, add 1.3 gram potassium hydroxide (content 〉=82%) and 2.7 gram methyl iodide, react after 2 hours, add dimethylamine agueous solution and 200 ml waters, stirred 30 minutes, with 100 milliliters of ethyl acetate extractions, separate organic layer and washing, anhydrous magnesium sulfate drying filters, steam desolventize white solid (formula III compound);
(3) white solid that obtains is dissolved in 100 milliliters of ethanol/waters (1: 1), adds 4 gram sodium bisulfites and 1 gram, 98% formic acid, and with reaction mixture refluxed 3 hours.Then, reaction mixture is adjusted to 10 with the dilution of 50 ml waters and with sodium hydroxide solution with the pH value, stirred reaction mixture is 1 hour under the ice-water bath, and filtering precipitate, washing and alcohol crystal obtain 6 gram clarithromycins, and its purity is 98%.
Claims (11)
1. the preparation method of a formula III compound, it is characterized in that: it comprises the steps: in the mixed solvent of 2-methyltetrahydrofuran and other polar aprotic solvent, under the effect of alkali and methylating reagent, 6 hydroxyls of formula II compound are carried out methylation reaction, the formula III compound;
Formula II formula III
Wherein, R
1Be oxime hydroxyl protecting group, R
2Be hydroxyl protecting group.
2. the preparation method of formula III compound as claimed in claim 1 is characterized in that: described oxime hydroxyl protecting group is for replacing or unsubstituted C
1~C
12, preferable C
1~C
6Alkyl, C
6~C
10Aryl substituent methyl or replacement C
1~C
12, preferable C
1~C
6Alkoxyl group;
Described replacement C
1~C
12, preferable C
1~C
6Substituting group in the alkyl is C
1~C
6Alkyl, the halogen phenyl and the C that replace
1~C
6In the alkoxyl group one or more; Described C
1~C
6Alkyl preferable be in phenyl, methyl, ethyl, sec.-propyl and the cyclohexyl one or more; Described C
1~C
6Alkoxyl group is one or more in methoxyl group, oxyethyl group and the isopropoxy;
Described replacement C
1~C
12, preferable C
1~C
6Substituting group in the alkoxyl group is one or more in phenyl, halogen substituted phenyl, methyl, ethyl, sec.-propyl and the cyclohexyl;
Described hydroxyl protecting group is TMS, carbobenzoxy-(Cbz) or allyloxycarbonyl; Described other polar aprotic solvent are N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), 1, one or more in 2-glycol dimethyl ether and the hexamethyl phosphoric triamide.
3. the preparation method of formula III compound as claimed in claim 1 or 2 is characterized in that: described oxime hydroxyl protecting group is trityl, benzyl, 2-benzyl chloride base, 1-methoxyl group-1-methylethyl, 1-oxyethyl group-1-methylethyl, 1-methoxyl group-1-cyclohexyl, 1-oxyethyl group-1-cyclohexyl or 1-isopropoxy-1-cyclohexyl.
4. as the preparation method of each described formula III compound in the claim 1~3, it is characterized in that: R in the described formula II compound
1Be 1-isopropoxy-1-cyclohexyl, R
2Be TMS, its structural formula is as follows:
5. as the preparation method of each described formula III compound in the claim 1~4, it is characterized in that: described methylating reagent is one or more in methyl chloride, monobromethane, methyl iodide, methyl-sulfate, methyl tosylate and the methyl methylsulfonate; The consumption of described methylating reagent is 1~10 times of formula II compound molar weight;
Described alkali is mineral alkali, one or more that preferable is in metal hydroxides, metal hydride and the metal carbonated, one or more that better is in potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride KH, salt of wormwood and the yellow soda ash; The consumption of described alkali is 1~10 times of formula II compound molar weight.
6. as the preparation method of each described formula III compound in the claim 1~5, it is characterized in that: the volume ratio of 2-methyltetrahydrofuran and other polar aprotic solvent is 1: 0.5~1: 5, and better is 1: 1.
7. as the preparation method of each described formula III compound in the claim 1~6, it is characterized in that: the temperature of described methylation reaction is 0~60 ℃, and preferable is 5~20 ℃; Till described methylation reaction ran out of with detecting reactant, preferable was 0.5~4 hour.
8. the preparation method of a clarithromycin, it comprises the steps: that (1) prepares the formula III compound by each described method in the claim 1~7; (2) with formula III compound 2 ', 4 " hydroxyl protecting group deprotection on the position, the oxime hydroxyl protecting group on 9 is hydrolyzed into carbonyl, clarithromycin;
Formula II formula III clarithromycin
Wherein, R
1And R
2With each is described in the claim 1~4.
9. the preparation method of clarithromycin as claimed in claim 8, it is characterized in that: described formula II compound is made by following method: in the solvent, under the effect of asccharin compounds, formula I compound and silylating reagent carry out 2 ' and 4 " position hydroxyl Silanization reaction, get final product;
Formula I formula II
Wherein, R
1Described with claim 8; R
2Be the trimethylammonium alkyl; What described asccharin compounds was preferable is asccharin and/or the trimethyl silicon based asccharin of N-; The consumption of described asccharin compounds is a catalytic amount.
10. the preparation method of clarithromycin as claimed in claim 9, it is characterized in that: the consumption of described asccharin compounds is 0.1~10% of a formula I compound molar weight, and preferable is 0.5~5%.
11. preparation method as claim 9 or 10 described clarithromycins, it is characterized in that: described silylating reagent is hexamethyldisilazane, trimethyl silicon based imidazole, N, N-two (trimethyl silicon based) ethanamide and N, one or more in N '-two (trimethyl silicon based) urea; The consumption of described silylating reagent is 1~10 times of formula I compound molar weight; Described solvent is a methylene dichloride, 1,2-ethylene dichloride, acetonitrile, N, one or more in dinethylformamide, N,N-dimethylacetamide, methyl tertiary butyl ether and the ethyl acetate; The temperature of reaction of described Silanization reaction is 0~100 ℃, and preferable is 15~40 ℃; Till the reaction times of described Silanization reaction ran out of with detecting reactant, preferable was 12~48 hours.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102718821A (en) * | 2012-06-27 | 2012-10-10 | 浙江国邦药业有限公司 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
CN103880901A (en) * | 2012-12-23 | 2014-06-25 | 菏泽市方明制药有限公司 | Preparation method of clarithromycin intermediate methide |
CN105418709A (en) * | 2015-12-18 | 2016-03-23 | 山东理工职业学院 | Method for preparing clarithromycin impurity |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102718821A (en) * | 2012-06-27 | 2012-10-10 | 浙江国邦药业有限公司 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
CN102718821B (en) * | 2012-06-27 | 2014-12-03 | 浙江国邦药业有限公司 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
CN103880901A (en) * | 2012-12-23 | 2014-06-25 | 菏泽市方明制药有限公司 | Preparation method of clarithromycin intermediate methide |
CN105418709A (en) * | 2015-12-18 | 2016-03-23 | 山东理工职业学院 | Method for preparing clarithromycin impurity |
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