CN102250173B - Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin - Google Patents

Abstract

The present invention provides a preparation method of a compound of formula III, which is characterized in that: it comprises the following steps: in a mixed solvent of 2-methyltetrahydrofuran and other polar inert solvents, under the action of a base and a methylating reagent , carry out methylation reaction on the 6-hydroxyl group of the compound of formula II to obtain the compound of formula III; wherein, R ₁ is an oxime hydroxyl protecting group, and R ₂ is a hydroxyl protecting group. The present invention overcomes the defects of the existing selective methylation method for compounds of formula II, such as low yield, low purity, difficult recovery of solvents, large pollution, high cost, etc., and provides a compound of formula III that is simple, economical, environmentally friendly and easy for industrial production And the preparation method of clarithromycin, the method can fully separate 2-methyltetrahydrofuran from other polar inert solvents after the reaction, save the amount of solvent, and can produce the compound of formula III and clarithromycin with high yield and high purity Mycin.

Description

A kind of preparation method of 6-O-methylerythromycin A derivative and clarithromycin

technical field

The invention relates to the field of drug synthesis, in particular to a preparation method of 6-O-methylerythromycin A derivatives and clarithromycin.

Background technique

6-O-methylerythromycin A (also known as clarithromycin) is a semi-synthetic new macrolide antibiotic of erythromycin A, which has strong antibacterial activity, high bioavailability, wide tissue distribution and The advantage of long half-life has a very broad prospect of clinical application.

Clarithromycin was first disclosed in US Patent No. 4,331,803. Since then, various methods for preparing clarithromycin have also been reported in the literature. Among them, the most conventional method includes the following steps: (a) protecting the 9-position oxime hydroxyl group; (b) protecting the 2' and 4"-position hydroxyl groups; (c) methylating the 6-position hydroxyl groups; (d) removing 2', 4 " and 9-position protecting groups. The key step in the synthesis of clarithromycin is the selective methylation of the 6-hydroxyl in step (c).

Wherein R ₁ is alkyl, which is substituted or unsubstituted; aryl substituted methyl; or substituted alkoxy; R ₂ is trimethylsilyl, benzyloxycarbonyl, allyloxycarbonyl or other hydrocarbyl protecting groups.

U.S. Patent No. 4,990,602 discloses the use of polar inert solvents such as a mixture of one or more of dimethyl sulfoxide, N,N-dimethylformamide and hexamethylphosphoric acid triamide and tetrahydrofuran in 6 selective methylation. In the method example, the reaction can be completed after 2 hours of reaction at 0-20°C, and the methylation is terminated with dimethylamine solution, and then extracted with hexane. The disadvantage of this method is that tetrahydrofuran is always uniformly distributed in the dimethyl sulfoxide water layer and the hexane layer, so it is very difficult to recycle and apply mechanically, and the cost is relatively high. The yield of this reaction is generally between 82% and 95%, but the mixed solvents are miscible and all soluble in water, so the separation is difficult, resulting in high cost of the solvent, which cannot be produced industrially. In addition, the patent also discloses a method for selectively silanizing the 2' and 4" hydroxyl groups of the compound of formula I using a silylating agent and a Lewis acid, such as using trimethylchlorosilane and triethylamine, trimethylchlorosilane React with trimethylsilyl imidazole, hexamethyldisilazane and ammonium chloride, or hexamethyldisilazane and pyridine hydrochloride, etc. The purity obtained by this method is generally 80-98% , in order to obtain a product with a high purity such as 98%, it is necessary to use a relatively expensive silylating agent, such as trimethylchlorosilane or trimethylsilyl imidazole, which leads to high production costs and is not suitable for industrial production.

US Patent No. 5,719,272 discloses a method for methylation, wherein a mixed solvent of methyl tert-butyl ether and a polar inert solvent is used.

US patent applications US2003/0023053 and US2004/0010128A respectively describe a methylation method, wherein a mixed solvent of dichloromethane or toluene and a polar inert solvent is used.

Most of the above methylation methods have the main disadvantage of low purity. In view of this, it is necessary to develop a method for selective methylation of the 6-hydroxyl group of erythromycin A derivatives that is simple, economical, environmentally friendly and easy for industrial production.

The disadvantage of the above silanization method is that the amount of Lewis acid is very large, which is 150-300% of the mole of the compound of formula I. Industrial production will lead to too many wastes, and most methods have the main disadvantages of low purity or high cost.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the low yield, low purity, difficult solvent recovery, heavy pollution, high cost, etc. Deficiency, provide a kind of simple, economical, environmental protection and the preparation method of the 6-O-methylerythromycin A derivative shown in formula III and the clarithromycin that are easy to industrialized production, this method can be with reaction after finishing The 2-methyltetrahydrofuran is fully separated from other polar inert solvents, the amount of solvent is saved, and the compound of formula III and clarithromycin with high yield and high purity can be prepared.

The present invention provides a kind of preparation method of 6-O-methylerythromycin A derivative as shown in formula III, it comprises the following steps: in the mixed solvent of 2-methyltetrahydrofuran and other polar inert solvent , under the action of a base and a methylating reagent, the 6-hydroxyl group of the compound of formula II is methylated to obtain a compound of formula III; wherein, R ₁ is an oxime hydroxyl protecting group, and R ₂ is a hydroxyl protecting group.

Adopt the mixed solvent of other polar inert solvent and 2-methyltetrahydrofuran among the present invention, can make 2-methyltetrahydrofuran and the aqueous layer that contains polar inert solvent when extracting after methylation reaction finishes, thereby facilitate Solvent recycling.

Wherein, the protecting group for the oxime hydroxyl group is a conventional protecting group used in the art for protecting the oxime hydroxyl group, preferably a substituted or unsubstituted C ₁ -C ₁₂ , preferably C ₁ -C ₆ alkyl, C ₆ ~C ₁₀ aryl substituted methyl or C ₁ ~C ₁₂ , preferably C ₁ ~C ₆ alkoxy;

The substituents in the substituted C ₁ -C ₁₂ , preferably C ₁ -C ₆ alkyl groups are one of C ₁ -C ₆ hydrocarbon groups, halogen substituted phenyl groups and C ₁ -C ₆ alkoxy groups one or more; the C ₁ -C ₆ hydrocarbon group is preferably an alkane and/or an aromatic hydrocarbon, more preferably one or more of phenyl, methyl, ethyl, isopropyl and cyclohexyl species; the C ₁ -C ₆ alkoxy group is one or more of methoxy, ethoxy and isopropoxy;

The substituents in the substituted C ₁ -C ₁₂ , preferably C ₁ -C ₆ alkoxy groups are one of phenyl, halogen substituted phenyl, methyl, ethyl, isopropyl and cyclohexyl or more.

The oxime hydroxyl protecting group described in the present invention is more preferably trityl, benzyl, 2-chlorobenzyl, 1-methoxyl-1-methylethyl, 1-ethoxyl-1-methyl Ethyl, 1-methoxy-1-cyclohexyl, 1-ethoxy-1-cyclohexyl or 1-isopropoxy-1-cyclohexyl, the best being 1-isopropoxy-1- cyclohexyl.

Wherein, the hydroxyl protecting group is a commonly used group for protecting hydroxyl in the art, preferably trimethylsilyl, benzyloxycarbonyl or allyloxycarbonyl.

In a preferred embodiment of the present invention, in the compound of formula II, R ₁ is 1-isopropoxy-1-cyclohexyl, R ₂ is trimethylsilyl, and its structural formula is as follows:

Wherein, the volume ratio of 2-methyltetrahydrofuran and other polar inert solvents can be selected according to conventional methods in the art, preferably 1:0.5-1:5, more preferably 1:1.

Wherein, the other polar inert solvent is a polar solvent other than 2-methyltetrahydrofuran that is routinely used in this type of methylation reaction in the art and does not react with the compound of formula II, preferably N , one or more of N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,2-dimethoxyethane and hexamethylphosphoric triamide , more preferably dimethyl sulfoxide.

Wherein, the methylating reagent is a well-known conventional methylating reagent in the prior art, such as methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate and methyl methylsulfonate, etc. one or more of. The amount of the methylating agent can be selected according to conventional methods in the art, preferably 1-10 times the molar amount of the compound of formula II, more preferably 1-2 times.

Wherein, the base is a base commonly used in this type of methylation reaction in the art, preferably an inorganic base, more preferably one or more of metal hydroxides, metal hydrides and metal carbonates species, the best being one or more of potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, potassium carbonate and sodium carbonate. The amount of the base can be selected according to conventional methods in the art, preferably 1-10 times the molar amount of the compound of formula II, more preferably 1-2 times.

The methylation reaction of the present invention can be carried out under mild conditions, and the specific reaction conditions can be selected according to common knowledge in the field. The reaction temperature is preferably 0-60°C, more preferably 5-20°C. Undesirable by-products can be reduced within the preferred reaction temperature range of the present invention. The reaction time of the methylation reaction is detected by high performance liquid chromatography until the reactants are consumed, preferably 0.5-4 hours, more preferably 2 hours.

After the methylation reaction of the present invention is finished, the following method is preferably used for post-treatment: dilute the reaction mixture with an aqueous solution of dimethylamine, separate the 2-methyltetrahydrofuran layer from the water layer containing other polar inert solvents, and use The compound of formula III is separated by distillation, thereby realizing a large amount of recovery and utilization of the solvent.

The present invention also provides a preparation method of clarithromycin, which comprises the following steps: (1) in a mixed solvent of 2-methyltetrahydrofuran and other polar inert solvents, under the action of a base and a methylating reagent , the 6-hydroxyl group of the compound of formula II is methylated to obtain the compound of formula III; (2) the hydroxyl protecting group on the 2' and 4" positions of the compound of formula III is deprotected, and the oxime hydroxyl protecting group on the 9-position is hydrolyzed into a carbonyl group to obtain clarithromycin; wherein, R ₁ and R ₂ are the same as mentioned above.

Wherein, the method and preferred conditions of the step (1) are the same as the aforementioned methylation reaction, and the step (2) can be carried out by the deprotection method commonly used in this type of reaction in the art.

In a preferred embodiment of the present invention, the compound of formula II is prepared by the following method: in a solvent, under the action of a saccharine compound, the compound of formula I and a silylating agent undergo 2' and 4" hydroxyl The silylation reaction can be; wherein, R ₁ is the same as above; R ₂ is a trimethylsilyl group.

Wherein, the saccharin compound is preferably saccharin and/or N-trimethylsilyl saccharin; the amount of the saccharin compound is preferably a catalytic amount, more preferably the molar amount of the compound of formula I 0.1-10%, the best is 0.5-5%. The saccharin compound in the present invention also plays the role of the Lewis acid in the existing reaction of this type, but its dosage is greatly reduced compared with the conventional Lewis acid, and it is only a catalytic amount, so that the reaction cost is greatly reduced.

Wherein, the silylating agent is a conventionally used silylating agent in the art, as long as it can silylize the hydroxyl groups at the 2' and 4" positions of the compound of formula I, preferably hexamethyldisilazane , trimethylsilyl imidazole, N,N-bis(trimethylsilyl)acetamide and N,N'-bis(trimethylsilyl)urea.The silanization The dosage of the reagent can be selected according to common knowledge in the field, preferably 1 to 10 times the molar weight of the compound of formula I.

Wherein, the solvent is a conventionally used solvent in this type of reaction in the present invention, such as dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylformamide One or more of methyl acetamide, methyl tert-butyl ether and ethyl acetate, preferably dichloromethane. The amount of the solvent can be selected according to common knowledge in the field, preferably 5-30ml/g compound of formula I.

Wherein, the silylation reaction can be carried out under mild conditions, and the reaction temperature is preferably 0-100°C, more preferably 15-40°C. Undesirable by-products can be reduced within this preferred reaction temperature range. The reaction time of the silylation reaction is detected by high performance liquid chromatography until the reactant is consumed, preferably 12-48 hours, more preferably 24 hours.

After the silylation reaction of the present invention is finished, the following method is preferably used for aftertreatment: dilute the reaction mixture with saturated aqueous sodium bicarbonate solution, separate the solvent layer and the water layer, and separate the compound of formula II by distillation, so as to achieve Extensive recycling of solvents.

In the present invention, the above-mentioned preferred conditions can be combined arbitrarily on the basis of conforming to common knowledge in the field, so as to obtain various preferred examples of the present invention.

The raw materials and reagents of the present invention are all commercially available.

The positive progress effect of the present invention is:

(1) The methylation reaction of the present invention can be carried out under mild conditions, which is beneficial to industrial production and environmental protection, and the mixed solvent used is easy to separate and can be recycled in large quantities.

(2) The methylation reaction of the present invention can obtain the compound of formula III and clarithromycin with high yield and high purity.

(3) Using the compound of formula III prepared by the present invention to prepare clarithromycin can obtain clarithromycin with high yield and high selectivity.

(4) The preparation method of the compound of formula III of the present invention is not limited by the type of compound of formula II, can be applicable to the methylation reaction of various compounds of formula II, and has a wide range of applications, especially for R ₁ is 1-isopropoxy -1-cyclohexyl, R ₂ is a compound of formula II of trimethylsilyl, and the effect is better.

(5) In a preferred embodiment of the present invention, the compound of formula II is prepared by a preferred method, in which saccharine compounds are used to replace other Lewis acids routinely used in the prior art, greatly reducing the amount used, And the yield and purity of the compound of formula II can be kept without decline, and the reaction cost can be greatly reduced.

Detailed ways

The technical solutions of the present invention will be further described below in conjunction with the examples, but the present invention is not limited thereto.

Table 1

Example 1

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)erythromycin A9-O-(1-ethoxy-1- Methyl ethyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 10 ℃, add 1.4 grams Potassium hydroxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.9 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, Stir for 30 minutes, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin The element A9-O-(1-ethoxy-1-methylethyl)oxime (compound of formula III, see Table 1) has a purity of 85%.

Example 2

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1-ethoxy-1 -cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 15 ° C, add 1.3 grams of hydrogen Potassium oxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.7 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, stir After 30 minutes, the organic layer was separated and washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-O-(1-ethoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1), the purity is 90%.

Example 3

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1-isopropoxy- 1-cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 10 ℃, add 1.3 grams Potassium hydroxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.7 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, Stir for 30 minutes, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin Element A9-O-(1-isopropoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1) with a purity of 92%.

Example 4

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1-isopropoxy- 1-cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 15 ° C, add 1.3 grams of Potassium hydroxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.7 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, Stir for 30 minutes, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin Element A9-O-(1-isopropoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1) with a purity of 93%.

Example 5

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1-isopropoxy- 1-cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 20 ℃, add 1.3 grams Potassium hydroxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.7 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, Stir for 30 minutes, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin Element A9-O-(1-isopropoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1), the purity is 95%.

Example 6

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1-isopropoxy- 1-cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 15 ° C, add 1.3 grams of Potassium hydroxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 1.8 grams of methyl bromide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, stir After 30 minutes, the organic layer was separated and washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-O-(1-isopropoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1), the purity is 90%.

Example 7

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1-isopropoxy- 1-cyclohexyl) oxime, then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 15 ° C, add 1.3 grams of potassium hydroxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.5 grams of dimethyl sulfate (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add dimethylamine aqueous solution and 200 milliliters of water, stir for 30 minutes, separate the organic layer and washed with water, dried over anhydrous magnesium sulfate, filtered, and evaporated to remove the solvent to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-O-(1 - Isopropoxy-1-cyclohexyl)oxime with a purity of 91%.

Example 8

Add 10 grams of 2', 4 "-O-bis(trimethylsilyl)-erythromycin A9-O-trityl oxime (formula II compound, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 500 milliliters of hexamethylphosphoric acid triamide, cool to 0°C, add 2 grams of sodium hydride (the molar weight of the compound of formula II 10 times) and 17 grams of methyl p-toluenesulfonate (10 times the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, stir for 30 minutes, separate the organic layer and wash with water, without Dry over magnesium sulfate, filter, and evaporate the solvent to obtain 10 grams of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-O-(trityl) Oxime (compound of formula III, see Table 1) with a purity of 92%.

Example 9

Add 10 grams of 2 ', 4 "-O-bis(trimethylsilyl)-erythromycin A9-O-benzyl oxime (compound of formula II, See Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to dissolve it, then add 100 milliliters of N,N-dimethylformamide, at 60 ° C, add 1.4 grams of potassium carbonate (the molar weight of the compound of formula II 1 times of) and 1.1 gram of methyl methanesulfonate (1 times of the molar weight of the compound of formula II), after reacting for 2 hours, add dimethylamine aqueous solution and 200 milliliters of water, stir for 30 minutes, separate the organic layer and wash with water, without Magnesium sulfate water was dried, filtered, and the solvent was evaporated to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-O-benzyl oxime (formula III Compound, see Table 1), the purity is 91%.

Example 10

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(2-chlorobenzyl)oxime to a 250 ml four-necked reaction flask equipped with a stirrer and a thermometer (Compound of Formula II, see Table 1), then add 100 ml of 2-methyltetrahydrofuran, stir to dissolve it, then add 50 ml of 1,2-dimethoxyethane, cool to 5°C, add 1.3 g of hydrogen Potassium oxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.5 grams of dimethyl sulfate (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water , stirred for 30 minutes, the organic layer was separated and washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methyl red Mycin A9-O-(2-chlorobenzyl)oxime (compound of formula III, see Table 1) has a purity of 91%.

Example 11

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)erythromycin A9-O-(1-methoxyl-1- Methyl ethyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 10 ℃, add 1.4 grams Potassium hydroxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.9 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, Stir for 30 minutes, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin The element A9-O-(1-ethoxy-1-methylethyl)oxime (compound of formula III, see Table 1) has a purity of 82%.

Example 12

Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1-methoxy-1 -cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 15 ° C, add 1.3 grams of hydrogen Potassium oxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.7 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, stir After 30 minutes, the organic layer was separated and washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-O-(1-methoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1), the purity is 89%.

Example 13

Add 10 grams of 2', 4"-O-bis(benzyloxycarbonyl)-erythromycin A9-O-(1-isopropoxy-1- Cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 10 ° C, add 1.2 grams of hydroxide Potassium (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.5 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, stir for 30 minutes, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, evaporate the solvent to obtain 10 grams of 2', 4"-O-bis(benzyloxycarbonyl)-6-O-methylerythromycin A9-O -(1-isopropoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1), with a purity of 90%.

Example 14

Add 10 grams of 2', 4"-O-bis(allyloxycarbonyl)-erythromycin A9-O-(1-isopropoxy-1 -cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 10 ° C, add 1.3 grams of hydrogen Potassium oxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.7 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, stir After 30 minutes, the organic layer was separated and washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain 10 grams of 2', 4"-O-di(allyloxycarbonyl)-6-O-methylerythromycin A9 -O-(1-isopropoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1), the purity is 90%.

Embodiment 15 prepares clarithromycin

10 g of the compound of formula III in Example 3 was dissolved in 100 ml of ethanol/water (1:1), 4 g of sodium bisulfite and 1 g of 98% formic acid were added, and the reaction mixture was refluxed for 3 hours. Then, the reaction mixture was diluted with 50 milliliters of water and the pH value was adjusted to 10 with sodium hydroxide solution, the reaction mixture was stirred for 1 hour in an ice-water bath, the precipitate was filtered, washed with water and crystallized with ethanol to obtain 6 grams of clarithromycin with a purity of 98 %.

Embodiment 16 prepares formula II compound

Add 10 grams of erythromycin A9-O-(1-isopropoxy-1-cyclohexyl) oxime to the 250 milliliter four-necked reaction flask equipped with stirrer, condenser tube and thermometer, then add 100 milliliters of dichloro Methane, stirred to make it dissolve, under reflux at 40°C, add 4.5 gram of hexamethyldisilazane and 0.07 gram of N-trimethylsilyl saccharin (2% of the molar weight of the compound of formula I), after reacting for 24 hours, Add 50 ml of saturated aqueous sodium bicarbonate solution, stir for 30 minutes, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain 11.4 g of 2',4"-O-bis(trimethylsilyl) -Erythromycin A9-O-(1-isopropoxy-1-cyclohexyl)oxime, the purity by HPLC is 98%.

Embodiment 17 prepares clarithromycin

(1) preparation formula II compound

Add 10 grams of erythromycin A9-O-(1-isopropoxy-1-cyclohexyl) oxime in 250 milliliters of four-necked reaction flasks equipped with stirrer and thermometer, then add 100 milliliters of dichloromethane, stir Make it dissolve, at 25 DEG C, add 4.5 grams of hexamethyldisilazane and 0.05 grams of saccharin (2% of the molar weight of the compound of formula I), after reacting for 24 hours, add 50 milliliters of saturated sodium bicarbonate aqueous solution, stir for 30 minutes, separated the organic layer and washed with water, dried over anhydrous magnesium sulfate, filtered, and evaporated to obtain 11.0 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1- The purity of isopropoxy-1-cyclohexyl) oxime (compound of formula II, see Table 1) is 98% by HPLC.

(2) preparation formula III compound

Dissolve 10 grams of the compound of formula II in 100 milliliters of tetrahydrofuran, then add 100 milliliters of dimethyl sulfoxide, cool to 10° C., add 1.3 grams of potassium hydroxide (content ≥ 82%) and 2.7 grams of methyl iodide, and react for 2 hours. Add aqueous dimethylamine solution and 200 ml of water, stir for 30 minutes, extract with 100 ml of ethyl acetate, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, evaporate the solvent to obtain a white solid (compound of formula III);

(3) The obtained white solid was dissolved in 100 ml of ethanol/water (1:1), 4 g of sodium bisulfite and 1 g of 98% formic acid were added, and the reaction mixture was refluxed for 3 hours. Then, the reaction mixture was diluted with 50 milliliters of water and the pH value was adjusted to 10 with sodium hydroxide solution, the reaction mixture was stirred for 1 hour in an ice-water bath, the precipitate was filtered, washed with water and crystallized with ethanol to obtain 6 grams of clarithromycin with a purity of 98 %.

Claims (15)

1. A preparation method of a compound of formula III, characterized in that: it comprises the steps of: (1) In the solvent, under the action of saccharin compounds, the compound of formula I and the silylating agent carry out the silanization reaction of the 2' and 4" hydroxyl groups to obtain the compound of formula II; the saccharin compounds are N-three Methylsilyl saccharin; the reaction temperature of the silylation reaction is 15-40°C; (2) In a mixed solvent of 2-methyltetrahydrofuran and other polar inert solvents, under the action of a base and a methylating agent, the 6-hydroxyl group of the compound of formula II is methylated to obtain the compound of formula III; Wherein, in the compounds of formula I, formula II and formula III, R ₁ is an oxime hydroxyl protecting group, R ₂ is a trimethylsilyl group; the other polar inert solvents are N,N-dimethylformamide, N , one or more of N-dimethylacetamide, dimethyl sulfoxide, 1,2-dimethoxyethane and hexamethylphosphoric triamide. 2. The preparation method of the compound of formula III as claimed in claim 1, characterized in that: the oxime hydroxyl protecting group is substituted or unsubstituted C ₁ -C ₁₂ alkyl or substituted C ₁ -C ₁₂ alkoxy ; The substituents in the substituted C ₁ -C ₁₂ alkyl groups are one or more of C ₁ -C ₆ hydrocarbon groups, halogen-substituted phenyl groups and C ₁ -C ₆ alkoxy groups; the C ₁ - _C6 alkoxy is one or more of methoxy, ethoxy and isopropoxy; The substituents in the substituted C ₁ -C ₁₂ alkoxy groups are one or more of phenyl, halogen-substituted phenyl, methyl, ethyl, isopropyl and cyclohexyl. 3. the preparation method of formula III compound as claimed in claim 2, is characterized in that: The substituted or unsubstituted C ₁ -C ₁₂ alkyl group is a substituted or unsubstituted C ₁ -C ₆ alkyl group; And/or, the substituted C ₁ -C ₁₂ alkoxy is a substituted C ₁ -C ₆ alkoxy; And/or, the C ₁ -C ₆ hydrocarbon group is phenyl, methyl, ethyl, isopropyl or cyclohexyl. 4. the preparation method of formula III compound as claimed in claim 1 is characterized in that: described oxime hydroxyl protecting group is trityl, benzyl, 2-chlorobenzyl, 1-methoxy-1- Methylethyl, 1-ethoxy-1-methylethyl, 1-methoxy-1-cyclohexyl, 1-ethoxy-1-cyclohexyl or 1-isopropoxy-1-cyclo Hexyl. 5. the preparation method of formula III compound as claimed in claim 1 is characterized in that: in described formula II compound R ₁ is 1-isopropoxy-1-cyclohexyl, R ₂ is trimethylsilyl , whose structure is as follows: 6. The preparation method of the compound of formula III as claimed in claim 1, characterized in that: in step (1), the amount of the saccharin compound is 0.1% to 10% of the molar weight of the compound of formula I; And/or, the silylating agent is hexamethyldisilazane, trimethylsilyl imidazole, N,N-bis(trimethylsilyl)acetamide and N,N'-bis(trimethylsilyl) One or more in urea; And/or, the amount of the silylating agent used is 1 to 10 times the molar amount of the compound of formula I; And/or, the solvent is dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, methyl tert-butyl ether and one or more of ethyl acetate; And/or, the reaction time of the silylation reaction is 12-48 hours. 7. the preparation method of formula III compound as claimed in claim 6 is characterized in that: The dosage of the saccharin compound is 0.5-5% of the molar weight of the compound of formula I; And/or, the time for the silylation reaction is 24 hours. 8. the preparation method of formula III compound as claimed in claim 1 is characterized in that: in step (2), described methylating reagent is methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, p-toluenesulfonate One or more of methyl esters and methyl methanesulfonate; the amount of the methylating agent is 1 to 10 times the molar weight of the compound of formula II; The base is an inorganic base; the amount of the base is 1 to 10 times the molar amount of the compound of formula II. 9. The preparation method of the compound of formula III as claimed in claim 8, characterized in that: the inorganic base is one or more of metal hydroxides, metal hydrides and metal carbonates. 10. the preparation method of formula III compound as claimed in claim 9 is characterized in that: described alkali is that metal hydroxide is potassium hydroxide and/or sodium hydroxide; Described metal hydride is sodium hydride and / or potassium hydride; the metal carbonate is potassium carbonate and / or sodium carbonate. 11. The preparation method of the compound of formula III according to claim 1, characterized in that: in step (2), the volume ratio of 2-methyltetrahydrofuran and other polar inert solvents is 1:0.5-1:5. 12. The preparation method of the compound of formula III as claimed in claim 11, characterized in that: the volume ratio of 2-methyltetrahydrofuran and other polar inert solvents is 1:1. 13. The preparation method of the compound of formula III as claimed in claim 1, characterized in that: in step (2), the temperature of the methylation reaction is 0-60°C; the time of the methylation reaction is 0.5 to 4 hours. 14. The preparation method of the compound of formula III according to claim 13, characterized in that: the temperature of the methylation reaction is 5-20°C. 15. A preparation method of clarithromycin, comprising the steps of: (1) preparing the compound of formula III according to the preparation method described in any one of claims 1 to 14; (2) preparing the compound of formula III 2', 4 The hydroxyl protecting group at the "position is deprotected, the oxime hydroxyl protecting group at the 9-position is hydrolyzed into a carbonyl group, and clarithromycin is obtained; Wherein, R ₁ and R ₂ are as described in any one of claims 1-5.