KR19990048084A - Method for preparing clarithromycin - Google Patents

Abstract

The present invention relates to a novel process for producing clarithromycin represented by the following formula (1) having a broad antibacterial activity as a macrolide antibiotic, and a novel intermediate that can be used for the synthesis thereof.

[Formula 1]

According to the preparation method of the present invention, trisilylate can be synthesized quantitatively by using an excess of hexamethyldisilazane, and easily and almost quantitatively using a t-butyldimethylsilyl group which is commercially available in large quantities as a protecting group of oxime. The protection reaction of oxime can be carried out, and since the t-butyldimethylsilyl group can be removed simultaneously with the trimethylsilyl group and the oxime group when deprotected under acidic conditions, the target compound can be obtained in a high yield in a short step.

Description

Method for preparing clarithromycin

The present invention relates to a novel process for producing clarithromycin represented by the following formula (1) having a broad antibacterial activity as a macrolide antibiotic, and a novel intermediate that can be used for the synthesis thereof.

The manufacturing method of the compound represented by the said General formula (1) known so far is a Korean patent application 91-5898 (Taisho), 91-7572 (Taisho), 91-2142 (Taisho), 95-9367 (Taisho), 96-434 (Taisho), Republic of Korea Patent Publication No. 90-18132 (Taisho), Republic of Korea Patent Publication No. 91-7953 (Taisho) in addition to a number of scholarly literature, such as J. Antibiotics (V.46, No.4 , 647 (1993)), J. Antibiotics (V.46, No. 7, 1163 (1993)), J. Antibiotics (V. 37, No. 2, 187 (1984)), Heterocycles (V.36, No) .2, 243 (1993), J. Antibiotics (286 (1990)) and the like.

These manufacturing methods can be summarized in the following three ways.

(First method)

The first method is a relatively early preparation method introduced in Korean Patent Application Nos. 91-5898 and 91-7572. The erythromycin 9-oxime derivative of oxime-protected -OH group is used as a carbenzyloxy group (Cbz group). After protecting the 3'-dimethylamino group and the 2'-OH group, the methylation of 6 -OH group should be used in excess of Cbz-Cl, which is relatively expensive, and the deprotection reaction should be carried out by hydrogen reaction. There is a disadvantage in that the reaction is not completed by the catalytic poison, and the process is difficult and long because the methyl group of the 3'-dimethylamino group is regenerated in the last step. Schematic of this method is shown in the following scheme (1).

(Second method)

The second method is a manufacturing method as described in the Republic of Korea Patent Application No. 91-2142, etc. Representatively, a method of protecting the 3'-dimethylamino group with the protection of the -OH group of the oxime by making a quaternary salt of the same group, the first As in the method, hydrogen should be used in the deprotection reaction, in which case the reaction is not completed by the catalyst poison. Schematic of this method is shown in the following scheme (2).

(Third method)

The third method is a method disclosed in Korean Patent Application Nos. 95-9367, 96-434, and the like. The oxime is protected using a benzyl derivative, a ketal derivative, and the like, and a silyl having a 2'-OH group and a 4 "-OH group is substituted. After protecting with a group, a 6-OH group is methylated, and a 9-oxime protecting group and a 2'-O-, 4 "-O- silyl group are simultaneously deprotected to obtain a target compound in a short step. In this case, the 9-oxime derivative used for the silylation reaction of 2'-OH and 4 "-OH is to use the salt free state. Such a method is represented as following Reaction Formula (3). Can be.

The synthesis of clarithromycin by Scheme 3 has been shown to be capable of synthesizing from erythromycin A in a total yield of about 45-50%, which is considered to be a commercially suitable method with ease of reaction and short steps. However, since the ketal derivative used as the protecting group of oxime is prepared after synthesis, the reaction step is actually increased.

Accordingly, the present inventors have continued a long research to solve the problems of the conventional method as described above and obtain a higher yield, and as a result of protecting the oxime, as described in J. Antibiotics, V.46, No. 4, 647 ( 1993)) stated that the methylation reaction was too unstable under basic conditions, so that it could not be reacted.However, by introducing a commercially available silyl derivative, a new and simple process was developed to produce a desired compound in high yield. Became me.

According to the present invention, the process for preparing clarithromycin represented by the following formula (1) includes the following steps:

[Formula 1]

a) The oxime derivative of formula (4) is reacted by reacting the hydrochloride of the erythromycin A 9-oxime derivative represented by the following formula (2) with 3 to 5 equivalents of hexamethyldisilazane and 0.1 to 1 equivalent of ammonium chloride. Gained,

b) silylation of the oxime derivative of formula (4) with 1 to 2 equivalents of t-butyldimethylsilylchloride in the presence of 1 to 2 equivalents of imidazole in an aprotic solvent. Obtaining a butyldimethylsilyl group protecting oxime derivative,

c) The compound of formula (6) is prepared by methylation of the oxime derivative of formula (5), followed by deprotection to prepare the target compound of formula (1).

The protection of the 2'-OH and 4 "-OH groups of erythromycin A 9-oxime in step a) is achieved by silylation with hexamethyldisilazane. However, in conventional methods erythromycin A 9- Oxylation of oxime with hexamethyldisilazane (2 equiv) / ammonium chloride (or pyridine hydrochloride) (1.5 equiv), where the reaction is not complete and the acid moiety that may be produced in the preparation of erythromycin A 9-oxime Depending on whether the salt is neutralized, the synthesis process may be increased by one step, but in the case of the present invention, instead of using the synthesized erythromycin 9-oxime hydrochloride directly in the silylation reaction, ammonium chloride (or pyridine hydrochloride) is used. , Using only 0.1 to 1 equivalent (preferably 0.5 equivalent) of pyridine p-toluenesulfonic acid) and 3 to 5 equivalents (preferably 5 equivalents) of hexamethyldisilazane to synthesize trisilyl derivatives.Water was added to only the trimethylsilyl group (TMS) of the oxime to selectively hydrolyzed 2'-O-, 4 "-O- bis trimethylsilyl-erythromycin A 9- the oxime derivative can be obtained in a high yield.

This step can be expressed as in the following scheme (4).

The oxime derivative produced by the above reaction formula (4) is oxime by t-butyldimethylsilyl group (TBDMS) by reaction with commercially readily available t-butyldimethylsilyl chloride as shown in the following reaction formula (5). To protect.

The oxime derivative (compound (5)) synthesized in Scheme (5) is subjected to methylation reaction to a 6-OH group to synthesize a compound of formula (6) as shown in Scheme (6), followed by deprotection. The target compound (1) can be synthesized.

The t-butyldimethylsilyl group used as a protecting group of oxime in the methylation reaction of the compound of formula (5) in the above scheme (6) is very unstable under basic conditions and easily hydrolyzed. In order to prevent this, in the present invention, a polar aprotic solvent such as dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) or a mixed solvent of these with a nonpolar solvent such as tetrahydrofuran (THF) (preferably DMSO: About 2-5 equivalents (preferably 2-3 equivalents) of sodium hydride under THF (1: 1) mixed solvent), at about 10-10-10 DEG C (preferably -2-5 DEG C), Using a mixed reagent of dimethylsulfate (0-10 equivalents) and methane iodide (10-10 equivalents) (preferably dimethylsulfate: methane iodide (3 equivalents: 5 equivalents)) from erythromycin A 9-oxime in high yield The compound of formula (6) was synthesized and deprotected to synthesize 49.1% of the target compound (Formula (1)) to complete the present invention.

The technical advances of the present invention are as follows.

First, in the prior art, when the oxime derivative of erythromycin is silylated using hexamethyldisilazane (HMDS), the desalting state of the erythromycin A 9-oxime derivative is used to neutralize the oxime derivative of erythromycin. The reaction should be carried out, but in the case of the present invention, since the silylation reaction uses the erythromycin A 9-oxime derivative in the hydrochloride state as it is, the manufacturing step can be reduced, and the amount of ammonium chloride used is also 0.1 to 1 equivalent (preferably 0.5 equivalent). In addition, when using 2.0 equivalents of HMDS, as in the prior art, the reaction is not completed due to trimethylsilylation of oxime, which is preferentially produced. Therefore, the use of excess HMDS (about 3 to 5 equivalents) can be used to synthesize trisilylide almost quantitatively.In this case, trimethylsilyl groups of oxime can be easily hydrolyzed by adding water to obtain desired bissilylide in high yield. Can be.

Second, in the case of the prior art, the use of benzyl derivatives as the protecting group of oxime is difficult to process because the hydrogenation reaction using a catalyst when deprotection, and there is a problem that the reaction is not completed due to the catalytic poisoning phenomenon. In addition, in the case of using a ketal derivative as a protecting group of oxime, there is an advantage that can be deprotected with a silyl group and an oxime at the time of deprotection, but there is a problem that the process is increased because the ketal derivative must be synthesized. However, in the present invention, a protective reaction of oxime can be easily performed almost quantitatively using t-butyldimethylsilyl group which is commercially available in large quantities as a protecting group of oxime. In addition, the degree of instability in methylation of silyl derivatives is also indicated by the use of a mixed solvent of DMSO and THF and a low temperature reaction (about -2 to -5 ° C), and the use of a mixed reagent of an appropriate ratio of dimethyl sulfate and methane iodide (about 3 equivalents: 5 equivalents). It can be stabilized by improving the reaction conditions. In addition, the t-butyldimethylsilyl group can be removed simultaneously with the trimethylsilyl group and the oxime group during deprotection under acidic conditions such as a ketal protecting group, thereby obtaining a target compound (Formula (1)) in a short step and high yield.

Hereinafter, the present invention will be described in more detail with reference to the following Examples, which are not intended to limit the scope of the present invention.

Example 1 Preparation of 2′-O-, 4 ″ -O-Bistrimethylsilyl-erythromycin A 9-Oxime

Into a 20 L flask add erythromycin A 9-oxime hydrochloride (1.57 kg, 2 mole) and ammonium chloride (54 g, 1 mole) and 6 L of dimethylformamide. Hexamethyldisilazane (HMDS, 2.17 L, 10 mol 1) was slowly added thereto and stirred at 35-40 ° C. for 1.5 hours. To this was added 300 ml of water, stirred for 1 hour, followed by the addition of 6 L of water. After stirring for 30 minutes, 1.5 L of 2N-NaOH was added and extracted using 6 L of dichloromethane, and the aqueous layer was extracted once more using 2 L of dichloromethane. The combined organic layers were washed with 2 L saturated brine, dehydrated using anhydrous MgSO ₄ , and the solvent was removed under reduced pressure to give 1704.5 g (yield 95.4%) of the target compound in the foam.

¹ H NMR (CDCl ₃ ) δ 0.16 (s, 9H, -OTMS), 0.19 (s, 9H, -OTMS)

Example 2: Preparation of 2'-O-, 4 "-O-bistrimethylsilyl-erythromycin A 9-O-t-butyldimethylsilyl oxime

2'-O-, 4 "-O-bistrimethylsilyl-erythromycin A 9-oxime (81.02 g, 0.091 mole) synthesized in Example 1 was dissolved in 400 ml of dichloromethane and then imidazole (8.17 g, 0.12 mole) t-butyldimethylsilylchloride (19.07 g, 0.12 mole) is added while maintaining the temperature at 20-25 ° C. After stirring for 30 minutes, 200 ml of water are added and 200 ml of hexane The organic layer was washed with saturated brine, dehydrated with anhydrous MgSO ₄ , filtered and dried to give 88.87 g of a foamy compound (yield: 97.24%).

¹ H NMR (CDCl ₃ ) δ 0.96 (s, 9H, t-BuSi-), 0.18 (s, 6H, Me ₂ Si-), 0.16 (s, 9H, -OTMS), 0.12 (s, 9H, -OTMS )

Example 3: Preparation of 2'-O-, 4 "-O-bistrimethylsilyl-6-O-methyl-erythromycin A 9-O-t-butyldimethylsilyl oxime

500 ml of 1: 1 mixed solvent of anhydrous THF and anhydrous DMSO is placed in a 2 L flask and the temperature is maintained at -2 to -4 ° C and 10 g of NaH (60%, 0.25 mole) is added. After stirring for about 10 minutes, dimethylsulfate (28.4 ml, 0.3 mole) and methane iodide (32.8 ml, 0.5 mole) are added. After stirring for about 10 minutes, 2'-O, 4 "-O-bistrimethylsilyl-erythromycin A 9-Ot-butyldimethylsilyl oxime synthesized in Example 2 dissolved in 100 ml of the mixed solvent was quickly prepared. After the reaction is completed, 300 ml of hexane and 600 ml of water are sequentially added and extracted, and the organic layer is washed with about 10% brine, dehydrated by adding anhydrous MgSO ₄ , and then filtered. The solvent was removed under reduced pressure to obtain 102.16 g of a foamy target compound (yield: 100%).

¹ H NMR (CDCl ₃ ) δ 3.06 (s, 3H, 6-OCH ₃ ), 0.94 (s, 9H, t-BuSi-), 0.14 (s, 15H, Me ₂ Si-, -OTMS), 0.09 (s , 9H, -OTMS)

Example 4 Preparation of Clarisomycin

102.16 g (0.1 mole) of 2'-O-, 4 "-O-bistrimethylsilyl-6-O-methyl-erythromycin A 9-Ot-butyldimethylsilyl oxime synthesized in Example 3 was added to 250 ml of ethanol. After dissolving, 250 ml of water are added, formic acid (5.66 ml, 0.15 mole) and NaHSO ₃ (41.6 g, 0.4 mole) are added and heated to reflux for 2 hours After completion of the reaction, 750 ml of water is added to hexane 100 Extract with ml The aqueous solution is extracted with 400 ml of ethyl acetate using 200 ml of 2N-NaOH to about pH = 10. The organic layer is washed with 250 ml of 10% brine and dried using anhydrous MgSO ₄ . After dehydration, filtration and removal of the solvent under reduced pressure yielded a crude product, 350 ml of ethanol was added to the resulting crude product, heated to reflux for 2 hours, and stirred for 8 hours at 60 ° C. The resulting solid was filtered to give a colorless transparent needle. 39.58 g (yield: 52.9%) of the target compound were obtained.

¹ H NMR (CDCl ₃ ) δ 5.08 (d, 1H), 4.93 (d, 1H), 4.44 (d, 1H), 4.02 (m, 1H), 3.99 (s, 1H), 3.78 (m, 2H), 3.67 (d, 1H), 3.33 to 3.46 (m, 2H), 3.34 (s, 3H), 3.19 (t, 2H), 3.06 (s, 3H), 2.89 to 3.02 (m, 2H), 2.89 (m, 1H), 2.58 (m, 1H), 2.40 (m, 2H), 2.29 (s, 6H), 1.93 (d, 1H), 1.40-1.95 (m, 6H), 1.42 (s, 3H), 1.10-1.35 (m, 6H), 0.85 (t, 3H)

According to the preparation method of the present invention, trisilylate can be synthesized quantitatively by using an excess of hexamethyldisilazane, and easily and almost quantitatively using a t-butyldimethylsilyl group which is commercially available in large quantities as a protecting group of oxime. The protection reaction of oxime can be carried out, and since the t-butyldimethylsilyl group can be removed simultaneously with the trimethylsilyl group and the oxime group when deprotected under acidic conditions, the target compound can be obtained in a high yield in a short step.

Claims (4)

Compound represented by the following formula (5 or 6): [Formula 5] (Wherein TBDMS represents a t-butylmethylsilyl group and TMS represents a trimethylsilyl group) [Formula 6] (Wherein TBDMS represents a t-butyldimethylsilyl group, TMS represents a trimethylsilyl group and Me represents a methyl group). Method for preparing clarithromycin represented by the following formula (1) including the following steps: [Formula 1] a) The oxime derivative of formula (4) is reacted by reacting the hydrochloride of the erythromycin A 9-oxime derivative represented by the following formula (2) with 3 to 5 equivalents of hexamethyldisilazane and 0.1 to 1 equivalent of ammonium chloride. Gained, [Formula 2] [Formula 4] (Wherein TMS represents a trimethylsilyl group) b) silylation of the oxime derivative of formula (4) with 1 to 2 equivalents of t-butyldimethylsilylchloride in the presence of 1 to 2 equivalents of imidazole in an aprotic solvent. Obtaining a butyldimethylsilyl group protecting oxime derivative, [Formula 5] (Wherein TBDMS represents a t-butyldimethylsilyl group and TMS represents a trimethylsilyl group) c) The compound of formula (6) is prepared by methylation of the oxime derivative of formula (5), followed by deprotection to prepare the target compound of formula (1). [Formula 6] (Wherein TBDMS represents a t-butyldimethylsilyl group, TMS represents a trimethylsilyl group and Me represents a methyl group). The reaction temperature according to claim 2, wherein the reaction temperature is 10 to 10 ° C. when the methylation reaction is carried out in step c), and the solvent is a 1: 1 mixed solvent of dimethyl sulfoxide and tetrahydrofuran. The reaction mixture was used in an amount of 10 to 10 times, using 2.0 to 5.0 equivalents of NaH as a base, and reacting the mixed solvent of dimethyl sulfate and methane iodide with 0 equivalents: 10 equivalents to 10 equivalents: 0 equivalents as a methylation reagent for 5 to 30 minutes. Manufacturing method characterized in that. The deprotection reaction according to claim 2, wherein the deprotection reaction is carried out by reacting the compound of formula (6) with 1.0-3.0 equivalents of formic acid and 2-5 equivalents of NaHSO _{3 in} a 1: 1 mixed solvent of ethanol and water. Manufacturing method characterized in that.