RU2001117216A

RU2001117216A - NEW INTERMEDIATE COMPOUNDS AND METHOD FOR PRODUCING MACROLIDE ANTIBIOTIC FROM THEM

Info

Publication number: RU2001117216A
Application number: RU2001117216/04A
Authority: RU
Inventors: Тае Сук ЛИ; Чанг Хиун ЙОО; Киоунг Соо Ким; Хиун Сук АН; Дзунг Янг КИМ; Ван Дзоо КИМ
Original assignee: Кемтек Рисерч Инкорпорейшн; Хансол Кеминс Ко., Лтд.
Priority date: 1998-11-24
Filing date: 1999-11-24
Publication date: 2003-05-27

Claims

1. Derivative of 9-O-benzodithidoxime erythromycin A, useful for the synthesis of clarithromycin, obtained by the reaction of 9-oxime erythromycin A or its hydrochloride with 1,3-benzodithiol-2-yl tetrafluoroborate (BDTF) represented by formula (III)

in which Y ₁ and Y ₂ represent hydrogen atoms or trimethylsilyl groups.

2. The intermediate compound according to claim 1, in which the compound of the above formula (III) (Y ₁ and Y ₂ represent trimethylsilyl groups) crystallizes in a mixed solvent of 5-10 parts by weight acetone and 1-5 parts by weight water, and the resulting crystalline solvate contains a compound of the specified formula and acetone in a ratio of 2: 1.

3. A method of producing clarithromycin of formula (I), comprising the steps of:

1) the interaction of the 9-oxime of erythromycin A of the following formula (II) or its hydrochloride with 1.0-1.2 equivalents of 1,3-benzodithiol-2-yl tetrafluoroborate (BDTF) in an aprotic non-polar organic solvent in the presence of 1.0- 2.0 equivalents of pyridine with the synthesis of the 9-O-BDT derivative of the erythromycin A oxime of formula (III) 'with an oxime group protected by a 1,3-benzodithiol (BDT) group, as shown in the following diagram:

where MS is methylene dichloride,

2) the reaction of the compounds of formula (III) ', synthesized in the above stage 1), with 3.0-5.0 equivalents of hexamethyldisilazane (HMDS), in the presence of salts such as ammonium chloride, pyridine hydrochloride or pyridine p-toluenesulfonate, s the formation of the 9-O-BDT derivative 2'-O-, 4 '' - O-bistrimethylsilylerythromycin A of the formula (V), in accordance with the scheme below:

3) methylation of the 6-OH group of the compound of formula (V) synthesized in the above step 2) with 2.0-3.0 equivalents of methyl iodide in an aprotic polar solvent in the presence of a strong base to form the 9-O-BDT derivative of oxime 2'- O, -4 '' - O-bistrimethylsilyl-6-O-methyerythromycin of the formula (VII) according to the following scheme:

4) deprotecting a compound of formula (VII) synthesized in the above step 3) to form a compound of the following formula (I). BDSA, and

5) mixing the compound of formula (I). BDSA synthesized in the above step 4) in water or in a mixture of water and a water-miscible organic solvent in the presence of an inorganic salt, followed by filtration to form clarithromycin represented by the following formula (I) :

4. The method according to claim 3, comprising the steps of adding hexamethyldisilazane (HMDS) to the 9-oxime of erythromycin A or its hydrochloride to form the 9'-oxime derivative 2'-O-4 '' - O-bistrimethylsilylerythromycin A of the following formula (IV), instead of the described step 1), and the interaction of the 9'-oxime derivative 2'-O-4 '' - O-bistrimethylsilylerythromycin A of the indicated formula (IV) in an aprotic organic solvent, in the presence of pyridine, with BDTF to form the 9-O-BDT oxime derivative 2'-O-4 '' - O-bistrimethylsilylerythromycin A of the formula (V), instead of the above step 2), as long as ano next following scheme:

5. The method according to claim 3, in which the methylation described above in step 3) is carried out at a temperature of (-5) to (+ 5) ° C, using an aprotic polar solvent such as DMF or DMSO, a mixture of the aprotic polar solvent and THF in a ratio of 1: 1, or a mixture of the specified aprotic polar solvent, THF and a non-polar organic solvent such as isopropyl ether or tert-butyl methyl ether, in a ratio of 2: 2: 0.3, in the presence of 1.0-3, 0 equivalents of such a strong base as KOH, alkoxide and NaH, and 2.0-3.0 equivalents of meth liodida as the methylating agent in the presence of 0-2.5 equivalents of Et ₃ N, for 30 min - 2 hr.

6. The method according to claim 3, wherein the water-miscible organic solvent in step 5) is methanol or ethanol.

7. The method according to claim 3, in which the deprotection in step 4) is carried out using 1.0-3.0 equivalents of formic acid and 4.0-8.0 equivalents of NaHSO ₃ , Na ₂ S ₂ O ₄ , Na ₂ S ₂ O ₅ or Na ₂ SO ₃ in 5-10 parts by weight mixtures of ethanol with water in a ratio of 1: 1, and before crystallization, the mixture was cooled to room temperature.

8. The method according to claim 3, in which the neutralization reaction of stage 5) is carried out by preparing a solution of the compound of the above formula (I). BDSA by mixing one mass part of the specified compound and 10-20 wt.h. water or 5-10 parts by weight water and 5-10 parts by weight methanol or ethanol, when the ratio in the mixture is 1: 1, and by adding to the specified solution 3-5 wt.h. solvent, including 1-2 parts by weight inorganic salt.