Title of Invention	A METHOD OF PREPARING CLARITHROMYCIN
Abstract	This invention discloses a method of manufacturing clarithromycin, where an erythromycin A 9-oxime thiocyanate salt is used directly to perform an etherification reaction, and then successively silanizattion, methylattion and hydrolysis reactions are sequentially conducted. It is a new process with simple process with a high yield, low cost, less pollution, high quality and is suitable for commercial manufacturing.

Title of Invention

A METHOD OF PREPARING CLARITHROMYCIN

Abstract

This invention discloses a method of manufacturing clarithromycin, where an erythromycin A 9-oxime thiocyanate salt is used directly to perform an etherification reaction, and then successively silanizattion, methylattion and hydrolysis reactions are sequentially conducted. It is a new process with simple process with a high yield, low cost, less pollution, high quality and is suitable for commercial manufacturing.

Full Text	FORM 2 THE PATENTS ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. ' A METHOD OF PREPARING CLARITHROMYCIN ' 2. 1. (A) Zhejiang Huayi Pharmaceutical Co., Ltd. (B) CHINESE (C) No.15 Shuangfeng Rd., Yinan industrial Park, Yiwu, 322002,China. The following specification particularly describes the invention and the manner in which it is to be performed. The present application claims the benefit of Chinese Patent Application No. 200910098150.x, filed on April 30, 2009, which is hereby incorproated by reference in its entirety. Field of Technology The present invention relates to the technical field of preparing an organic compound, specifically a method of preparing clarithromycin. Background Clarithromycin (structural formula I), also known as methyl-erythromycin, is a macrolide antibiotic obtained from methylation of 6-position hydroxyl group of erythromycin. It exhibits excellent anti-bacterial activity against Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, mycoplasma and chlamydia. Its activity is 2-4 times stronger than erythromycin. However, its toxicity is only about half (½) to one twentyfourth (1/24) of the toxicity of erythromycin. (I) U.S. Patent No. 4,331,803 discloses a method of making clarithromycin by protecting the hydroxyl group at 2’-position and the dimethylamine group at 3’-position of erythromycin A, conudcting methylation of 6-position hydroxyl group of erythromycin A, and removing the protective groups from erythromycin. Because the hydroxyl group at the 11, 12, and 4’ positions of erythromycin A can be easily methylated in a methylation reaction, many by-products are produced. It makes purification of the product difficult and affects the quality and the yield of the product. In order to effectively methylate hydroxyl groups at the 6-positions, EP0272110 discloses a method of preparing clarithromycin. First, erythromycin A 9-oxime is etherified with an acid catalysis to protect the hydroxyl group at the 9-position. Next, the hydroxyl groups at the 2’-position and 4’’-position are silylanized to be protected. Then, the hydroxymethylation reaction is conducted at the 6-positions. Finally, hydrolyzation is conducted to remove the protecting groups at the 2’-position, the 4’’-position and the 9-position to obtain clarithromycin. This technological route is long and the yield is not high. Morever, because macrolide antibiotic is not stable to acid, when an acid catalysis is used to protect the hydroxyl group at the 9-position, erythromycin A 9-oxime is easily destroyed, thereby the yield is reduced. The total yield is about 50% (according to erythromycin A 9-oxime). Summary of The Invention An object of the present invention is to provide a synthesis method of clarithromycin which has a simple process, a high yield, low cost, less pollution, high quality and is suitable for the commercial manufacturing. To solve the technical problems mentioned above, the present invention adopts the following technical solution: Erythromycin A 9-oxime thiocyanate salt (formula II) is etherified directly, then sequentially goes through the silanization, methylation and hydrolysis reactions. The reaction route is as follows: (II) (III) (I) (IV) wherein: R1 is the protective group of the etherification reaction and R1 can be 1-ethoxy-1-methylethyl, 1-methoxyl-1-methylethyl, 2-ethoxypropyl or 1-ethoxycyclohexyl, etc.; R2 is trimethylchlorosilane. The present invention comprises the following steps: 1. Erythromycin A 9-oxime thiocyanate salt is dissolved in an oganic solvent. An etherifying agent is added until the reaction completes. Then, a silanizing agent is added into the reaction and erythromycin A 9-oxime silanization derivatives (III) are obtained. The oganic solvent herein can be haloalkanes, dimethyl sulfoxide, dimethylformamide, methylbenzene, C6 to C10 lower paraffin hydrocarbon, ethyl acetate, acetone,etc., preferably dichloromethane. The etherifying agent can be 2-ethoxypropene, 2-methoxypropene, 2,2-dimethoxypropane, 1,1-dimethoxy-Cyclohexane, preferably 2-ethoxypropene. The temperature of the etherification can be -20°C to 80°C, preferably the room temperature. The dosage of the etherifying agent is equivalent to 1-20 times of erythromycin A 9-oxime thiocyanate salt, preferably 6 times. The silanizing agent can be trimethylchlorosilane, hexamethyldisilazane, preferably trimethylchlorosilane. The dosage of the silanizing agent is equivalent to 1-2 times of erythromycin A 9-oxime thiocyanate salt. The temperature of the silanization can be -10°C to 50°C, preferably the room temperature. 2. The next step is to methylate the silanization derivatives from the previous step. After the reaction completes, water is added to obtain methide (IV). The methylating agent can be halomethane, the dosage of which is equivalent to 1-5 times of silanization derivatives. The alkali can be selected from sodium hydroxide and potassium hydroxide, the dosage of which is equivalent to 1-5 times of silanization derivatives. The methylation solvent can adopt the mixture of dimethyl sulfoxide and tetrahydrofuran. The reaction temperature is -10 to 30oC. 3. Hydrolysis reaction of the methide from the last step removes the protective groups and obtain clarithromycin (I). Ethanol can be the solvent of the hydrolysis reaction. Formic acid and sodium bisulfite can be used as a reductant in a reflux reaction. Erythromycin A 9-oxime thiocyanate salt used as the starting material of the present invention can be prepared in an usual processes (such as J.Antibio.1991,44(3), 313-330). Comparing the prior technology adopting erythromycin A 9-oxime in the etherification, the present invention uses erythromycin A 9-oxime thiocyanate salt to achieve the etherification. The present invention has following advantages: 1. The present invention leaves out a reaction step of the transformation from erythromycin A 9-oxime thiocyanate salt to erythromycin A 9-oxime, which simplifies the production process. In addition, there is no need to conduct the unit operations, such as neutralization reaction of alkali, extraction, water-washing, centrifugal and drying and so on. 2. In the present invention, reducing the reaction step saves the materials required for the step (usually dichloromethane, ammonia and methanol), thereby the cost of final product clarithromycin can be reduced. 3. Because of reducing the one reaction step and centrifugal process, the exhaust and the pollution are decreased. 4. There is no need to add acid catalyst in the etherification. Therefore, the etherification reaction is stable and the acidity destruction is avoided. 5. The present invetion uses erythromycin A 9-oxime thiocyanate as the raw material to operate etherification directly, then sequentially performs silicon alkylation, methylation and hydrolysis reactions to obtain clarithromycin. Compared with the method of using erythromycin A 9-oxime as the raw material, the yield of the preesnt invention is higher. The total yield is above 60% (accounting in erythromycin A 9-oxime thiocyanate salt), and the product quality of the present invention is better. Embodiments of The Invention The following embodiemnts help to further comprehend the present invention. However, the contents of the invention are not limited to these embodimetns. Example 1: Preparation of erythromycin A 9-oxime thiocyanate salt 200 g of methanol, 200 g of erythromycin thiocyanate, 100 g of hydroxylamine hydrochloride, and 60 g of triethylamine were added into a 1000ml 4-neck flask with a stirring paddle. The mixture in the flask was heated up until circumfluence, and kept warm for 24 hours. Then its temperature was dropped to 0oC. It was filtered and dried to obtain 176g of erythromycin A 9-oxime thiocyanate salt. The yield was 86.2 %. Example 2: Preparation of 2’,4’’-O-Bis (trimethylsilyl)erythromycin A9-[O-(1-ethoxy-1-methylethyloxime)] 100g of dichloromethane and 30g of erythromycin A 9-oxime thiocyanate salt were added into a 500 ml reaction bulb. 20g of 2-Ethoxypropene was added dropwise at the normal temperature during 20 minutes. After the mixture was kept warm for 10 minuntes, 15g of imidazole, 15g of trimethylchlorosilane were added dropwisely at the normal temprature during 30 minutes. After the mixture was kept warm for 10 minuntes, 50 ml of water was added. The mixture went through delamination and the aqueous layer was removed. The dichloromethane layer was washed twice with water(50 ml X2). The dichloromethane layer was concentrated to dry. 100g of methanol was added. The mixture was filtered and dried to obtain 37g of 2’,4’’-O-Bis(trimethylsilyl)erythromycin A 9-[O-(1-ethoxy-1-methylethyloxime)] ( erythromycin A 9-oxime silanization derivatives). The yield is 94.1 %. Example 3: Preparation of 2’,4’’-O-Bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-ethoxy-1-methylethyloxime)] 35g of erythromycin A 9-oxime silanization derivatives and 150g of tetrahydrofuran were added into a 500 ml reaction bulb. After complete dissolution, 165g dimethyl sulfoxide, 13.5g of iodomethane and 8.5g of KOH were added. The mixture was kept warm at the room temperature for 60 minutes. 100 ml of water was added. The mixture was filtered to obtain 35.5g 2’,4’’-O-Bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-ethoxy-1-methylethyloxime)](methide). The yield is 100%. Example 4: Preparation of clarithromycin 35g of methide obtained in Example 3, 112g of ethanol, 10g of formic acid, 30g of sodium bisulfite and 100g of water were added into a 500 ml reaction bulb. The mixture was heated up until circumfluence. After the reaction lasted for 8 hours, the temperature was dropped to the normal temprature. 250g of dichloromethane was added for extraction and delaminating the mixture. The dichloromethane layer was concentrated to dry and 17.5g clarithromycin was obtained. The yield is 66.7%. WE CLAIM:- 1. A method of preparing clarithromycin, comprsiing the steps of: using erythromycin A 9-oxime thiocyanate as a raw material to directly conduct an etherification reaction, then sequentially conducting a silicon alkylation reaction, a methylation reaction and a hydrolysis reaction to obtain clarithromycin. 2. The method of preparing clarithromycin said in Claim 1, wherein solvent adopted in the etherification reaction is selected from haloalkanes, dimethyl sulfoxide, dimethylformamide, methylbenzene, and C6 to C10 lower paraffin hydrocarbon. 3. The method of preparing clarithromycin said in Claim 1, wherein an etherifying agent used in the etherification reaction is selected from 2-Ethoxypropene, 2-Methoxypropene, 2,2-Diethoxypropane, and 1,1-diethoxy-Cyclohexane in etherification. 4. The method of preparing clarithromycin said in Claim 1, wherein the reaction temperature of the etherification reaction is between -20°C to 80°C. Dated this 22nd day of April 2010.

Full Text

FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. ' A METHOD OF PREPARING CLARITHROMYCIN '

2.

1. (A) Zhejiang Huayi Pharmaceutical Co., Ltd.
(B) CHINESE
(C) No.15 Shuangfeng Rd., Yinan industrial Park, Yiwu, 322002,China.

The following specification particularly describes the invention and the manner in which it is to be performed.

The present application claims the benefit of Chinese Patent Application No. 200910098150.x, filed on April 30, 2009, which is hereby incorproated by reference in its entirety.
Field of Technology
The present invention relates to the technical field of preparing an organic compound, specifically a method of preparing clarithromycin.
Background
Clarithromycin (structural formula I), also known as methyl-erythromycin, is a macrolide antibiotic obtained from methylation of 6-position hydroxyl group of erythromycin. It exhibits excellent anti-bacterial activity against Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, mycoplasma and chlamydia. Its activity is 2-4 times stronger than erythromycin. However, its toxicity is only about half (½) to one twentyfourth (1/24) of the toxicity of erythromycin.

(I)
U.S. Patent No. 4,331,803 discloses a method of making clarithromycin by protecting the hydroxyl group at 2’-position and the dimethylamine group at 3’-position of erythromycin A, conudcting methylation of 6-position hydroxyl group of erythromycin A, and removing the protective groups from erythromycin. Because the hydroxyl group at the 11, 12, and 4’ positions of erythromycin A can be easily methylated in a methylation reaction, many by-products are produced. It makes purification of the product difficult and affects the quality and the yield of the product.
In order to effectively methylate hydroxyl groups at the 6-positions, EP0272110 discloses a method of preparing clarithromycin. First, erythromycin A 9-oxime is etherified with an acid catalysis to protect the hydroxyl group at the 9-position. Next, the hydroxyl groups at the 2’-position and 4’’-position are silylanized to be protected. Then, the hydroxymethylation reaction is conducted at the 6-positions. Finally, hydrolyzation is conducted to remove the protecting groups at the 2’-position, the 4’’-position and the 9-position to obtain clarithromycin. This technological route is long and the yield is not high. Morever, because macrolide antibiotic is not stable to acid, when an acid catalysis is used to protect the hydroxyl group at the 9-position, erythromycin A 9-oxime is easily destroyed, thereby the yield is reduced. The total yield is about 50% (according to erythromycin A 9-oxime).
Summary of The Invention
An object of the present invention is to provide a synthesis method of clarithromycin which has a simple process, a high yield, low cost, less pollution, high quality and is suitable for the commercial manufacturing. To solve the technical problems mentioned above, the present invention adopts the following technical solution:
Erythromycin A 9-oxime thiocyanate salt (formula II) is etherified directly, then sequentially goes through the silanization, methylation and hydrolysis reactions. The reaction route is as follows:

(II) (III)
(I)
(IV)
wherein: R1 is the protective group of the etherification reaction and R1 can be 1-ethoxy-1-methylethyl, 1-methoxyl-1-methylethyl, 2-ethoxypropyl or 1-ethoxycyclohexyl, etc.; R2 is trimethylchlorosilane.
The present invention comprises the following steps:
1. Erythromycin A 9-oxime thiocyanate salt is dissolved in an oganic solvent. An etherifying agent is added until the reaction completes. Then, a silanizing agent is added into the reaction and erythromycin A 9-oxime silanization derivatives (III) are obtained. The oganic solvent herein can be haloalkanes, dimethyl sulfoxide, dimethylformamide, methylbenzene, C6 to C10 lower paraffin hydrocarbon, ethyl acetate, acetone,etc., preferably dichloromethane. The etherifying agent can be 2-ethoxypropene, 2-methoxypropene, 2,2-dimethoxypropane, 1,1-dimethoxy-Cyclohexane, preferably 2-ethoxypropene. The temperature of the etherification can be -20°C to 80°C, preferably the room temperature. The dosage of the etherifying agent is equivalent to 1-20 times of erythromycin A 9-oxime thiocyanate salt, preferably 6 times. The silanizing agent can be trimethylchlorosilane, hexamethyldisilazane, preferably trimethylchlorosilane. The dosage of the silanizing agent is equivalent to 1-2 times of erythromycin A 9-oxime thiocyanate salt. The temperature of the silanization can be -10°C to 50°C, preferably the room temperature.
2. The next step is to methylate the silanization derivatives from the previous step. After the reaction completes, water is added to obtain methide (IV). The methylating agent can be halomethane, the dosage of which is equivalent to 1-5 times of silanization derivatives. The alkali can be selected from sodium hydroxide and potassium hydroxide, the dosage of which is equivalent to 1-5 times of silanization derivatives. The methylation solvent can adopt the mixture of dimethyl sulfoxide and tetrahydrofuran. The reaction temperature is -10 to 30oC.
3. Hydrolysis reaction of the methide from the last step removes the protective groups and obtain clarithromycin (I). Ethanol can be the solvent of the hydrolysis reaction. Formic acid and sodium bisulfite can be used as a reductant in a reflux reaction.
Erythromycin A 9-oxime thiocyanate salt used as the starting material of the present invention can be prepared in an usual processes (such as J.Antibio.1991,44(3), 313-330).
Comparing the prior technology adopting erythromycin A 9-oxime in the etherification, the present invention uses erythromycin A 9-oxime thiocyanate salt to achieve the etherification. The present invention has following advantages:
1. The present invention leaves out a reaction step of the transformation from erythromycin A 9-oxime thiocyanate salt to erythromycin A 9-oxime, which simplifies the production process. In addition, there is no need to conduct the unit operations, such as neutralization reaction of alkali, extraction, water-washing, centrifugal and drying and so on.
2. In the present invention, reducing the reaction step saves the materials required for the step (usually dichloromethane, ammonia and methanol), thereby the cost of final product clarithromycin can be reduced.
3. Because of reducing the one reaction step and centrifugal process, the exhaust and the pollution are decreased.
4. There is no need to add acid catalyst in the etherification. Therefore, the etherification reaction is stable and the acidity destruction is avoided.
5. The present invetion uses erythromycin A 9-oxime thiocyanate as the raw material to operate etherification directly, then sequentially performs silicon alkylation, methylation and hydrolysis reactions to obtain clarithromycin. Compared with the method of using erythromycin A 9-oxime as the raw material, the yield of the preesnt invention is higher. The total yield is above 60% (accounting in erythromycin A 9-oxime thiocyanate salt), and the product quality of the present invention is better.
Embodiments of The Invention
The following embodiemnts help to further comprehend the present invention. However, the contents of the invention are not limited to these embodimetns.
Example 1:
Preparation of erythromycin A 9-oxime thiocyanate salt
200 g of methanol, 200 g of erythromycin thiocyanate, 100 g of hydroxylamine hydrochloride, and 60 g of triethylamine were added into a 1000ml 4-neck flask with a stirring paddle. The mixture in the flask was heated up until circumfluence, and kept warm for 24 hours. Then its temperature was dropped to 0oC. It was filtered and dried to obtain 176g of erythromycin A 9-oxime thiocyanate salt. The yield was 86.2 %.
Example 2:
Preparation of 2’,4’’-O-Bis (trimethylsilyl)erythromycin A9-[O-(1-ethoxy-1-methylethyloxime)]
100g of dichloromethane and 30g of erythromycin A 9-oxime thiocyanate salt were added into a 500 ml reaction bulb. 20g of 2-Ethoxypropene was added dropwise at the normal temperature during 20 minutes. After the mixture was kept warm for 10 minuntes, 15g of imidazole, 15g of trimethylchlorosilane were added dropwisely at the normal temprature during 30 minutes. After the mixture was kept warm for 10 minuntes, 50 ml of water was added. The mixture went through delamination and the aqueous layer was removed. The dichloromethane layer was washed twice with water(50 ml X2). The dichloromethane layer was concentrated to dry. 100g of methanol was added. The mixture was filtered and dried to obtain 37g of 2’,4’’-O-Bis(trimethylsilyl)erythromycin A 9-[O-(1-ethoxy-1-methylethyloxime)] ( erythromycin A 9-oxime silanization derivatives). The yield is 94.1 %.
Example 3:
Preparation of 2’,4’’-O-Bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-ethoxy-1-methylethyloxime)]
35g of erythromycin A 9-oxime silanization derivatives and 150g of tetrahydrofuran were added into a 500 ml reaction bulb. After complete dissolution, 165g dimethyl sulfoxide, 13.5g of iodomethane and 8.5g of KOH were added. The mixture was kept warm at the room temperature for 60 minutes. 100 ml of water was added. The mixture was filtered to obtain 35.5g 2’,4’’-O-Bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-ethoxy-1-methylethyloxime)](methide). The yield is 100%.
Example 4:
Preparation of clarithromycin
35g of methide obtained in Example 3, 112g of ethanol, 10g of formic acid, 30g of sodium bisulfite and 100g of water were added into a 500 ml reaction bulb. The mixture was heated up until circumfluence. After the reaction lasted for 8 hours, the temperature was dropped to the normal temprature. 250g of dichloromethane was added for extraction and delaminating the mixture. The dichloromethane layer was concentrated to dry and 17.5g clarithromycin was obtained. The yield is 66.7%.

WE CLAIM:-
1. A method of preparing clarithromycin, comprsiing the steps of: using erythromycin A 9-oxime thiocyanate as a raw material to directly conduct an etherification reaction, then sequentially conducting a silicon alkylation reaction, a methylation reaction and a hydrolysis reaction to obtain clarithromycin.
2. The method of preparing clarithromycin said in Claim 1, wherein solvent adopted in the etherification reaction is selected from haloalkanes, dimethyl sulfoxide, dimethylformamide, methylbenzene, and C6 to C10 lower paraffin hydrocarbon.
3. The method of preparing clarithromycin said in Claim 1, wherein an etherifying agent used in the etherification reaction is selected from 2-Ethoxypropene, 2-Methoxypropene, 2,2-Diethoxypropane, and 1,1-diethoxy-Cyclohexane in etherification.
4. The method of preparing clarithromycin said in Claim 1, wherein the reaction temperature of the etherification reaction is between -20°C to 80°C.
Dated this 22nd day of April 2010.

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Patent Number

270352

Indian Patent Application Number

1309/MUM/2010

PG Journal Number

51/2015

Publication Date

18-Dec-2015

Grant Date

15-Dec-2015

Date of Filing

22-Apr-2010

Name of Patentee

Zhejiang Huayi Pharmaceutical Co. Ltd.

Applicant Address

No.15 Shuangfeng Rd. Yinan industrial Park Yiwu 322002 China

Inventors:

#	Inventor's Name	Inventor's Address
1	RAO Xintang	No.15 Shuangfeng Rd. Yinan industrial Park Yiwu 322002 China
2	DING Zhijian	No.15 Shuangfeng Rd. Yinan industrial Park Yiwu 322002 China
3	LOU Hangbin	No.15 Shuangfeng Rd. Yinan industrial Park Yiwu 322002 China
4	WU Jing	No.15 Shuangfeng Rd. Yinan industrial Park Yiwu 322002 China
5	FANG Yanglin	No.15 Shuangfeng Rd. Yinan industrial Park Yiwu 322002 China
6	DENG Baineng	No.15 Shuangfeng Rd. Yinan industrial Park Yiwu 322002 China

PCT International Classification Number

C07H17/08

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	200910098150.X	2009-04-30	China