KR100228264B1 - The synthetic method of crystalline cefuroxime axetil - Google Patents

Abstract

In the present invention, a mixture of water and ethyl acetate is added to cefuroxime acetyl prepared by reacting sodium cefuroxime with bromide (RS) -1-acetoxyethyl, or water is first added to ethyl acetate. The present invention relates to a method for preparing crystalline cefuroxime axetyl (Cefuroxime axetile), characterized in that the mixture is stirred and then washed with water to separate and dry crystalline cefuroxime axetyl.

Description

Manufacturing Method of Crystalline Sepuroxime Axetyl

1 shows the IR spectrum of crystalline cefuroxime axetyl prepared according to the present invention,

2 shows the X-ray spectrum of crystalline cefuroxime axetyl prepared according to the present invention.

The present invention relates to a method for preparing crystalline cefuroxime axetile, and more particularly, to cefuroxime acex produced by reacting sodium cefuroxime with brominated (RS) -1-acetoxyethyl. Water is mixed with ethyl acetate (ethyl acetate), or water is added first, followed by stirring with ethyl acetate, followed by washing with water to separate and dry crystalline cefuroxime acetyl. cefuroxime axetile).

Cepuroxime axetile is an oral cephaic antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative microorganisms. In addition, cefuroxime axetyl is a mixture containing an absent carbon in its substituent, and it is reported that amorphous cefuroxime axetyl having an isomer ratio of R and S type of about 1: 1 has a better effect, and isomers of R and S type Amorphous cefuroxime axetyl with a ratio of about 1: 1 is currently available.

British Patent No. 1,571.683 discloses a process for the preparation of cefuroxime axetyl. However, the cefuroxime axetyl produced by the preparation method disclosed in British Patent No. 1,571,683 contains residual solvents as impurities to prepare the product in crystalline form for removal thereof, and then converts it to amorphous cefuroxime axetyl. By doing so, cefuroxime axetyl from which impurities such as residual solvent are removed is produced (European Patent No. 107,276). Thus crystalline cefuroxime axetyl can be used as a starting material for preparing amorphous cefuroxime axetyl.

Meanwhile, Korean Patent Publication No. 91-8377 discloses a method for preparing crystalline cepuroxime axetyl, and Korean Patent Publication No. 91-8377 discloses a cepuroxime manufactured by a conventional general manufacturing method (British Patent No. 1,571,683). Disclosed is a process for dissolving acetyl in a suitable solvent to crystallize it and then separating it. Solvents disclosed as suitable solvents in the present invention include (1) ether, (2) esters that can be mixed with hydrocarbons, (3) halogenated hydrocarbons that can be mixed with hydrocarbons, (4) ketones mixed with water, (5) amides mixed with water, or (6) mixed with water. It can be alcohol.

However, ethers (eg, diisopropyl ether, petroleum ether) disclosed as crystallization solvents in the conventional manufacturing method have a low flash point and have a risk of explosion in mass production. There is a disadvantage in that the manufacturing cost is increased by using an excess solvent to dissolve the acetyl.

In particular, the crystalline cefuroxime axetyl produced by the conventional manufacturing method, since the static electricity is severely generated, the product is stuck to the reaction vessel in the manufacturing process, the loss occurs, the next reaction (for example, amorphous production process) There is a disadvantage that the handling is very difficult when performing.

Therefore, the inventors of the present invention reduce the risk of explosion by minimizing the use of organic solvents in the manufacturing process. ③ As a result of research to develop a new method for preparing crystalline cefuroxime acetyl without generating static electricity of the product, cefuroxime acex produced by reacting sodium cefuroxime with brominated (RS) -1-acetoxyethyl When the mixture of water and ethyl acetate is added to the ethyl, or water is added first, and then ethyl acetate is added, the mixture is stirred, and then washed with water to separate and dry the crystalline cefuroxime acetyl. Not only is it unnecessary, it has been found that no static electricity is generated, thus completing the present invention.

Hereinafter, the present invention will be described in detail.

In the present invention, a mixture of water and ethyl acetate is added to cefuroxime acetyl prepared by reacting sodium cefuroxime with bromide (RS) -1-acetoxyethyl, or water is first added to ethyl acetate. It is an object of the present invention to provide a method for preparing crystalline cefuroxime axetile, characterized in that the mixture is stirred, and then washed with water to separate and dry crystalline cefuroxime acetil.

Hereinafter, the present invention will be described in more detail.

Sepuroxime axetyl used as a starting material in the production method according to the present invention may be prepared by the production method disclosed in British Patent No. 1,571,683, and may be used as a starting material of the production method according to the present invention without separating or separating it separately. Can be. When the cefuroxime axetyl prepared by the preparation method disclosed in British Patent No. 1,571,683 is used in the reaction without being separated, the starting material of the present invention, cefuroxime axetyl, is used in the present invention as a foam phase. Will be. The preparation method according to the invention can use both cefuroxime axetyl and foamed sefuroxime axetyl on the foam separately.

인 것이 바람직하다.The volume ratio of water and ethyl acetate in the mixed solution of water and ethyl acetate, which are characteristically used in the preparation method of the crystalline cefuroxime acetyl according to the present invention (including separately added), is the ratio of ethyl acetate to water. 5 to 20 volume ratio

Is preferably.

에서 반응시키는 것이 바람직하고, 교반시간은 5 내지 24시간이 바람직하다.In addition, the reaction temperature is 5 to 35 when a mixed solution of water and ethyl acetate (including those added separately) is added to cefuroxime acetil.

It is preferable to make it react at, and the stirring time of 5 to 24 hours is preferable.

When the crystalline cefuroxime axetyl is prepared by the preparation method according to the present invention as described above, the crystalline cefuroxime axetyl can be effectively produced as can be seen in the following examples, and the isomer ratio of R: S is about 1: 1. Crystalline cefuroxime axetyl maintained at 1 can be prepared.

In particular, the manufacturing method according to the present invention, unlike the conventional manufacturing method, it is possible to exclude the risk of explosion by using a small amount of organic solvent and reacting most of the reaction through water, dissolving the starting material cefuroxime axetyl Since it is possible to prepare the crystalline cefuroxime axetyl immediately without the use, there is an advantage that does not require the use of excess solvent as in the conventional manufacturing method. In addition, the manufacturing method of the present invention has the advantage that it is easy to handle and no loss occurs during the drying process because no static electricity is generated at all.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the scope of the invention. The R and S isomers of cefuroxime axetyl are represented by A and B, respectively, and the isomer ratio is represented by A: B.

[Reference Example]

[Preparation of Sepuroxime Axetyl on Foam]

에 나트륨 세푸록심 30g을 투입하고 0 내지 5

로 냉각한 후 브롬화 (RS)-1-아세톡시에틸 18g을 가하여 동온도에서 1.5시간 교반하였다. 여기에 탄산칼륨 0.78g을 넣고 동온도에서 2시간 교반하였다. 반응액을 1N HCI 1300

에 투입한 후 에틸아세테이트 900

를 첨가한 후 유기층을 분리하였다. 유기층을 3

중탄산나트륨 용액으로 세척한 후, 목탄 3g을 투입하여 30분간 교반하였다. 에틸아세테이트로 세척된 규조토 베드를 사용하여 이를 여과한 후 에틸아세테이트로 세척하여 얻은 유기층을 완전히 감압증류하여 포움상의 세푸록심 악세틸(32g)을 얻었다.Sepuroxime axetyl was prepared by the preparation method disclosed in British Patent No. 1,571,683. Dimethylacetamide 165

30 g of sodium cefuroxime is added to 0-5

After cooling to 18 g of brominated (RS) -1-acetoxyethyl was added and stirred at the same temperature for 1.5 hours. 0.78 g of potassium carbonate was added thereto and stirred at the same temperature for 2 hours. 1N HCI 1300

Ethyl acetate 900

After the addition of the organic layer was separated. Organic layer 3

After washing with sodium bicarbonate solution, 3 g of charcoal was added and stirred for 30 minutes. The diatomaceous earth bed washed with ethyl acetate was filtered and the organic layer obtained by washing with ethyl acetate was completely distilled under reduced pressure to obtain cefuroxime acetil (32 g) on foam.

Example 1

와 증류수 1500

혼합용액을 20

에서 가하여 12시간 동안 교반한 후 이를 여과한 다음, 물 150

로 세척한 후 건조하여 결정형 세푸록심 악세틸 30g을 수득하였다.Cefuroxime Axetyl on foam prepared in Reference Example Ethyl Acetate 150

And distilled water 1500

Mixed solution 20

Stirred for 12 hours, filtered and water 150

Washed with and dried to obtain 30 g of crystalline cefuroxime axetyl.

Yield; 87.4

A: B; 1.04: 1.00

(HPLC)content; 98

(HPLC)

Example 2

를 사용한 것을 제외하고는 실시예1과 동일한 방법으로 반응시켜 결정형 세푸록심 악세틸 29.4g을 수득하였다.Ethyl Acetate 79

Except for using, the reaction was carried out in the same manner as in Example 1, to obtain 29.4 g of crystalline cefuroxime axetyl.

Yield; 85.7

A: B; 1.06: 1.00

(HPLC)content ; 97.2

(HPLC)

Example 3

를 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응시켜 결정형 세푸록심 악세틸 30.2g을 수득하였다.Ethyl acetate 118.5

Except for using, the reaction was carried out in the same manner as in Example 1, to obtain 30.2 g of crystalline cefuroxime axetyl.

Yield; 87.9

A: B; 1.02: 1.00

(HPLC)content; 98.2

(HPLC)

Example 4

를 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응시켜 결정형 세푸록심 악세틸 27g을 수득하였다.Ethyl acetate 264.7

Reaction was carried out in the same manner as in Example 1, except that 27 g of crystalline cefuroxime axetyl was obtained.

Example 5

와 증류수 1500

혼합용액을 20

에서 가하여 8시간동안 교반한 후 이를 여과한 다음, 물 150

로 세척한 후 건조하여 결정형 세푸록심 악세틸 25g을 수득하였다.Cefuroxime Axetyl Ethyl Acetate 150 Prepared in Reference Example

And distilled water 1500

Mixed solution 20

Stirred for 8 hours, filtered and water 150

Washed with and dried to obtain 25g of crystalline cefuroxime axetyl.

Yield; 72.8

A: B; 1.10: 1.00

(HPLC)content; 96.8

(HPLC)

Example 6

와 증류수 1500

혼합용액을 5에서 가하여 12시간 동안 교반한 후 이를 여과한 다음, 물 150

로 세척한 후 건조하여 결정형 세푸록심 악세틸 29g을 수득하였다.Cefuroxime Axetyl Ethyl Acetate 150 Prepared in Reference Example

And distilled water 1500

Mixed solution 5 Stirred for 12 hours, filtered and water 150

Washed with and dried to obtain 29 g of crystalline cefuroxime axetyl.

Yield: 84.5

A: B; 1.03: 1.00

(HPLC)content ; 97.8

(HPLC)

Example 7

를 20

에서 가하여 30분간 교반 한 후 에틸아세테이트 150

를 서서히 가하였다. 20

에서 12시간 동안 교반한 후 이를 여과한 다음, 물 150

로 세척한 후 건조하여 결정형 세푸록심 악세틸 30g을 수득하였다.Sepuroxime Acetyl produced in Reference Example 1500 distilled water

20

After stirring for 30 minutes, ethyl acetate 150

Was added slowly. 20

After stirring for 12 hours at filtered water, 150

Washed with and dried to obtain 30 g of crystalline cefuroxime axetyl.

Yield; 87.4

A: B; 1.04: 1.00

(HPLC)content; 98

(HPLC)

[Test Example 1]

[Crystalline Formation Test (IR Test)]

As a result of measuring the infrared spectrum of the crystalline cefuroxime axetyl prepared in Example 1 by the KBr method (6 amendments to the Korean Pharmacopoeia), as shown in FIG. ^It is shown in ^cm-1 that the crystalline Sepuroxime Axetyl is effectively produced.

[Test Example 2]

Crystalline Identification Test (X-Ray Spectrum Test)

As a result of measuring the X-ray spectrum of the crystalline Sepuroxime Axetyl prepared in Example 1, as shown in FIG. 2, it shows the characteristic diffraction spectrum of the crystalline Sepuroxime Axetyl effectively It can be seen that it was manufactured.

Claims (4)

A mixture of water and ethyl acetate is added to the cefuroxime acetyl prepared by reacting sodium cefuroxime with brominated (RS) -1-acetoxyethyl, or water is added first, followed by ethylacetate. Method of producing crystalline cefuoxime sxetile characterized in that the mixture is stirred, and then washed with water to separate and dry crystalline cefuroxime axetyl. The method of claim 1, wherein the volume ratio of ethyl acetate to water is 5 to 20

A process for producing crystalline cefuroxime axetyl, characterized in that. According to claim 1, wherein the reaction temperature is 5 to 35

A method for producing crystalline cefuroxime axetyl, characterized in that the reaction is maintained by. 4. The process according to claim 1, wherein the cefuroxime axetyl is crystallized at an isomer ratio of R: S of about 1: 1. 5.

Images