KR100214709B1 - The synthetic method of amorphous cefuroxime axetil - Google Patents
The synthetic method of amorphous cefuroxime axetil Download PDFInfo
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- KR100214709B1 KR100214709B1 KR1019970037144A KR19970037144A KR100214709B1 KR 100214709 B1 KR100214709 B1 KR 100214709B1 KR 1019970037144 A KR1019970037144 A KR 1019970037144A KR 19970037144 A KR19970037144 A KR 19970037144A KR 100214709 B1 KR100214709 B1 KR 100214709B1
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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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Abstract
본 발명은 0 내지 30℃ 하에서 세푸록심 악세틸에 물을 가하여 교반한 다음, 분리건조하는 것을 특징으로 하는 무정형 세푸록심 악세틸(Cefuroxime axerile)의 제조방법에 관한 것이다.The present invention relates to a method for producing amorphous cefuroxime axerile (Cefuroxime axerile) characterized in that the water is added to the cefuroxime axetyl under 0 to 30 ℃ stirred, and then separated and dried.
Description
제1도는 본 발명에 따른 제조방법으로 제조한 무정형 세푸록심 악세틸의 IR 스펙트럼을 나타낸 것이다.Figure 1 shows the IR spectrum of amorphous cefuroxime axetyl prepared by the preparation method according to the present invention.
본 발명은 무정형 세푸록심 악세틸(amorphous efuroxime axetile)의 제조방법에 관한 것으로, 더욱 상세하게는 일정온도하에서 세푸록심 악세틸에 물을 가하여 교반한 다음, 분리건조하는 것을 특징으로 하는 무정형 세푸록심 악세틸(amorphous cefuroxime axetile)의 제조방법에 관한 것이다.The present invention relates to a method for producing amorphous cefuroxime axetile, and more particularly, to anhydrous cefuroxime acetil under constant temperature, stirring and then drying and separating the amorphous cefuroxime acex. The present invention relates to a method for preparing amorphous cefuroxime axetile.
세푸록심 악세틸(Cefuroxime axetile)은 그람양성 및 그람음성 미생물에 대하여 광범위한 활성스펙트럼을 갖는 경구용 세파계 항생제이다. 또한 세푸록심 악세틸은 그 치환기내에 부재탄소를 함유한 화합물로서 R 및 S형의 이성체비가 약 1 : 1인 무정형 세푸록심 악세틸이 더욱 우수한 효과를 갖는 것으로 보고되고 있어, R 및 S형의 이성체비가 약 1 : 1 인 무정형 세푸록심 악세틸이 현재 시판되고 있다.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 compound containing absent carbon in the substituent, and amorphous cepuroxime axetyl having an isomer ratio of about 1: 1 is reported to have more excellent effect, and isomers of R and S type Amorphous cefuroxime axetyl with a ratio of about 1: 1 is currently commercially available.
영국특허 제1,571,683호에서는 세푸록심 악세틸의 제조방법을 개시하고 있다. 그러나 영국특허 제 1,571,683호에서 개시한 제조방법에 의해 생성된 세푸록심 악세틸은 결정형과 무정형이 혼합된 상태로 얻어지기 때문에, 무정형으로 제조하기 위하여는 별도의 반응이 필요하다. 한편, 대한민국 특허공고 제91 -46호에서는 영국특허 제1,571,683호에서 개시한 제조방법에 의해 생성된 세푸록심 악세틸을 ①유기용매, ②유기용매의 균질한 혼합물 또는 .③종이상의 유기용매와 물의 균질한 혼합물에 용해시켜 세푸록심 악세틸 용액을 제조한 후, 이를 급속용매제거법 또는 용매침전법등에 의해 무정형 세푸록심 악세틸을 제조하는 방법이 개시된 바 있다.British Patent No. 1,571,683 discloses a process for the preparation of cefuroxime axetyl. However, since the cepuroxime axetyl produced by the preparation method disclosed in British Patent No. 1,571,683 is obtained in a mixture of crystalline and amorphous forms, a separate reaction is required to prepare amorphous. On the other hand, Korean Patent Publication No. 91-46 discloses cefuroxime acetyl produced by the manufacturing method disclosed in British Patent No. 1,571,683, which is a homogeneous mixture of (1) organic solvent, (2) organic solvent, or (3) more than one organic solvent and water. After dissolving in a homogeneous mixture to prepare a cefuroxime axetyl solution, there has been disclosed a method for producing amorphous cefuroxime axetyl by rapid solvent removal method or solvent precipitation method.
그러나 상기 종래의 제조방법은 일단 세푸록심 악세틸을 유기용매등에 용해시켜 용액상태로 제조하여야 하기 때문에 과량의 유기용매 사용이 불가피하여 제조 단가가 높아질 뿐 아니라 취급이 곤란한 유기용매를 사용하여야 한다는 단점이 있다. 또한, 용액상태로 제조한 세푸록심 악세틸용액으로부터 무정형 세푸록심 악세틸을 회수하기 위하여는 별도의 분리건조시설 즉, 분무건조시설, 로울러건조시설, 동결건조시설 등의 특수시설을 사용해야 하기 때문에 제조단가가 높아지는 문제점이 있다.However, the conventional manufacturing method has to be prepared by dissolving cefuroxime acetyl in an organic solvent, etc., so that an excessive amount of organic solvent is inevitably used, which increases manufacturing cost and makes it difficult to use an organic solvent that is difficult to handle. have. In addition, in order to recover the amorphous cefuroxime acetyl from the solution produced in the solution state of the cefuroxime acetyl solution, it is necessary to use a separate separate drying facilities, that is, special facilities such as spray drying facilities, roller drying facilities, and freeze drying facilities. There is a problem that the unit price increases.
이에 본 발명자들은 ①제조과정중 유기용매를 사용함이 없이 비용이 저렴한 물만을 사용하고, ②별도의 회수시설(예를 들어, 분무건조시설, 로울러건조시설, 동결건조시설 등)을 사용하지 않고 통상의 건조방법으로 무정형 세푸록심 악세틸 제조방법을 개발하고자 연구를 거듭한 결과, 일정온도하에서 세푸록심 악세틸 물만을 가하여 교반한 다음, 분리건조하였을 때, 세푸록심 악세틸이 효과적으로 무정형 세푸록심 악세틸로 전환될 수 있다는 것을 발견하여 본 발명을 완성하게 되었다.Therefore, the present inventors use only low cost water without using an organic solvent during the manufacturing process, and ② do not use a separate recovery facility (for example, spray drying facility, roller drying facility, freeze drying facility, etc.). As a result of the research to develop a method for preparing amorphous cefuroxime acetyl as a drying method, the cefuroxime acetyl is effectively amorphous cepuroxime acetyl when it is stirred by adding only cepuroxime acetyl water at a certain temperature and then separated and dried. The present invention has been completed by discovering that it can be converted to.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 일정온도하에서 세푸록심 악세틸에 물을 가하여 교반한 다음, 분리건조하는 것을 특징으로 하는 무정형 세푸록심 악세틸의 제조방법을 것을 목적으로 한다.It is an object of the present invention to prepare a method for producing amorphous cefuroxime axetyl, characterized in that the water is added to the cefuroxime axetyl at a constant temperature, followed by stirring.
이하 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명에 따른 제조방법에서 출발물질로 사용한 세푸록심 악세틸은 영국특허 제1,571,683호에서 개시한 제조방법으로 제조될 수 있으며, 이를 따로 분리하거나 분리하지 아니하고 본 발명에 따른 제조방법의 출발물질로 사용할 수 있다. 영국특허 제1,571,683호에서 개시한 제조방법으로 제조된 세푸록심 악세틸을 따로 분리하지 않고 그대로 반응에 이용할 경우, 본 발명의 출발물질인 세푸톡심 악세틸은 포움상(foom phase)으로 본 발명에 사용되게 된다. 본 발명에 따른 제조방법은 포움상의 세푸록심 악세틸 및 따로 분리된 세푸록심 악세틸 모두를 사용할 수 있다.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 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, ceputoxime 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.
본 발명에 따른 제조방법은 상기 종래기술(대한민국 특허공고 제91-46호)과 달리 유기용매를 사용하지 않고 물만을 사용하며, 특히 출발물질인 세푸록심 악세틸을 용해시킬 필요없이 물을 가하여 교반시키면 바로 무정형의 세푸록심 악세틸이 얻어질 수 있다.Unlike the prior art (Korean Patent Publication No. 91-46), the manufacturing method according to the present invention uses only water without using an organic solvent, and in particular, adds and stirs water without having to dissolve the starting material cepuroxime acetil. Amorphous cefuroxime axetyl can be obtained immediately.
본 발명에 따른 제조방법에서 세푸록심 악세틸에 물을 가할 때의 반응온도는 0 내지 30℃에서 반응시키는 것이 바람직하고, 교반시간은 0.5 내지 6시간이 바람직하다.In the production method according to the present invention, the reaction temperature when water is added to cefuroxime axetyl is preferably reacted at 0 to 30 ° C, and the stirring time is preferably 0.5 to 6 hours.
상기와 같은 본 발명에 따른 제조방법으로 무정형 세푸록심 악세틸을 제조할 경우 하기 실시예에서 확인할 수 있는 바와 같이 유기용매를 사용함이 없이 물만을 사용하여 효과적으로 무정형 세푸록심 악세틸을 제조할 수 있으며, 또한 별도의 특수건조시설이 필요없어 낮은 제조단가로 무정형 세푸록심 악세틸을 제조할 수 있다. 특히, 하기 실시예에서 확인할 수 있는 바와 같이 본 발명에 따른 제조방법에 의해 제조된 무정형 세푸록심 악세틸은 R : S의 이성체비가 약 1 : 1로 유지되는 것을 확인할 수 있다.When preparing amorphous cepuroxime acetil with the preparation method according to the present invention as described above, it is possible to effectively prepare amorphous cefuroxime axetyl using only water without using an organic solvent, as can be seen in the following examples, In addition, there is no need for a special drying facility to produce amorphous cefuroxime axetyl at low manufacturing costs. In particular, as can be seen in the following examples, the amorphous cefuroxime axetyl produced by the production method according to the present invention can be seen that the isomer ratio of R: S is maintained at about 1: 1.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 이것이 본 발명의 범위를 제한하는 것은 아니다. 하기 실시예에서 이성체비는 R-이성체 및 S-이성체의 비율을 나타낸다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the scope of the invention. In the examples below, the isomer ratio represents the ratio of R- and S-isomers.
[실시예 1]Example 1
디메틸아세트아미드 165ml에 세푸록심 나트륨 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 1NHCI 1300ml에 투입한 후 에틸아세테이트 90ml를 첨가한 후 유기층을 분리하였다.30 g of cefuroxime sodium was added to 165 ml of dimethylacetamide, the mixture was cooled to 0 to 5 ° C, and 18 g of brominated (RS) -1-acetoxyethyl was added thereto, followed by stirring 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. The reaction solution was added to 1300 ml of 1NHCI, 90 ml of ethyl acetate was added, and the organic layer was separated.
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. 5℃에서 증류수 800ml를 가하여 30분간 교반하였다. 이를 여과하여 물 500ml로 세척한 후 건조하여 무정형 세푸록심 악세틸 28.8g을 수득하였다.The organic layer was washed with 3% sodium bicarbonate solution, and then 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 filtration and washing with ethyl acetate was completely distilled under reduced pressure to obtain cefuroxime acetil (32 g) on foam. 800 ml of distilled water was added at 5 degreeC, and it stirred for 30 minutes. It was filtered, washed with 500 ml of water and dried to give 28.8 g of amorphous cefuroxime axetyl.
수율; 84%yield; 84%
이성체비; 1.04 : 1.00Isomer ratio; 1.04: 1.00
함량; 98.5% (HPLC)content; 98.5% (HPLC)
[실시예 2]Example 2
1N HCI 1300 ml 대신 0.1N 황산 900 ml를 사용한 것을 제외하고는 실시예 1과 도일한 방법으로 반응시켜 세푸록심 악세틸 27.8g을 얻었다.The reaction was carried out in the same manner as in Example 1, except that 900 ml of 0.1 N sulfuric acid was used instead of 1300 ml of 1N HCI to obtain 27.8 g of cefuroxime acetyl.
수율; 83.4%yield; 83.4%
이성체비; 1.04 : 1.00Isomer ratio; 1.04: 1.00
함량; 98% (HPLC)content; 98% (HPLC)
[실시예 3]Example 3
물 투입온도를 5CO대신 30CO에서 반응시킨 것을 제외하고는 실시예 1과 동일한 방법으로 반응시켜 무정형 세푸록심 악세틸 26g을 수득하였다.Except that the water added at the reaction temperature was 30C instead of 5C O and O is reacted in the same manner as in Example 1 to give an amorphous cefuroxime axetil 26g.
수율; 75.7 %yield; 75.7%
이성체비; 1.17 : 1.00Isomer ratio; 1.17: 1.00
함량; 96.2 % (HPLC)content; 96.2% (HPLC)
[실시예 4]Example 4
물 투입 후, 30분간 교반하여 반응시킨 대신 5시간동안 반응시킨 것을 제외하고는 실시예 1과 동일한 방법으로 반응시켜 무정형 세푸록심 악세틸 28.9 g을 수득 하였다.After adding water, the reaction was carried out in the same manner as in Example 1 except that the reaction was carried out for 5 hours instead of stirring for 30 minutes to obtain 28.9 g of amorphous cefuroxime acetyl.
수율; 84.2 %yield; 84.2%
이성체비; 1.04 : 1.00Isomer ratio; 1.04: 1.00
함량; 98.2 % (HPLC)content; 98.2% (HPLC)
[실시예 5]Example 5
실시예 2에서 물 500ml를 투입하여 세척한 후, 다시 10 % 아세톤수용액 100 ml(물 95 ml, 아세톤 5 ml)로 세척한 다음, 건조하여 무정형 세푸록심 악세틸 28g을 수득하였다.In Example 2, 500 ml of water was added thereto, followed by washing with 100 ml of 10% aqueous acetone solution (95 ml of water and 5 ml of acetone), followed by drying, to obtain 28 g of amorphous cefuroxime acetil.
수율; 84 %yield; 84%
이성체비; 1.03 : 1.00Isomer ratio; 1.03: 1.00
함량; 97.8 % (HPLC)content; 97.8% (HPLC)
[시험예, 무정형 확인시험(IR 시험)][Test example, amorphous confirmation test (IR test)]
실시예 1에서 제조한 무정형 세푸록심 악세틸을 KBr 방법(대한약전 6개정)으로 적외선 스펙트럼을 측정한 결과, 제1도에서 확인할 수 있는 바와 같이 무정형 세푸록심 악세틸의 특징인 스펙트럼이 1500 - 2000 cm-1에서 보여주고 있어 무정형 세푸록심 악세틸이 효과적으로 제조된 것을 알 수 있다.As a result of measuring the infrared spectrum of the amorphous cepuroxime axetyl prepared in Example 1 by the KBr method (6 KP), the spectrum characteristic of amorphous cepuroxime axetyl is 1500-2000. It can be seen from cm -1 that amorphous cefuroxime axetyl was effectively produced.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20020016052A (en) * | 2000-08-24 | 2002-03-04 | 최현식 | New method for the manufacture of amorphous cefuroxime axetil |
| KR100357816B1 (en) * | 2000-05-09 | 2002-10-18 | 보령제약 주식회사 | Process for the preparation of amorphous cefuroxime axetil and the isolation process thereof |
| KR100362230B1 (en) * | 2000-04-21 | 2002-11-23 | 주식회사 대웅제약 | Process for preparing amorphous cefuroxime axetil having a low melting point |
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1997
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100362230B1 (en) * | 2000-04-21 | 2002-11-23 | 주식회사 대웅제약 | Process for preparing amorphous cefuroxime axetil having a low melting point |
| KR100357816B1 (en) * | 2000-05-09 | 2002-10-18 | 보령제약 주식회사 | Process for the preparation of amorphous cefuroxime axetil and the isolation process thereof |
| KR20020016052A (en) * | 2000-08-24 | 2002-03-04 | 최현식 | New method for the manufacture of amorphous cefuroxime axetil |
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