KR100841041B1 - Process for preparation of bamifylline hydrochloride - Google Patents
Process for preparation of bamifylline hydrochloride Download PDFInfo
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- KR100841041B1 KR100841041B1 KR1020070051550A KR20070051550A KR100841041B1 KR 100841041 B1 KR100841041 B1 KR 100841041B1 KR 1020070051550 A KR1020070051550 A KR 1020070051550A KR 20070051550 A KR20070051550 A KR 20070051550A KR 100841041 B1 KR100841041 B1 KR 100841041B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
Abstract
Description
본 발명은 바미필린 염산염의 제조방법에 관한 것으로서, 더욱 상세하게는, 천식 및 만성폐쇄성 폐질환 치료에 유용한 바미필린 염산염의 신규한 제조방법에 관한 것이다.FIELD OF THE INVENTION The present invention relates to a process for the preparation of bamiphylline hydrochloride, and more particularly, to a novel process for the preparation of bamiphylline hydrochloride useful for the treatment of asthma and chronic obstructive pulmonary disease.
하기 화학식 1로 표시되는 8-벤질-7-[2-(에틸-(2-하이드록시에틸)아미노)에틸]-1,3-디메틸-퓨린-2,6-디온 염산염 (8-Benzyl-7-[2-(ethyl-(2-hydroxyethyl) amino)ethyl]-1,3-dimethyl-purine-2,6-dione hydrochloride), 즉 바미필린 염산염(Bamifylline hydrochloride)은, 잔틴(Xanthine) 유도체의 하나로서, 기도 폐쇄성 장애에 의한 호흡곤란, 기관지 천식, 만성 기관지염 등의 치료에 효과적으로 사용된다.8-benzyl-7- [2- (ethyl- (2-hydroxyethyl) amino) ethyl] -1,3-dimethyl-purine-2,6-dione hydrochloride represented by the following formula (1): (8-Benzyl-7 -[2- (ethyl- (2-hydroxyethyl) amino) ethyl] -1,3-dimethyl-purine-2,6-dione hydrochloride, that is, Bamifylline hydrochloride, is a derivative of Xanthine derivatives. As one, it is effectively used for the treatment of dyspnea caused by airway obstructive disorder, bronchial asthma, chronic bronchitis and the like.
상기 바미필린 염산염의 제조방법으로서, 벨기에 특허 BE-A-602,888호(1961년)는, 하기 반응식 1에 나타낸 바와 같이, 중간체로서 화학식 (V)로 표시되는 7-(β-클로로에틸)-8-벤질데오필린(7-(β-Chloroethyl)-8-benzyltheophylline)을 제조한 후, 이를 화학식 (III)의 2-(에틸아미노)에탄올 및 무수 소디움카보네이트와 반응시켜, 바미필린을 제조하고, 이를 바미필린 염산염으로 전환하는 방법을 개시하고 있다. 그러나, 상기 방법은 수율이 낮고(약 57 내지 75%), 부반응물로서 화학식(VI)로 표시되는 7-바이닐-8-벤질데오필린이 다량(수율: 25~43%) 생성되는 단점이 있다.As a method for preparing the camifil hydrochloride, Belgian Patent BE-A-602,888 (1961), 7- (β-chloroethyl)-, represented by the formula (V) as an intermediate, is shown in Scheme 1 below. 8-benzyldeophylline (7- (β-Chloroethyl) -8-benzyltheophylline) was prepared and then reacted with 2- (ethylamino) ethanol of formula (III) and anhydrous sodium carbonate to prepare camifilin And a process for converting it to vapiline hydrochloride. However, this method has a disadvantage in that the yield is low (about 57 to 75%) and a large amount (yield: 25 to 43%) of 7-vinyl-8-benzyldeophylline represented by formula (VI) as a side reaction is produced. .
또한, 벨기에 특허 BE-A-883,654호(1980년)는, 하기 반응식 2에 나타낸 바와 같은 바미필린 염산염의 제조방법을 개시하고 있으나, 하기 반응은 반응 시간이 비 교적 길고(52시간, 80℃), 부산물로서 화학식 (V)로 표시되는 화합물이 다량 생성되므로, 대량 생산에 적합하지 않다.In addition, Belgian Patent BE-A-883,654 (1980) discloses a process for preparing camifil hydrochloride as shown in Scheme 2 below, but the following reaction has a relatively long reaction time (52 hours, 80 ° C). ), It is not suitable for mass production because a large amount of the compound represented by the formula (V) is produced as a by-product.
또한, 미국특허 5,739,331호(1998년)에 개시된 바미필린 염산염의 제조방법은, 수율이 향상되었으나, 고온 및 고압(온도: 90~125 ℃, 압력: 4 x 105 Pa 이상)의 반응조건이 필요하므로, 대량 생산에 부적합할 뿐만 아니라, 안전성 및 장치적 문제도 발생할 수 있다.In addition, the manufacturing method of the bamiphylline hydrochloride disclosed in US Patent No. 5,739,331 (1998), the yield is improved, but the reaction conditions of high temperature and high pressure (temperature: 90 ~ 125 ℃, pressure: 4 x 10 5 Pa or more) As necessary, not only are they unsuitable for mass production, but also safety and device problems may arise.
본 발명자들은, 바미필린 염산염의 제조시 발생하는 상술한 문제, 즉 고온, 고압 반응의 문제점, 부산물의 생성, 긴 반응시간 등의 문제점을 해결할 수 있는, 새로운 바미필린 염산염의 제조방법에 대하여 연구를 진행한 결과, 본 발명을 완성하게 되었다.The inventors of the present invention provide a method for preparing a new camifil hydrochloride, which can solve the above-described problems occurring during the production of camifil hydrochloride, that is, problems such as high temperature, high pressure reaction, generation of by-products, and long reaction time. As a result of the research, the present invention has been completed.
따라서, 본 발명의 목적은, 단순한 반응 공정을 통하여, 고순도 및 고수율로 바미필린 염산염을 제조하는 방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a process for producing vamiphylline hydrochloride with high purity and high yield through a simple reaction process.
본 발명의 다른 목적은, 경제적으로 대량 생산에 적합한 바미필린 염산염의 제조방법을 제공하는 것이다.It is another object of the present invention to provide a process for preparing vapiline hydrochloride which is economically suitable for mass production.
상기 목적을 달성하기 위하여, 본 발명은, 입경이 50 내지 200㎛인 무수 탄산나트륨의 존재 하에서, 8-벤질데오필린, 2-(에틸아미노)에탄올 및 1,2-디클로로에탄을 비극성 유기용매 중에서 반응시키는 단계; 및 상기 반응의 반응액에 유기용매와 물의 혼합물을 투입하여, 바미필린을 유기층으로 추출한 후, 염산을 가하여, 결정 형태의 바미필린 염산염을 수득하는 단계를 포함하는 바미필린 염산염의 제조방법을 제공한다. 여기서, 상기 비극성 유기용매는 디옥산, 자일렌 및 이들의 혼합물로 이루어진 군으로부터 선택되는 것이 바람직하다. In order to achieve the above object, the present invention, the particle diameter is 50 to 200㎛ Reacting 8-benzyldeophylline, 2- (ethylamino) ethanol and 1,2-dichloroethane in a nonpolar organic solvent in the presence of anhydrous sodium carbonate; And injecting a mixture of an organic solvent and water into the reaction solution of the reaction, extracting vamiphylline into an organic layer, and then adding hydrochloric acid to obtain the crystal form of vamiphylline hydrochloride. To provide. Herein, the nonpolar organic solvent is preferably selected from the group consisting of dioxane, xylene, and mixtures thereof.
이하, 본 발명을 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.
본 발명에 따라, 바미필린 염산염을 제조하기 위해서는, 먼저, 하기 반응식 3에 나타낸 바와 같이, 무수 탄산나트륨(Anhydrous Na2CO3)의 존재 하에서, 화학식 (II)로 표시되는 8-벤질데오필린(8-Benzyltheophylline, 8-Benzyl-1,3-dimethyl-7H -purine-2,6-dione), 화학식 (III)으로 표시되는 2-(에틸아미노)에탄올(2-(ethyl amino)ethanol) 및 화학식 (IV)로 표시되는 1,2-디클로로에탄(1,2-Dichloroethane)을 반응시켜, 바미필린을 합성한다.According to the present invention, in order to prepare the camifilline hydrochloride, first, as shown in Scheme 3 below, 8-benzyldeophylline represented by the formula (II) in the presence of anhydrous sodium carbonate (Anhydrous Na 2 CO 3 ) ( 8-Benzyltheophylline, 8-Benzyl-1,3-dimethyl-7H -purine-2,6-dione), 2- (ethyl amino) ethanol represented by formula (III) and formula Bamiphylline is synthesized by reacting 1,2-dichloroethane (1,2-Dichloroethane) represented by (IV).
상기 반응식 3에서, 화학식 (III)으로 표시되는 2-(에틸아미노)에탄올은, 화학식 (II)로 표시되는 8-벤질데오필린 1당량에 대하여 1.2 내지 1.7 당량 사용하는 것이 바람직하다. 상기 2-(에틸아미노)에탄올의 사용량이 너무 작으면, 반응이 완결되지 않는 문제가 있고, 너무 많으면 별다른 장점이 없이, 최종제품이 오염될 우려가 있다. 상기 화학식 (IV)로 표시되는 1,2-디클로로에탄은, 용매 및 반응물의 역할을 동시에 수행하는 것으로서, 화학식 (II)의 화합물 1g에 대하여 3 내지 5ml 를 사용하는 것이 바람직하다. 상기 1,2-디클로로에탄의 사용량이 너무 작으면, 반응이 완결되지 않을 우려가 있으며, 너무 많으면, 특별한 이익이 없이 경제적으로 불리할 뿐이다. 상기 반응은, 비극성 유기용매 중에서 수행되며, 상기 비극성 유기용매로는 디옥산, 자일렌, 이들의 혼합물 등을 예시할 수 있다. 유기용매를 사용하지 않거나, n-펜타놀 등의 극성 용매를 사용하는 경우에는, 상기 구조식 (V)의 불순물이 소량 생성되므로, 디옥산, 자일렌 등의 비극성 유기 용매를 단독 또는 혼합하여 사용하는 것이 바람직하다. 상기 유기용매의 사용량은 화학식 (II)의 화합물 1g에 대하여 3 내지 5ml가 바람직하다. 상기 유기용매의 사용량이 너무 작으면, 반응시간이 길어지고, 부반응물이 생성될 우려가 있으며, 너무 많으면, 특별한 이익 이 없이 경제적으로 불리할 뿐이다.In Scheme 3, 2- (ethylamino) ethanol represented by the formula (III) is preferably used in an amount of 1.2 to 1.7 equivalents based on 1 equivalent of 8-benzyldeophylline represented by the formula (II). If the amount of 2- (ethylamino) ethanol is too small, there is a problem that the reaction is not completed. If the amount of 2- (ethylamino) ethanol is too small, there is a possibility that the final product may be contaminated without any advantage. 1,2-dichloroethane represented by the general formula (IV) is used as the solvent and the reactant at the same time, it is preferable to use 3 to 5ml per 1g of the compound of the general formula (II). If the amount of the 1,2-dichloroethane used is too small, there is a fear that the reaction may not be completed. If the amount of the 1,2-dichloroethane is too small, it is economically disadvantageous without any particular benefit. The reaction is performed in a nonpolar organic solvent, and examples of the nonpolar organic solvent may include dioxane, xylene, and mixtures thereof. In the case of not using an organic solvent or using a polar solvent such as n-pentanol, since a small amount of impurities of the above structural formula (V) are generated, a nonpolar organic solvent such as dioxane or xylene may be used alone or in combination. It is preferable. The amount of the organic solvent is preferably 3 to 5 ml based on 1 g of the compound of formula (II). If the amount of the organic solvent is too small, the reaction time is long, there is a fear that side reactions are generated, if too large, it is economically disadvantageous without any particular benefit.
상기 반응에서, 무기염기로 사용되는 무수 탄산나트륨은 약염기의 무수물로서, 화학식 (II)의 화합물 1당량에 대하여 1 내지 3당량을 사용하는 것이 바람직하고, 1.5 내지 2당량을 사용하면 더욱 바람직하다. 상기 무수 탄산나트륨의 사용량이 너무 작으면, 반응이 완결되지 않을 우려가 있고, 너무 많으면, 특별한 이익이 없이 경제적으로 불리할 뿐이다. 일반적으로 사용되는 탄산나트륨의 경우, 입경 100㎛ 이하인 탄산나트륨 함량이 5중량%, 입경 600㎛ 이상인 탄산나트륨 함량이 12중량%, 입경 300 내지 600㎛인 탄산나트륨의 함량이 40중량%이며, 입경 100 내지 300㎛인 탄산나트륨의 함량이 43중량% 정도이다. 그러나, 본 발명에 사용되는 무수 탄산나트륨은 입경이 50 내지 200㎛, 바람직하게는 50 내지 100 ㎛인 것을 특징으로 하며, 상기 미립 탄산나트륨은 통상의 탄산나트륨을 분쇄기로 분쇄한 후, 분자체를 이용하여 작은 입경의 탄산나트륨을 선별함으로서 얻을 수 있었다. 본 발명에 사용되는 탄산나트륨의 실질적인 입경이 200㎛를 초과하면, 반응시간이 과도하게 길어지는 문제가 있고, 입경이 50㎛ 미만이면, 특별한 이익이 없이, 탄산나트륨의 취급 및 제조가 곤란한 단점이 있다. 본 발명에 사용되는 탄산나트륨은 상기 입경 범위 이외의 입경을 가지는 탄산나트륨을 소량 (예를 들면, 10중량%, 바람직하게는 5중량% 이하) 포함할 수 있으나, 이 경우에도, 본 발명의 반응은 실질적으로 상기 입경 범위의 탄산나트륨에 의하여 대부분 진행된다.In the above reaction, the anhydrous sodium carbonate used as the inorganic base is preferably an anhydride of the weak base, and it is preferable to use 1 to 3 equivalents, more preferably 1.5 to 2 equivalents, based on 1 equivalent of the compound of the formula (II). If the amount of the anhydrous sodium carbonate is too small, the reaction may not be completed. If the amount of the anhydrous sodium carbonate is too small, it is economically disadvantageous without any particular benefit. In the case of sodium carbonate which is generally used, 5% by weight of sodium carbonate having a particle size of 100 μm or less, 12% by weight of sodium carbonate having a particle diameter of 600 μm or more, 40% by weight of sodium carbonate having a particle size of 300 to 600 μm, and a particle size of 100 to 300 μm The content of sodium phosphate is about 43% by weight. However, the anhydrous sodium carbonate used in the present invention is characterized by having a particle size of 50 to 200 ㎛, preferably 50 to 100 ㎛, the fine sodium carbonate is pulverized with a conventional sodium carbonate in a grinder, and then using a small It was obtained by selecting sodium carbonate having a particle size. If the substantial particle diameter of sodium carbonate used in the present invention exceeds 200 µm, there is a problem that the reaction time is excessively long, and if the particle diameter is less than 50 µm, there is a disadvantage in that handling and production of sodium carbonate are difficult without any particular benefit. Sodium carbonate used in the present invention may include a small amount (for example, 10% by weight, preferably 5% by weight or less) of sodium carbonate having a particle size outside the particle size range, even in this case, the reaction of the present invention is substantially Mostly proceed with sodium carbonate in the particle size range.
상기 반응의 반응시간은, 염기로 사용되는 무수 탄산나트륨의 입자 크기에 따라 민감하게 달라지며, 입경 200㎛ 이하의 무수 탄산나트륨을 사용할 경우, 통상 10 내지 24시간 이내, 구체적으로 12 내지 24시간 이내에 반응이 완결된다. 여기서, 무수 탄산나트륨의 입경에 따라 반응시간이 달라지는 이유는, 본 발명의 반응 매질을 구성하는 반응물 및 반응용매가 1,2-디클로로에탄, 1,4-디옥산, 자일렌 등과 같은 비극성 용매이므로, 반응액(매질) 중에서, 무수 탄산나트륨의 용해도가 매우 낮기 때문인 것으로 추정된다. 즉, 본 발명에 따른 바미필린 염산염의 제조방법에 있어서는, 반응물과 고체 무수 탄산나트륨이 직접 접촉하여, 반응이 진행되므로, 무수 탄산나트륨 입자의 크기가 반응시간에 크게 영향을 미치게 된다. 즉, 알코올계 용매 중에서, 고체 상태의 탄산나트륨이 사용될 경우, 탄산나트륨 입자가 용매에 용해되어, 그 크기가 점점 작아지므로, 탄산나트륨의 입자 크기가 중요하지 않으나, 본 발명과 같이, 비극성 비양성자성 용매 중에서 탄산나트륨이 사용되면, 탄산나트륨 입자가 용매에 용해되지 않으므로, 작은 입경의 탄산나트륨을 사용하는 것이 매우 중요하다. 상기 반응의 반응온도는, 1,2-디클로로에탄의 환류온도이상의 온도가 바람직하고, 반응압력은 통상 상압(대기압)이며, 반응의 완결은 TLC(thin-layer chromatography)로 확인할 수 있다. 만일, 반응온도가 너무 낮으면, 반응시간이 길어지며, 너무 높으면 가압이 필요하므로 바람직하지 않다. The reaction time of the reaction is sensitively dependent on the particle size of the anhydrous sodium carbonate used as the base, when using anhydrous sodium carbonate having a particle diameter of 200㎛ or less, usually within 10 to 24 hours, specifically 12 to 24 hours Is completed. The reason why the reaction time varies depending on the particle size of the anhydrous sodium carbonate is that the reactants and the reaction solvent constituting the reaction medium of the present invention are nonpolar solvents such as 1,2-dichloroethane, 1,4-dioxane, xylene, and the like. It is presumed that the solubility of anhydrous sodium carbonate is very low in the reaction liquid (medium). In other words, in the method for producing bamiphylline hydrochloride according to the present invention, since the reactant is directly contacted with the solid anhydrous sodium carbonate and the reaction proceeds, the size of the anhydrous sodium carbonate particles greatly affects the reaction time. That is, in the alcoholic solvent, when sodium carbonate in the solid state is used, the sodium carbonate particles are dissolved in the solvent and the size thereof becomes smaller, so that the particle size of sodium carbonate is not important, but in the nonpolar aprotic solvent as in the present invention. If sodium carbonate is used, it is very important to use sodium carbonate with a small particle size because sodium carbonate particles are not dissolved in the solvent. The reaction temperature of the reaction is preferably a temperature higher than the reflux temperature of 1,2-dichloroethane, the reaction pressure is usually atmospheric pressure (atmospheric pressure), the completion of the reaction can be confirmed by thin-layer chromatography (TLC). If the reaction temperature is too low, the reaction time is long, and if too high, pressurization is not preferable.
상기 반응이 완료되면, 필요에 따라, 감압 하에서 반응 용매를 제거하고, 에틸아세테이트, 디클로로메탄 등의 유기용매와 물의 혼합물을 반응액에 투입하여, 바미필린을 유기층으로 추출한 후, 감압 하에서 유기층을 농축한다. 이때, 물 및 유기용매의 혼합비율은, 합성된 바미필린과 물에 용해되는 미반응 물질이 원활히 분리될 수 있을 정도이면 충분하고, 예를 들면, 물 및 유기용매의 혼합비율이 부피비로 1: 2 내지 5일 수 있다. 다음으로, 농축된 유기층에, 생성될 바미필린 염산염에 대하여 중량비로 2 내지 5배의 메탄올을 투입하여 바미필린을 용해시키고, 바미필린에 대하여 1.2 내지 1.5당량의 염산을 가하여, 결정 형태의 바미필린 염산염을 수득할 수 있다. 본 발명에 따른 방법에 있어서, 최종 목적물인 바미필린 염산염의 제조 수율은 약 87 내지 92%이다. When the reaction is complete, if necessary, the reaction solvent is removed under reduced pressure, a mixture of organic solvent and water such as ethyl acetate, dichloromethane and the like is added to the reaction solution, and the extract is extracted with the organic layer, and then the organic layer is removed under reduced pressure. Concentrate. At this time, the mixing ratio of water and the organic solvent is sufficient enough to be able to separate the synthesized vamiphylline and the unreacted substance dissolved in the water, for example, the mixing ratio of water and the organic solvent is 1 by volume ratio : May be from 2 to 5. Next, to the concentrated organic layer, 2 to 5 times methanol was added in a weight ratio with respect to the produced bamiphylline hydrochloride to dissolve the barmiphylline, and 1.2 to 1.5 equivalents of hydrochloric acid was added to the vamiphylline to form a crystalline form. Vamiphylline hydrochloride of can be obtained. In the process according to the invention, the yield of the preparation of the final target bodiphyline hydrochloride is about 87-92%.
이하, 실시예를 통해 본 발명을 더욱 구체적으로 설명하나, 본 발명이 하기 실시예에 의하여 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.
[실시예 1] 바미필린 염산염의 제조 Example 1 Preparation of Bamiphylline Hydrochloride
교반기가 장착된 3L 반응기에, 8-벤질데오필린 200g, 2-(에틸아미노)에탄올 100g, 입경 100㎛ 이하의 분쇄된 무수 탄산나트륨 146g, 1,2-디클로로에탄 600ml 및 1,4-디옥산 600ml를 넣고, 12시간 동안 가열 환류시켰다. TLC(thin-layer chromatography)로 반응의 완결을 확인하여, 반응이 완결되면, 감압 하에 용매를 농축시키고, 에틸아세테이트 1L 및 물 1L의 혼합액을 넣고 층분리하였다. 유기층을 분리하고, 분리된 유기층을 다시 감압 하에 농축한 다음, 메탄올을 넣어 바미필른을 완전히 용해시켰다. 다음으로, 반응액에 진한 염산 80ml를 가하고 냉각한 다음, 생성되는 결정을 여과하고 60℃에서 건조하여, 백색의 목적화합물 288.3g(수율: 92.1%, m.p.: 186℃)을 얻었다. In a 3L reactor equipped with a stirrer, 200 g of 8-benzyldeophylline, 100 g of 2- (ethylamino) ethanol, 146 g of ground anhydrous sodium carbonate having a particle diameter of 100 μm or less, 600 ml of 1,2-dichloroethane and 600 ml of 1,4-dioxane Was added and heated to reflux for 12 h. After completion of the reaction by TLC (thin-layer chromatography), the reaction was completed, the solvent was concentrated under reduced pressure, a mixture of 1L ethyl acetate and 1L of water was added and the layers were separated. The organic layer was separated, and the separated organic layer was concentrated again under reduced pressure, and methanol was added to completely dissolve the barmifiln. Next, 80 ml of concentrated hydrochloric acid was added to the reaction solution, followed by cooling, and the resulting crystals were filtered and dried at 60 ° C to give 288.3 g of a white target compound (yield: 92.1%, m.p .: 186 ° C).
[실시예 2] 바미필린 염산염의 제조 Example 2 Preparation of Bamiphylline Hydrochloride
교반기가 장착된 3L 반응기에, 8-벤질데오필린 200g, 2-(에틸아미노)에탄올 100g, 입경 100㎛ 이하의 분쇄된 무수 탄산나트륨 146g, 1,2-디클로로에탄 600ml 및 자일렌 600ml를 넣고, 16시간 동안 가열 환류시켰다. TLC(thin-layer chromatography)로 반응의 완결을 확인하여, 반응이 완결되면, 감압 하에 용매를 농축시키고, 에틸아세테이트 1L 및 물 1L의 혼합액을 넣고 층분리하였다. 유기층을 분리하고, 분리된 유기층을 다시 감압 하에 농축한 다음, 메탄올을 넣어 바미필른을 완전히 용해시켰다. 다음으로, 반응액에 진한 염산 80ml를 가하고 냉각한 다음, 생성되는 결정을 여과하고 60℃에서 건조하여, 백색의 목적화합물 279.5g(수율: 89.3%, m.p.: 185℃)을 얻었다.Into a 3L reactor equipped with a stirrer, 200 g of 8-benzyldeophylline, 100 g of 2- (ethylamino) ethanol, 146 g of ground anhydrous sodium carbonate having a particle diameter of 100 μm or less, 600 ml of 1,2-dichloroethane and 600 ml of xylene were added. Heated to reflux for hours. After completion of the reaction by TLC (thin-layer chromatography), the reaction was completed, the solvent was concentrated under reduced pressure, a mixture of 1L ethyl acetate and 1L of water was added and the layers were separated. The organic layer was separated, and the separated organic layer was concentrated again under reduced pressure, and methanol was added to completely dissolve the barmifiln. Next, 80 ml of concentrated hydrochloric acid was added to the reaction solution, followed by cooling. The resulting crystals were filtered and dried at 60 캜 to obtain 279.5 g of a white target compound (yield: 89.3%, m.p .: 185 캜).
[실시예 3, 비교예 1~2] 바미필린 염산염의 제조 Example 3, Comparative Examples 1 and 2 Preparation of Bamiphylline Hydrochloride
하기 표 1에 나타낸 바와 같은 입경의 무수 탄산나트륨을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 바미필린 염산염(m.p.: 185℃)을 제조하였으며, 이때 소요된 반응시간을 표 1에 함께 나타내었다. Bamiphylline hydrochloride (mp: 185 ° C.) was prepared in the same manner as in Example 1, except that anhydrous sodium carbonate having a particle size as shown in Table 1 was used, and the reaction time required was shown in Table 1 together. It was.
[비교예 1] 바미필린 염산염의 제조 Comparative Example 1 Preparation of Bamiphylline Hydrochloride
벨기에 특허 BE-A-883,654호에 개시된 바에 따라, 8-벤질데오필린 100kg, 2-(에틸아미노)에탄올 36L, 상세한 설명에서 언급한 통상의 무수 탄산나트륨 71kg 및 1,2-디클로로에탄 300L를 혼합하고, 반응액을 80℃에서 52시간 동안 가열 환류시켰다. 반응이 완결되면, 반응액에 물 및 염산을 넣어 수층을 추출하였으며, 추출된 수층을 탄산나트륨으로 중화하고, 디클로로메탄을 사용하여 다시 바미필린을 추출한 다음, 수분을 제거한 후, 농축하였다. 여기에, 메탄올을 넣어 바미필린을 용해시킨 후, 진한 염산을 가한 다음, 생성되는 결정을 여과하고 건조하여, 바미필린 염산염을 얻었다(수율: 81%). 이때 약 7%의 부반응물도 함께 생성되었다.As disclosed in Belgian Patent BE-A-883,654, 100 kg of 8-benzyldeophylline, 36 L of 2- (ethylamino) ethanol, 71 kg of conventional anhydrous sodium carbonate and 300 L of 1,2-dichloroethane mentioned in the detailed description are mixed and The reaction solution was heated to reflux at 80 ° C. for 52 hours. Upon completion of the reaction, water and hydrochloric acid were added to the reaction solution to extract the aqueous layer. The extracted aqueous layer was neutralized with sodium carbonate, extracted with Bamiphylline again using dichloromethane, and then water was removed and concentrated. Methanol was added thereto to dissolve vamiphylline, and then concentrated hydrochloric acid was added, and the resulting crystals were filtered and dried to obtain vamiphylline hydrochloride (yield: 81%). At this time, about 7% of the side reactions were also produced.
[비교예 2] 바미필린 염산염의 제조 Comparative Example 2 Preparation of Bamiphylline Hydrochloride
미국 특허 5,739,331호의 실시예 1에 개시된 바에 따라, 오토클레이브 장치에 8-벤질데오필린 15g, 2-(에틸아미노)에탄올 7.6g, 상기한 설명에서 언급한 통상의 무수 탄산나트륨 11g 및 1,2-디클로로에탄 45ml를 넣고, 125℃에서 4 x 105 Pa 이상의 압력을 유지하면서, 3시간 동안 교반하였다. 반응이 완결된 후, 반응액에 물 및 염산을 넣어 수층을 추출하였으며, 추출된 수층을 탄산나트륨으로 중화하고, 디클로로메탄을 사용하여 다시 바미필린을 추출한 다음, 수분을 제거한 후, 농축하였다. 여기에, 메탄올을 넣어 바미필린을 용해시킨 후, 진한 염산을 가한 다음, 생성되는 결정을 여과하고 건조하여, 바미필린 염산염을 얻었다(수율: 93%).As disclosed in Example 1 of US Pat. No. 5,739,331, 15 g of 8-benzyldeophylline, 7.6 g of 2- (ethylamino) ethanol, 11 g of the usual anhydrous sodium carbonate and 1,2-dichloro mentioned in the above description are described in the autoclave apparatus. 45 ml of ethane was added and stirred for 3 hours while maintaining a pressure of 4 × 10 5 Pa or more at 125 ° C. After the reaction was completed, water and hydrochloric acid were added to the reaction solution to extract the aqueous layer, and the extracted aqueous layer was neutralized with sodium carbonate, extracted with chloromethane again, followed by extraction of vamiphylline, followed by concentration of water. Methanol was added thereto to dissolve vamiphylline, and then concentrated hydrochloric acid was added, and the resulting crystals were filtered and dried to obtain vamiphylline hydrochloride (yield: 93%).
이상 상술한 바와 같이, 본 발명에 따른 바미필린 염산염의 제조방법은, 고온, 고압 반응을 수행할 필요가 없으므로, 오토클레이브(autoclave system) 등의 고가 장비가 불필요하고, 공정의 위험성이 현저히 줄어드는 장점이 있다. 또한, 본 발명에 따른 바미필린 염산염의 제조방법은, 짧은 반응시간 동안에, 고수율 및 고순도로 바미필린 염산염을 얻을 수 있을 뿐만 아니라, 부산물의 생성이 적으며, 반응 공정 단계가 최소화되어, 상업적 대량 생산 공정에 특히 적합하다.As described above, since the method for producing camifilline hydrochloride according to the present invention does not need to perform a high temperature and high pressure reaction, expensive equipment such as an autoclave system is unnecessary, and the risk of the process is significantly reduced. There is an advantage. In addition, the method for producing vamiphylline hydrochloride according to the present invention, in a short reaction time, not only can be obtained in high yield and high purity of camifil hydrochloride, but also less by-products generated, the reaction process step is minimized, It is particularly suitable for commercial mass production processes.
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