KR19980027016A - Method for Purifying Taurusodeoxycholic Acid - Google Patents
Method for Purifying Taurusodeoxycholic Acid Download PDFInfo
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- KR19980027016A KR19980027016A KR1019960045669A KR19960045669A KR19980027016A KR 19980027016 A KR19980027016 A KR 19980027016A KR 1019960045669 A KR1019960045669 A KR 1019960045669A KR 19960045669 A KR19960045669 A KR 19960045669A KR 19980027016 A KR19980027016 A KR 19980027016A
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- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
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Abstract
본 발명은 합성된 조담즙산을 물과 분리가 되는 유기용제에 용해 또는 현탁된 용액에 산성제 또는 알카리제로 처리 수용액으로 한 다음 산성 조건 또는 알칼리 조건하에서 무기염으로 포화시킨 후 교반하여 층분리하고 유기층을 반복 추출 분리하여 정제하거나, 비이온성 앰버라이트 XAD계 포리머 흡착제로 정제하는 방법을 특징으로 하는 담즙산 또는 그 염의 제조방법에 관한 것이며, 본 발명의 방법으로 고순도 및 고수율로 담즙산을 정제할 수 있다.The present invention is treated with an acidic or alkaline agent in a solution dissolved or suspended in an organic solvent that is separated or synthesized crude bile acid in water, and then saturated with an inorganic salt under acidic or alkaline conditions, and then separated by stirring to separate the organic layer. The present invention relates to a method for preparing bile acids or salts thereof, which is characterized by a method of repetitively extracting and refining or purifying with a nonionic amberlite XAD-based polymer adsorbent. .
Description
본 발명은 의약품으로 중요한 생리물질로서 체내기관이나 담에 널리 분포되어 있으며, 약학적으로 콜레스테롤성 담석의 용해제, 담즙분비이상으로 인한 소화불량, 이담제 등 치료학적으로 유용한 타우로우르소데옥시콜린산을 얻기 위한 정제방법에 관한 것이다.The present invention is widely distributed in the body organs and bile as an important physiological substance as a medicine, pharmacologically useful taurusodeoxycholic acid, such as soluble drugs of cholesterol gallstones, indigestion due to bile secretion abnormalities, biliary drugs It relates to a purification method to obtain.
일반적으로 타우로우르소데옥시콜린산은 우르소데옥시콜린산을 원료물질로 하여 용매중에서 염기하 산무수물 등 산활성체를 제조한 후, 타우린의 염기염이나 알카리금속염으로 용해하여 축합시키는 일련의 공정으로 제조시, 공정상 어쩔 수 없이 생성수반되는 여러 가지의 부생성물 및 원료, 즉 우르소데옥시콜린산, 타우린, 유기염, 무기염 등의 잔류로 물리적 화학적 방법으로 효과적으로 분리정제하기에는, 이들이 수용성이고 용해성이 유사하여 통상의 방법으로는 상당한 곤란이 따른다.Generally, taurusodeoxycholic acid is a series of processes in which an acid activator such as a base acid anhydride is prepared in a solvent using ursodeoxycholic acid as a raw material, and then dissolved by condensation with a base salt or an alkali metal salt of taurine. In preparation, they are water-soluble and soluble to effectively separate and purify by various chemical by-products and raw materials, namely ursodeoxycholic acid, taurine, organic salt, inorganic salt, etc. Similarly, the conventional method involves considerable difficulty.
이 산의 분리정제에 대한 종래의 분리정제방법을 대별하면The conventional separation and purification method for the separation and purification of this acid
(1) 직접 정제법(일본화학잡지 79권, p605, 1958년, 한국공개특허 제89-6164호, 한국특허공고 제85-1573호)(1) Direct refining method (Japanese Chemical Magazine No. 79, p605, 1958, Korean Patent Publication No. 89-6164, Korean Patent Publication No. 85-1573)
(2) 실리카 분리법(벨기에특허 제901069호, 유럽특허 제272462호)(2) Silica Separation Method (Belgium Patent No. 901069, European Patent No. 272462)
(3) 이온 수지에 의한 정제법(유럽특허 제400695호)(3) Purification by ion resin (European Patent No. 400695)
(4) 전기투석법(일본공개특허 제91-27396호)등으로 현재 알려져 있다.(4) It is currently known as an electrodialysis method (Japanese Patent Laid-Open No. 91-27396) and the like.
또한 이 산의 제조는 공지방법(일본화학잡지, 79년, p605, 1958년; 일본화학잡지 76권, p505, 1995년; Acta chemical scandinavia, 7권, p1126, 1953년; Arkiv. Kemi., 8권, p331, 1955년; 벨기에특허 제901069호 등)으로 합성이 가능하며, 본 발명자들은 종래의 제조방법을 개량하였다.In addition, the preparation of this acid is known method (Japanese Chemical Magazine, 79, p605, 1958; Japanese Chemical Magazine, Vol. 76, p505, 1995; Acta chemical scandinavia, Vol. 7, p1126, 1953; Arkiv. Kemi., 8 Kwon, p331, 1955; Belgian Patent No. 901069) and the like, and the present inventors have improved the conventional manufacturing method.
한편, 종래 정제 방법중 (1)의 방법 즉, 제조에서 얻어진 조결정을 에탄올이나 톨루엔 등 가용용매에 용매후 수회에 걸쳐 반복정제한 것을 대용매(Anti Solvent)로 단리하는 것으로 되어 있으나, 단순한 용해도의 차이를 이용하여 혼재하는 유무기염 및 타우로우르소데옥시콜린산유도체등으로부터 고순도의 산을 정제하여 고수율로 얻을 수 없다. (2)의 방법은 공업적으로 반복 생산하는데 있어서 회수재생 또는 재사용의 문제 및 저수율 등의 문제점이 있으며, (3)의 방법은 생성되는 부산물이 양이온성 물질 및 음이온성 물질이 동시에 혼재하기 때문에 양이온 수지와 음이온 수지를 사용함에 따라, 분리 공정조작이 많아지고 또한 저수율이다. (4)의 방법은 이온성투석막을 이용한 막분리로, 고순도로 기재되어 있으나, 이온성 분리물질과 목적산의 분자량의 차가 적어 분리조작시 목적산도 같이 투석되고 운전시 막유지가 번거로운 점 등 바람직한 방법이라고는 할 수 없다.On the other hand, the method of (1) of the conventional purification method, i.e., the crude crystal obtained in the preparation is repeatedly isolated several times after the solvent in a soluble solvent such as ethanol or toluene by anti-solvent, but simple solubility. By using the difference of high purity acid from the mixed organic inorganic salts and taurusodeoxycholic acid derivatives and the like cannot be obtained in high yield. The method of (2) has problems of recovery and regeneration or reuse and low yield in industrial repeat production, and the method of (3) has a positive ion because cationic and anionic materials are mixed at the same time. As the resin and the anionic resin are used, the separation process operation is increased and the yield is low. The method of (4) is a membrane separation using an ionic dialysis membrane, which is described in high purity. However, the difference in molecular weight between the ionic separation material and the target acid is small, so that the target acid is also dialyzed during the separation operation and the membrane maintenance is cumbersome during operation. It's not a way.
본 발명자들은 상기의 공지기술을 개량한 조제 담즙산의 공업적 정제방법으로 특히 타우로우르소데옥시콜린산 등 담즙산의 정제에 유효하다. 즉, 물과 분리가 되는 유기용제와 산성 또는 알칼리 수용액을 이용한 두층액 추출법에 의한 것으로 처리조작이 간편하고 단시간에 분리가 가능하다. 또한 이 방법은 고순도, 고수율로 수득할 수 있어 대량공업생산의 정제법으로 우수하다.MEANS TO SOLVE THE PROBLEM The present inventors are an industrial purification method of the prepared bile acid which improved the said well-known technique, and it is especially effective for the purification of bile acids, such as taurroxodeoxycholine acid. That is, by the two-layer liquid extraction method using an organic solvent and an acidic or alkaline aqueous solution to be separated from water, the treatment operation is simple and can be separated in a short time. In addition, this method can be obtained with high purity and high yield, and is excellent as a purification method for mass industrial production.
다음에 본 발명을 상세히 설명한다.Next, the present invention will be described in detail.
순도55%-95%의 조제담즙산을 물과 층분리가 가능한 유기용제 예를 들면, 이소부탄올, 노르말부탄올, 이소프로판올, n-부탄올, t-부탄올, 테트라하이드로퓨란, 에틸헥산올, 에탄올 등의 단독 또는 혼합용액에 용해한다.Organic solvents capable of layering crude bile acids having a purity of 55% -95% with water, such as isobutanol, normal butanol, isopropanol, n-butanol, t-butanol, tetrahydrofuran, ethylhexanol, ethanol, and the like Or dissolved in a mixed solution.
바람직하게는 이소부탄올, 이소프로판올, t-부탄올, 에틸헥산올, 2-부탄올 또는 테트라하이드로퓨란이며, 필요시 물에 불용인 헥산, 에틸아세테이트, 벤젠 등을 혼합하는 것도 좋다. 담즙산 무게당 5-20배 상기 유기용제의 사용이 다음 처리공정에 유리하다. 동량의 물을 가해 잠시 교반하고, 조제 담즙산 각 몰에 대해 산성제 0.1당량-0.5당량의 산성수용액을 가해 비교적 강한 산수용액으로 조정해 주거나, 조제담즙산 각 몰에 대해 알카리제 0.1-0.65당량의 알카리수용액을 가해 비교적 강한 염기성용액으로 조정해 준다. 이때 바람직하기는 산 또는 알카리의 사용량은 용액 pH에 좌우되며 이는 담즙산과 부생성물의 추출제거에 유리하다. 이 용액에 수층을 포화시키고자 수용성 무기염 즉 알칼리금속의 할라이드등을 사용하며, 바람직하기로는 소디움 클로라이드, 포타시움 클로라이드이다. 이때 포화상태에 따라 유기용제에 추출되는 담즙산의 이행정도가 다르며, 용액중에 무기염이 소량 남은 상태가 바람직하였다.Preferably, isobutanol, isopropanol, t-butanol, ethylhexanol, 2-butanol or tetrahydrofuran may be mixed with hexane, ethyl acetate, benzene or the like which is insoluble in water if necessary. The use of the organic solvent 5-20 times per bile acid weight is advantageous for the next treatment. Add the same amount of water and stir for a while, add 0.1 equivalent to 0.5 equivalent acidic acid solution to each mole of bile acid prepared to adjust to relatively strong acid aqueous solution, or 0.1-0.65 equivalents of alkali to each mole of bile acid prepared. Aqueous solution is added and adjusted to a relatively strong basic solution. In this case, preferably, the amount of acid or alkali depends on the solution pH, which is advantageous for the extraction and removal of bile acids and by-products. In order to saturate the aqueous layer in this solution, a water-soluble inorganic salt, that is, a halide of an alkali metal, is used, and sodium chloride and potassium salt are preferable. At this time, the degree of transition of the bile acid extracted into the organic solvent was different according to the saturation state, and a state in which a small amount of inorganic salt remained in the solution was preferable.
일련의 조작은 실온에서 행하며, 이상(二相:two phase)을 적절히 분배를 위해 15-30분 교반후, 방치하면 두 개의 층으로 분액이 되는데 이때 유기층을 분취한다. 이 조작을 조제담즙산의 순도에 따라 2-5회 또는 그 이상 행할 수 있다. 상기와 같은 조작에 의해 보다 수용성 원료물질인 우르소데옥시콜린산의 염, 타우린, 무기염 등이 수용액층으로 분배되어 제거될 수 있다. 산성제로서는 염산, 황산, 질산, 초산, 인산, 개미산 등이 가능하고 염산, 초산이 바람직하다. 알카리제로서는 유기알킬아민 즉, 트리에틸아민, 피리딘, 트리메틸아민, 디에틸아민 등이며, 무기알카리 즉, 소디움하이드록사이드, 암모니아용액, 포타시움 하이드록사이드 등으로 조절되며, 좋기로는 소디움하이드록사이드, 암모니아 용액이다.A series of operations are carried out at room temperature, and after 15-30 minutes of stirring for proper distribution of two phases, the solution is separated into two layers if left to stand, and the organic layer is separated. This operation can be performed 2-5 times or more depending on the purity of the prepared bile acid. By the above operation, salts, taurine, inorganic salts, and the like of water-soluble raw material urethane deoxycholine may be distributed to and removed from the aqueous solution layer. As an acidic agent, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, formic acid, etc. are possible, and hydrochloric acid and acetic acid are preferable. Examples of the alkali agent include organic alkylamines such as triethylamine, pyridine, trimethylamine, diethylamine, and the like, and are controlled with inorganic alkalis, such as sodium hydroxide, ammonia solution, potassium hydroxide, and the like, preferably sodium hydroxide. Said, ammonia solution.
이때, 수층의 포화소금물액의 추출 pH는 0.5이하를 보이며, 상층의 유기층을 탈수보조제로 처리 후 농축하면 1차 정제된 조제 담즙산을 얻을 수 있는데, 액체 크로마토그래피법으로 95% 이상의 순도로 얻어진다. 얻어진 담즙산은 산성제를 사용할 때는 타우로우르소콜린산의 산성염을 알칼리제를 사용할 때 타우로우르소콜린산의 알칼리염으로 수득된다.At this time, the extraction pH of the saturated salt water solution of the aqueous layer shows 0.5 or less, and when the organic layer of the upper layer is concentrated after treatment with a dehydration aid, a crude purified bile acid can be obtained, which is obtained with a purity of 95% or more by liquid chromatography. . The bile acid obtained is obtained as an acid salt of taurusorcholic acid when an acidic agent is used and as an alkali salt of taurusorcholic acid when an alkali agent is used.
상기의 방법으로 얻어진 담즙산은 기존 방법에서 얻어진 공기중 급격한 인습문제, 부생물의 잔존문제 등을 해결하였고 고수율로 정제되었다. 보다 정제된 조제담즙산을 제조키 위해 흡착포리머 앰버라이트 XAD계 흡착제 즉, XAD-2, XAD-4, XAD-7, XAD-16 등을 사용할 수 있는데, 본 담즙산을 상용 앰버라이트의 조작에 따라 흡착할 수도 있고, 바로 흡착없이 용리할 수도 있다.The bile acid obtained by the above method solved the problem of rapid humidity in the air obtained by the conventional method, the problem of remaining by-products, etc., and was purified with high yield. Adsorbent polymers Amberlite XAD-based adsorbents, ie, XAD-2, XAD-4, XAD-7, XAD-16, etc. can be used to prepare more crude crude bile acids. It can be done or eluted immediately without adsorption.
비이온성 흡착제는 수용액중 또는 기타 극성 용매중에 녹아 있는 물질을 이온성에 무관하게 분자내 친수성 부위나, 소수성 부위를 극성결합(수소결합 등)의 성질을 이용하여 앰버라이트에 흡착 또는 분배시켜 목적하는 담즙산을 정제 분리할 수 있다. 사용 XAD계 앰버라이트는 통상의 방법에 의거 활성화시켜 반복 재사용할 수 있다.A nonionic adsorbent is a bile acid of interest that is dissolved in an aqueous solution or in another polar solvent by adsorbing or distributing the hydrophilic or intramolecular hydrophobic moiety to an amberlite regardless of ionicity. Can be purified and separated. The XAD-based amber light can be activated and reused according to conventional methods.
본 발명자들은 상기의 이상액상 추출법에 의해 정제된 조제담즙산을 물에 용해후, pH를 중성으로 조정하고, XAD계 앰브라이트 재생방법에 의거 활성화된 앰브라이트에 흡착하여, 물, 메탄올, 아세톤, 에탄올, 암모니아수 또는 이들의 혼합용액으로 용리할 수 있다. 이때 앰브라이트 종류에 따라 설정조건이 다소 다를 수 있으나, 수세후, 그레디안트(농도증가) 메탄올 또는 아세톤에서 가장 바람직하다. 통상의 방법으로 분획하여 TLC로 확인하고 회수분을 모아 농축하고 동결건조, 스프레이드라이 또는 아세톤으로 처리하면 99.5% 이상의 고순도의 목적 담즙산을 얻을 수 있다. 순도는 액체크로마토법에 의해 측정하였다.The inventors of the present invention dissolved the crude bile acid purified by the above-mentioned liquid phase extraction method in water, adjusted the pH to neutral, and adsorbed to the activated amber based on the XAD-based amberite regeneration method, thereby adsorbing water, methanol, acetone, ethanol Eluted with aqueous ammonia or a mixture thereof. At this time, the setting conditions may vary slightly depending on the type of Ambrite, but after washing with water, it is most preferable in gradient (increase in concentration) methanol or acetone. Fractionated by conventional methods, confirmed by TLC, the collected fractions are concentrated, lyophilized, spray-dried or treated with acetone to obtain 99.5% or more of the desired high purity bile acid. Purity was measured by liquid chromatography.
이 조제 담즙산은 타우로우르소데옥시콜린산의 수화물로 되고 필요시 분획되어진 정제담즙산 수용액에 소디움하이드록사이드, 소디움바이카보네이트틀 당량 투입, 조제담즙산의 나트륨염을 상기 방법으로 제조, 수득되며 기준에 상응한다.This crude bile acid is a hydrate of taurousodeoxycholine acid and is added to the aqueous solution of purified bile acid, which is fractionated if necessary, into sodium hydroxide, sodium bicarbonate, and the sodium salt of crude bile acid is prepared and obtained by the above method. Corresponds.
다음에 실시예로 본 발명을 더욱 상세히 설명하며, 이 실시예가 본 발명을 제한하는 것은 아니다.The present invention is described in more detail with reference to the following Examples, which do not limit the present invention.
실시예 1:Example 1:
조담즙산의 제조Preparation of Crude Bile Acid
반응부에 테트라하이드로퓨란 120ml를 투입하고 실온에서 우르소데옥시콜린산 12.17g(0.0131M)을 가하여 교반하여 용해한다. 같은 온도에서 트리에틸아민 5.0ml를 투입후 10분 교반하고 질소 기류하 빙냉하고, 10분 반응하여 산의 염을 제조한다. 같은 온도에서 메틸클로르포르메이트 2.59ml를 30분간 적하하면서 교반하여 산활성 에스테르를 제조한다. 무수물의 백탁물질에 타우린 4.5g을 노르말 수산화나트륨 30ml에 녹인 용액을 5℃ 빙욕하 30분간 가하고 동 온도에서 2시간, 상온에서 3시간 교반하여 반응을 종결시킨다. 잔류물에 이소프로필알콜 180ml를 투입 가온 후, 냉각하여 불용물을 유거한다. 여액을 오일상이 될 때까지 농축한 잔사에 아세톤 150ml를 가해 결정화한 크루드 담즙산을 여과하고 건조하면 인슘성의 백색결정 24g이 얻어진다. 순도는 63%(HPLC법)이다.120 ml of tetrahydrofuran was added to the reaction portion, and 12.17 g (0.0131 M) of ursodeoxycholic acid was added at room temperature, followed by stirring to dissolve. After adding 5.0 ml of triethylamine at the same temperature, the mixture was stirred for 10 minutes, ice-cooled under a stream of nitrogen, and reacted for 10 minutes to prepare a salt of an acid. At the same temperature, 2.59 ml of methyl chloroformate was added dropwise for 30 minutes, followed by stirring to prepare an acid active ester. A solution of 4.5 g of taurine in 30 ml of normal sodium hydroxide was added to an anhydrous turbid material for 30 minutes under an ice bath at 5 ° C, and the reaction was terminated by stirring for 2 hours at the same temperature and 3 hours at room temperature. 180 ml of isopropyl alcohol was added to the residue, followed by cooling, to remove insoluble matters. A filtrate of 150 ml of acetone was added to the concentrated residue until the filtrate became an oil phase. The crude crude bile acid was filtered and dried to obtain 24 g of phosphorus white crystals. Purity is 63% (HPLC method).
실시예 2:Example 2:
담즙산의 2상액 정제Two-phase Purification of Bile Acids
(1) 산성제처리(1) acid treatment
실시예 1에서 제조한 담즙산 크루드상태의 잔류물에 순수 120ml를 가해 녹이고, 에틸아세테이트 70ml를 가해 상온에서 잠시 교반한 후 분리건조에서 방치, 분액하여 미반응 담즙산을 제거한다. 수층을 모아 교반하면서 2노르말염산 2.5ml를 가해 산성으로 하고, t-부탄올 130ml 를 가한 후 소디움클로라이드를 가해 수층을 포화시킨다. 다시 상온(30℃)에서 15분 교반후 분리하여 수용성 유기염 및 타우린을 제거한다.120 ml of pure water was added to the residue of the bile acid crude prepared in Example 1, and 70 ml of ethyl acetate was added thereto, stirred at room temperature for a while, and then separated and left to separate and dried to remove unreacted bile acids. 2.5 ml of 2-normal hydrochloric acid was added and made acidic, stirring, aqueous layer was added, 130 ml of t-butanol were added, sodium chloride was added, and the aqueous layer was saturated. Again, after 15 minutes stirring at room temperature (30 ℃) to remove the water-soluble organic salt and taurine.
상층의 유기층을 모아 포화소금물 120ml를 가한 후 2노르말 염산 2ml를 가해 교반하고 분리한다. 다시 위와 같은 방법으로 유기층을 회수하여 새로운 포화소금물의 상태에 따라 1-2회 추가 조작으로 액액분리추출을 실시한다. 이 조작은 추출회수에 따라 담즙산의 순도는 증가하며 4-5회가 바람직하다. 유기층에 활성탄을 가해 탈색하고 여과보조제 셀라이트를 깔아 여과 처리 후 농축한 잔류물에 에탄올 10ml 및 아세톤 120ml를 가해 상온에서 결정화한 후 여과건조하면 백색 결정으로 타우로 우르소콜린산의 염산염 16.3g(98%)을 얻는다. 순도는 95.5%(HPLC법)이며, 녹는 점은 168-172℃이다.The organic layer of the upper layer was collected, 120 ml of saturated salt water was added, 2 ml of 2-normal hydrochloric acid was added, stirred, and separated. The organic layer is recovered in the same manner as described above and subjected to liquid extraction by 1-2 additional operations depending on the state of the new saturated salts. This operation increases the purity of the bile acid according to the number of extraction, preferably 4-5 times. Activated charcoal was added to the organic layer to be decolorized and the filter aid was coated with celite. After filtration, 10 ml of ethanol and 120 ml of acetone were added to the concentrated residue, which was then crystallized at room temperature and filtered and dried. 98%). The purity is 95.5% (HPLC method) and melting point is 168-172 degreeC.
(2) 알카리제 처리(2) alkaline treatment
제1공정의 산성제 처리방법과 동일하게 처리하되 2 노르말 염산 대신에 2노르말 가성소오다 4ml를 사용 처리하고 t-부탄올을 사용한 후 수층을 포화 소금물로 추출하여 결정화한 후 여과 건조하면 백색의 결정인 타우로우르소데옥시콜린산의 소디움염 15.4g(95%)을 얻는다. 순도는 95.2%(HPLC법)이며, 녹는 점은 170-175℃이다.The acidic agent treatment was carried out in the same manner as in the first step, but 4 ml of 2-normal caustic soda was used instead of 2-normal hydrochloric acid. After using t-butanol, the aqueous layer was extracted with saturated brine and crystallized. 15.4 g (95%) of sodium salt of phosphorus taurusodeoxycholic acid is obtained. The purity is 95.2% (HPLC method) and melting point is 170-175 degreeC.
실시예 3:Example 3:
비이온성 포리머형 앰버라이트에 의한 정제Purification by Nonionic Polymeric Amberlite
실시예 2의 제2공정에서 제조된 담즙산의 잔류물에 순수 60ml에 용해후 2노르말 가성소오다 용액을 가해 용액의 pH를 중성으로 조정하여 미리 활성화되고 정열을 완료한 앰버라이트 XAD-7 0.8리터에 가한 후 천천히 흡착시킨다. 투입이 완료되면 순수 1.2리터를 넣어 서서히 용출, 미흡착물을 세척해낸다. 게속하여 메탄올 2.4리터를 가해 용해하면서 박층 크로마토그래피 제어 확인하고 분획 용출액을 감압 농축하여 오일상이 되면 에타올 7ml에 용해하고, 아세톤 120ml를 가해 상온에서 결정화하면 목적의 백색 분말로 타우로 우르소콜린산의 2수화물 15.5g(93%)을 얻는다.0.8 liters of Amberlite XAD-7 which was previously activated and completed alignment by dissolving in 60 ml of pure water to the residue of bile acid prepared in Example 2, adding 2 normal caustic soda solution to neutral and adjusting the pH of the solution to neutral. After adsorbing, slowly adsorb. When the feeding is completed, 1.2 liters of pure water is added and the eluent is slowly washed off. 2.4 liters of methanol was added to the solution to confirm thin layer chromatography control. The fractional eluate was concentrated under reduced pressure, and dissolved in 7 ml of ethanol when it became an oil phase. 120 ml of acetone was added to crystallize at room temperature. 15.5 g (93%) of dihydrate is obtained.
순도99.6%(HPLC법, 무수물로서)Purity 96.9% (HPLC method, as anhydride)
원소분석:실측치C:58.32%H:8.51% N:2.59%Elemental Analysis: Found C: 58.32% H: 8.51% N: 2.59%
:실측치C:58.29%H:8.47% N:2.61%Found: C: 58.29% H: 8.47% N: 2.61%
녹는점:178-180℃, 215℃(분해)Melting Point: 178-180 ℃, 215 ℃ (Decomposition)
[α]D:+45°(1% 메탄올)[α] D : + 45 ° (1% methanol)
실시예 4:Example 4:
담즙산 나트륨염의 제조Preparation of Bile Sodium Salt
정제한 타우로우르소데옥시콜린산 2수화물 5g을 물 10ml에 투입하고 소디움하이드로겐카보네이트 0.8g을 가해 잠시 가온하여 용해하고 나트륨염 4.77g(98%)을 얻는다.5 g of purified taurusodeoxycholic acid dihydrate is added to 10 ml of water, 0.8 g of sodium hydrogen carbonate is added thereto, and then warmed and dissolved to obtain 4.77 g (98%) of sodium salt.
순도:99.7%(HPLC법, 무수물로서)Purity: 99.7% (as HPLC method, anhydride)
녹는점:215-218℃(분해)Melting Point: 215-218 ° C (Decomposition)
[α]D:+35°(1% 메탄올)[α] D: + 35 ° (1% methanol)
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CN111825737A (en) * | 2019-04-16 | 2020-10-27 | 迪法玛弗朗西斯有限公司 | Purification of cholanic acid conjugates |
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US5260462A (en) * | 1989-05-30 | 1993-11-09 | Prodotti Chimici E Alimentari S.P.A. | Purification of tauroursodesoxycholic acid dihydrate |
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CN111825737A (en) * | 2019-04-16 | 2020-10-27 | 迪法玛弗朗西斯有限公司 | Purification of cholanic acid conjugates |
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