KR20120108225A - PROCESS FOR THE PREPARATION OF N-[O-(P-PIVALOYLOXYBENZENESULFONYLAMINO)-BENZOYL]GLYCIN AND FOR THE FORMULATION OF THE LYOPHILIZATION CONTAINING ITS MONONATRIUM SALT•4 hydrate - Google Patents
PROCESS FOR THE PREPARATION OF N-[O-(P-PIVALOYLOXYBENZENESULFONYLAMINO)-BENZOYL]GLYCIN AND FOR THE FORMULATION OF THE LYOPHILIZATION CONTAINING ITS MONONATRIUM SALT•4 hydrate Download PDFInfo
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- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
Description
본 발명은 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신의 신규 제조 방법 및 그 모노나트륨염ㆍ4 수화물의 동결 건조 제제의 제조 방법에 관한 것이다.The present invention relates to a novel method for producing N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine and a method for producing a freeze-dried preparation of monosodium salt tetrahydrate thereof.
상세하게는 본 발명은 안트라닐릭산을 카복실산이 알카리 조건하에서 쉽게 제거될 수 있는 보호기로 치환된 글리신 유도체와 아미드 결합을 시켜 카복실산 보호된 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신을 얻은 후, 이 화합물을 탈 보호시켜 유리된 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신을 얻은 다음, 그리고 나서 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신을 물에 녹인 후 나트륨 에탄올레이트로 pH를 7.5 - 8.5로 조절하여 용액상으로 제조하고, 동결 건조하여 목적하는 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신 모노나트륨염ㆍ4 수화물의 신규 제조 방법에 관한 것이다.
Specifically, the present invention relates to carboxylic acid-protected N- [O- (P-pivaloyloxybenzenesulfonylamino by combining an anthranilic acid with a glycine derivative substituted with a protecting group in which carboxylic acid can be easily removed under alkaline conditions. ) Benzoyl] glycine, then deprotected to obtain free N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine, and then N- [O- (P- After dissolving pivaloyloxybenzenesulfonylamino) benzoyl] glycine in water, it was prepared in solution by adjusting the pH to 7.5-8.5 with sodium ethanolate, and freeze-dried to give the desired N- [O- (P-Pivalo). The present invention relates to a novel process for producing monooxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate.
본 발명에서 사용하는 화합물은 그 유리체인 화학식 Ⅱ로 표시되는 화합물이 일본특허 공개 평성 제3-20253호의 실시예(63)에 기재되어 있고, 화학식 Ⅰ로 표시되는 나트륨염ㆍ4 수화물(이하 화학식 Ⅰ이라 약자로 표시하는 경우가 있음)은 일본특허 공개 평성 제5-194366호의 실시예 3 및 일본특허 공개 제9-40692호의 참고예에 기재되어 있다. In the compound used in the present invention, the compound represented by the formula (II) which is the vitreous body is described in Example 63 of JP-A-3-20253, and the sodium salt and the tetrahydrate represented by the formula (I) May be abbreviated), and are described in Example 3 of Japanese Patent Laid-Open No. 5-194366 and Reference Examples of Japanese Patent Laid-Open No. 9-40692.
화학식 I의 화합물은 엘라스타제 억제 활성을 가지며, 급성 폐 장해의 치료에 이용되고 있는 매우 유용한 화합물이다. 급성 폐 장해에 있어서는 환자는 중독인 상태에 있어, 화학식 I의 화합물은 비경구, 바람직하게는 주사제로서 장시간(24시간-수일간) 연속적으로 투여해야 한다. 이러한 사용 상황에 알맞은 제제 형태는 주사제 또는 용해시켜 사용하는 고형 조성물, 바람직하게는 동결 건조 제제이며, 또한 편의성을 고려하면 유효성분 함량에 대해 바이알 사이즈가 작은 고용량 제제가 바람직하다. 또한 화학식 II 화합물의 제조 방법은 일본공개 특허 평성 제3-20253호에 반응공정식 I과 같이 예시되어 있다.Compounds of formula (I) are very useful compounds that have elastase inhibitory activity and are used for the treatment of acute lung disorders. In acute lung disorders, the patient is in a poisoning state, and the compound of formula (I) must be administered parenterally, preferably for a long time (24 hours to several days) as an injection. Formulation forms suitable for such use situations are solid compositions for injection or dissolution, preferably freeze-dried formulations, and, for convenience, high dose formulations having a small vial size for the active ingredient content are preferred. In addition, a method for preparing the compound of Formula II is exemplified in Reaction Process I in Japanese Patent Application Laid-Open No. 3-20253.
[반응공정식 I][Reaction Process Formula I]
상기의 방법은 알려진 바와 같이 반응공정식 I에서 아미드화 반응 중 (e) 화합물의 유리 아미노기가 구핵성이 크게 약화되어 (f) 화합물의 술포닐기의 할라이드가 아미노기와 축합반응을 하여 술폰아미드 결합을 형성하면서 동시에 글리신 유도체의 카르복실산 부위와도 일부 반응을 일으킨다. 이렇게 하여 혼합된 산 무수물을 형성시키고, 결국 목적 화합물과 그 이외의 여러 가지 부산물이 형성된다.As described above, in the reaction formula I, the free amino group of the compound (e) is significantly weakened in nucleophilicity in the amidation reaction reaction reaction formula (I) so that the halide of the sulfonyl group of the compound condenses with the amino group to form a sulfonamide bond. At the same time, some reactions occur with the carboxylic acid moiety of the glycine derivative. In this way, mixed acid anhydrides are formed, which eventually results in the formation of the desired compound and various other by-products.
따라서, 수율이 크게 떨어지는 결과를 초래하여 전체 공정 수득율이 약 30 % 밖에는 되지 않는다. 상기 반응공정식 I은 공업적 합성 방법으로서 만족할 만한 제조 방법이라고는 볼 수가 없다.Thus, the yield is greatly reduced, resulting in only about 30% overall process yield. The reaction formula I is not a satisfactory production method as an industrial synthesis method.
상기 반응공정식 I의 약점을 크게 보완시킨 방법으로, 아래 반응공정식 II가 있다. As a method to greatly compensate for the weak point of the reaction formula (I) is the reaction formula II below.
즉, 글리신은 가격이 저렴한 것에 비해 글리신 벤질에스터(h) 화합물은 제조 방법이 까다로워 매우 고가인 것이 커다란 결점이다.That is, glycine is a low cost compared to glycine benzyl ester (h) compound is a very difficult manufacturing method is very expensive.
글리신 유도체 (h)는 하기와 같은 별도의 방법에 의해 제조하여 사용할 수 있다.Glycine derivative (h) can be manufactured and used by the following separate method.
그러나, 벤질 보호기를 제거하기 위해 환원성 절단 반응을 해야 하는데 이 반응에서 생각지 못한 부반응이 많이 발생하여 피발로일기가 절단된 하이드록실체 및 글리신의 에스터체가 알콜체로 변화하는 복잡한 반응이 진행된다.However, in order to remove the benzyl protecting group, a reductive cleavage reaction has to be carried out. In this reaction, many undesired side reactions occur, and a complex reaction in which the ester body of hydroxyl and glycine in which the pivaloyl group is cleaved is changed into an alcohol body.
[반응공정식 II][Reaction Process Formula II]
또다른 변형 방법으로, 목적하는 [II] 화합물은 하기와 같은 반응공정식 III에 따라 제조될 수 있다.In another variation, the desired compound [II] can be prepared according to Scheme III.
[반응공정식 III][Reaction Process Formula III]
상기 식에서, R은 Si(CH3)3 이다. Wherein R is Si (CH 3 ) 3 .
상기 반응공정식 III에서 볼 수 있는 바와 같이, 출발 물질 2-아미노벤조산(l)을 (f) 화합물과 술폰아미드 반응을 시켜 (m) 화합물을 얻고, 별도로 제조한 실릴 보호된 글리신 유도체 (n)을 축합시켜 카르복시아미드 화합물 (o)을 얻은 다음, 상기 화합물을 산수용액 내에서 탈보호시켜 목적 화합물 (II)를 얻는다. 그러나, 이 방법도 몇 가지 결점을 지니고 있다. 즉, 실릴 보호된 글리신 유도체 (n) 화합물도 별도로 제조해야 한다.As can be seen in Reaction Scheme III, starting material 2-aminobenzoic acid (l) was subjected to sulfonamide reaction with (f) compound to obtain (m) compound, and a separately prepared silyl protected glycine derivative (n) was obtained. Condensation yields the carboxyamide compound (o), and then the compound is deprotected in an acid aqueous solution to obtain the target compound (II). However, this method also has some drawbacks. That is, the silyl protected glycine derivative (n) compound must also be prepared separately.
마찬가지로 글리신 유도체 (n) 화합물의 제조가 까다로워 매우 고가인 것이 커다란 결점이다.Likewise, the production of glycine derivative (n) compounds is difficult and very expensive, which is a major drawback.
또한, 실릴 유도체 보호기를 제거하기 위해 산수용액 내에서 탈보호 반응을 진행할 경우 피발로일기가 동시에 제거되어 목적 화합물의 수득율이 실제로는 매우 낮은 것이 결점이다.
In addition, when the deprotection reaction is performed in an acid aqueous solution to remove the silyl derivative protecting group, the pivaloyl group is simultaneously removed, so that the yield of the target compound is actually very low.
따라서, 본 발명자들은 이러한 지금까지의 결점을 크게 보완하여 획기적인 수율로 목적 화합물 (II)를 공장화 방법으로 제조할 수 있는 기술을 개발하였기에 본 발명을 완성할 수 있었다.
Accordingly, the present inventors have been able to complete the present invention by developing a technology capable of producing the target compound (II) by a factory method in a breakthrough yield by greatly supplementing the above drawbacks.
[발명의 상세한 설명]DETAILED DESCRIPTION OF THE INVENTION [
본 발명은 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신의 신규 제조 방법 및 그 모노나트륨염ㆍ4 수화물의 동결 건조 제제의 제조 방법에 관한 것이다.The present invention relates to a novel method for producing N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine and a method for producing a freeze-dried preparation of monosodium salt tetrahydrate thereof.
상세하게는 본 발명은 안트라닐릭산을 카복실산이 알카리 조건하에서 쉽게 제거될 수 있는 보호기로 치환된 글리신 유도체와 아미드 결합을 시켜 카복실산 보호된 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신을 얻은 후, 이 화합물을 탈 보호시켜 유리된 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신을 얻은 다음, 그리고 나서 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신을 물에 녹인 후 나트륨 에탄올레이트로 pH를 7.5 - 8.5로 조절하여 용액상으로 제조하고, 동결 건조하여 목적하는 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신 모노나트륨염ㆍ4 수화물의 신규 제조 방법에 관한 것이다. Specifically, the present invention relates to carboxylic acid-protected N- [O- (P-pivaloyloxybenzenesulfonylamino by combining an anthranilic acid with a glycine derivative substituted with a protecting group in which carboxylic acid can be easily removed under alkaline conditions. ) Benzoyl] glycine, then deprotected to obtain free N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine, and then N- [O- (P- After dissolving pivaloyloxybenzenesulfonylamino) benzoyl] glycine in water, it was prepared in solution by adjusting the pH to 7.5-8.5 with sodium ethanolate, and freeze-dried to give the desired N- [O- (P-Pivalo). The present invention relates to a novel process for producing monooxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate.
본 발명의 제조 방법은 하기 반응공정식 IV로 나타낼 수 있다.The production method of the present invention can be represented by the following Reaction Scheme IV.
[반응공정식 IV][Reaction Process Formula IV]
다음에 본 화합물의 제조 방법에 대해 상세히 설명한다.Next, the manufacturing method of this compound is demonstrated in detail.
본 발명의 반응공정식 IV 중의 각 공정의 반응을 단계별로 설명한다.The reaction of each step in Reaction Process Formula IV of the present invention will be described step by step.
화합물 (l)을 화합물 (p)로 아미드화 하는 반응경로로써, 화합물 (l)로는 As a reaction route for amidating compound (l) to compound (p),
1) 2-아미노벤조일할라이드를 이용하는 방법,1) using 2-aminobenzoyl halide,
2) 2-아미노벤조산을 이용하는 방법.2) using 2-aminobenzoic acid.
3) 혼합산 무수물을 이용하는 방법이 있다.
3) There is a method using mixed acid anhydride.
좀더 구체적으로 아미드 반응 방법을 설명하면, 예를 들면,More specifically describing the amide reaction method, for example,
첫째, 2-아미노벤조산을 불활성 유기용매 (N,N-디메칠포름아미드, 초산에틸, 클로로포름, 염화메틸렌, 디에틸에테르, 테트라하이드로푸란, 디옥산 등의 단독 또는 2종류 이상의 혼합물) 중 또는 용매 없이 산 할라이드(옥살릴클로라이드, 티오닐클로라이드 등)와 -20~환류 온도에서 반응시켜 얻어진 2-아미노벤조일클로라이드를, 삼급 아민(피콜린, 피리딘, 트리에틸아민, 디메틸아닐린, 디메틸아미노피리딘 등) 존재하에서 글리신의 카르복실기가 보호된 글리신 유도체와 불활성 유기용매 (N,N-디메틸포름아미드, 클로로포름, 염화메틸렌, 디에틸에테르, 테트라하이드로푸란, 디옥산, 초산에틸, 아세토니트릴 등) 중에서 0~환류 온도하에서 반응시켜 (q)화합물을 얻거나,First, 2-aminobenzoic acid is used in an inert organic solvent (N, N-dimethylformamide, ethyl acetate, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, dioxane or the like or a mixture of two or more thereof) or a solvent. Tertiary amines (picolin, pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) obtained by reacting an acid halide (oxalyl chloride, thionyl chloride, etc.) with 2-aminobenzoyl chloride obtained at -20 to reflux temperature without 0 to reflux in glycine derivatives protected with carboxyl groups of glycine and inert organic solvents (N, N-dimethylformamide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, etc.) in the presence React under temperature to obtain (q) a compound, or
둘째, 2-아미노벤조산을 불활성 유기용매 (N,N-디메칠포름아미드, 클로로포름, 염화메틸렌, 디에틸에테르, 테트라하이드로푸란, 디옥산, 초산에틸, 아세토니트릴 등) 중에서 축합제 (1,3-디시클로헥실카르보디이미드(DCC); 1-에틸-2-[3-(디메칠아미노)푸로필]카르복시이미드(EDC); 2-클로로-1-메틸피리디늄요오드 등)과 함께 가하고 0~환류 온도하에서 반응을 시켜 생성된 불용성 물질을 여과에 의해 제거하고 여액을 농축 제거하여 (q) 화합물을 얻거나, Second, 2-aminobenzoic acid is condensed in an inert organic solvent (N, N-dimethylformamide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, etc.). -Dicyclohexylcarbodiimide (DCC); 1-ethyl-2- [3- (dimethylamino) furophyll] carboxyimide (EDC); 2-chloro-1-methylpyridinium iodine and the like) The insoluble material produced by the reaction at the reflux temperature is removed by filtration and the filtrate is concentrated to remove (q),
셋째, 2-아미노벤조산을 불활성 유기용매 (N,N-디메칠포름아미드, 초산에틸,클로로포름, 염화메틸렌, 디에틸에테르, 테트라하이드로푸란, 디옥산드의 단독 혹은 2종류 이상의 혼합물) 중 또는 용매없이 산 무수물(무수초산, 무수푸로피온산, 무수이소푸로피온산 등)과 -20~환류 온도에서 반응시켜 얻어진 2-아미노벤조일저급알킬 치환 산 무수물을, 삼급 아민(피콜린, 피리딘, 트리에틸아민, 디메틸아닐린, 디메틸아미노피리딘 등) 존재하에서 글리신의 카르복실기가 보호된 글리신 유도체와 불활성 유기용매 (N,N-디메틸포름아미드, 클로로포름, 염화메틸렌, 디에틸에테르, 테트라하이드로푸란, 디옥산, 초산에틸, 아세토니트릴 등) 중에서 0 ℃~환류 온도하에서 반응시켜 (q) 화합물을 얻는다.
Third, 2-aminobenzoic acid in an inert organic solvent (N, N-dimethylformamide, ethyl acetate, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, a mixture of two or more kinds of dioxane) or a solvent 2-aminobenzoyl lower alkyl substituted acid anhydrides obtained by reacting an acid anhydride (acetic anhydride, anhydrous acetic anhydride, isopropionic anhydride, etc.) with -20 to reflux temperature without the use of tertiary amines (picoline, pyridine, triethyl) Glycine derivatives protected with carboxyl groups of glycine and inert organic solvents (N, N-dimethylformamide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, dioxane, acetic acid) in the presence of amine, dimethylaniline, dimethylaminopyridine, etc.) Ethyl, acetonitrile, etc.) to react at 0 ° C to reflux temperature to obtain (q) compound.
이렇게 얻은 (q) 화합물을 (f) 화합물인 트리메틸 카보닐 옥시 벤젠술포닐 클로라이드와 술폰아미드 반응을 시킨다. 즉, 불활성 유기용매 (염화메틸렌, 클로로포름, 사염화탄소, 테트라클로로에탄, 헥사클로로에탄, 테트라하이드로푸란, 테트라하이드로피란, 디옥산, 디메틸에틸, 디이소푸로필에텔, 디페닐에텔, 메틸에틸에텔) 중에 (q) 화합물과 (f) 화합물을 가해 용해하고 반응액을 0 ℃~환류 온도를 유지하면서 아민류(트리에틸아민, 피리딘, 피콜린, 디메틸아닐린, 아닐린, 이소푸로필아민 등)를 유기용매에 가해 녹여서 혹은 유기용매 없이 적가하여 (r) 화합물을 얻는다. 이렇게 얻은 (r) 화합물을The (q) compound thus obtained is subjected to a sulfonamide reaction with trimethyl carbonyl oxybenzenesulfonyl chloride as the (f) compound. That is, in an inert organic solvent (methylene chloride, chloroform, carbon tetrachloride, tetrachloroethane, hexachloroethane, tetrahydrofuran, tetrahydropyran, dioxane, dimethylethyl, diisofurophyl ether, diphenyl ether, methyl ethyl ether) Compounds (q) and (f) were added to dissolve and the reaction solution was kept at 0 ° C. to reflux temperature, while amines (triethylamine, pyridine, picoline, dimethylaniline, aniline, isoprophylamine, etc.) were added to the organic solvent. It is dissolved or added dropwise without an organic solvent to obtain the compound (r). Thus obtained (r) compound
첫째, 불활성 에테르 유기용매 (테트라하이드로푸란, 테트라하이드로피란, 디옥산, 디에틸에텔, 디메틸에텔 등)와 물, 초산(3 : 1 : 1)을 섞어 25 ℃ 이하에서 탈보호 반응을 시켜 (II) 화합물을 얻거나,First, an inert ether organic solvent (tetrahydrofuran, tetrahydropyran, dioxane, diethyl ether, dimethyl ether, etc.), water and acetic acid (3: 1: 1) are mixed and deprotected at 25 ° C. or lower (II ) A compound,
둘째, 나토리움설파이드를 (r) 화합물과 함께 케톤 용매(아세톤, 메틸에틸케톤, 메틸이소부틸케톤 등)에 가하고 물을 가하여 0~ 실온에서 탈보호 반응을 시켜 (II) 화합물을 얻거나,Secondly, nathrium sulfide is added to a ketone solvent (acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.) together with the compound (r) and water is added to deprotection at 0 to room temperature to obtain a compound (II),
셋째, (r) 화합물을 불활성 유기용매 중에 가해 녹인 후 아연 분말을 가하고 0 ℃~ 실온에서 탈보호 반응을 시켜 (II) 화합물을 얻거나,Third, (r) the compound was added to an inert organic solvent to dissolve it, followed by zinc powder and deprotection at 0 ° C. to room temperature to obtain (II) compound.
마지막으로, (r) 화합물을 불활성 유기용매 중에 가해 용해시킨 후 유기산(개미산, 트리플루오로초산, 취산을 포함한 초산, 염산을 포함한 초산) 등을 가해 0 ℃~ 실온에서 탈보호 반응을 시켜 (II) 화합물을 얻는다.
Finally, the compound (r) is added and dissolved in an inert organic solvent, followed by addition of an organic acid (formic acid, trifluoroacetic acid, acetic acid including hydrochloric acid, acetic acid including hydrochloric acid) and deprotection reaction at 0 ° C to room temperature. ) To obtain a compound.
염가의 글리신을 일반적으로 용이하게 사용되는 카르복실산 보호기 t-Boc, 시아노에틸, 트리클로로에틸 등을 이용하여 화합물 (p)을 제조한다. 이렇게 얻은 (p) 화합물을 2-아미노벤조일클로라이드와 아미드 반응을 하여 (q) 화합물을 얻고 이 (q) 화합물을 (f) 화합물과 술폰아미드 반응을 시켜 (r) 화합물을 얻는다.Compound (p) is prepared using a carboxylic acid protecting group t-Boc, cyanoethyl, trichloroethyl, etc., in which inexpensive glycine is generally used easily. The compound (p) thus obtained is subjected to an amide reaction with 2-aminobenzoyl chloride to obtain a compound (q), and the compound (q) is subjected to a sulfonamide reaction with the compound (f) to obtain a compound (r).
이 (r) 화합물을 일반적인 탈보호 반응을 시켜 목적하는 (II) 화합물을 고수율로 제조할 수 있다.The compound (r) can be subjected to a general deprotection reaction to produce the desired compound (II) in high yield.
본 발명의 특징은 (q) 화합물과 (f) 화합물을 술폰아미드 반응을 시킬 때 카르복시 보호기가 있는 상태이기 때문에 아미노기와 선택적 반응을 고수율로 진행시킬 수 있으며, 이렇게 얻은 (r) 화합물을 수용액상이 아닌 유기용매 혹은 무수산상태 조건하에서 탈보호 반응을 시켜 부반응 없이 목적화합물 (II)를 고수율로 얻을 수 있다.A feature of the present invention is that the (q) and (f) compounds have a carboxy protecting group in the sulfonamide reaction, so that the selective reaction of the amino groups with a high yield can be carried out. By deprotection under organic solvent or anhydrous conditions, the target compound (II) can be obtained in high yield without side reaction.
지금까지 공지된 방법에 비해 무수 조건하에서 탈보호 반응을 하기 때문에 수용액 상태에서 발생하는 가수 분해 반응이 일어나지 않아 고수율로 (II) 화합물을 얻는다.Since the deprotection reaction is carried out under anhydrous conditions compared to the known methods so far, the hydrolysis reaction occurring in the aqueous solution does not occur, thereby obtaining the compound (II) in high yield.
참고로, 글리세린 유도체 구조식을 갖는 (p) 화합물은 다음과 같이 제조한다.For reference, the compound (p) having a glycerin derivative structure is prepared as follows.
글리신을 구조식 (s) 화합물과 불활성 유기용매 내에서 삼급아민 (피콜린, 트리에틸아민, 디메틸아닐린, 디메틸아미노피리딘 등) 혹은 축합제 (1,3-디시클로헥실카르보디이미드(DCC); 1-에틸-3-3-(디메틸아미노)푸로필]카르복시이미드(EDC); 2-클로로-1-메틸피리디늄요오드 등)과 함께 에스터 반응을 시켜 구조식 (p) 화합물을 용이하게 얻는다. (p) 화합물의 예로는 t-부틸글리시네이트(p-1), 시아노에틸글리시네이트(p-2) 또는 2,2,2-트리클로로에틸글리시네이트(p-3)를 들 수 있다.Glycine in tertiary amines (picolin, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) or condensing agents (1,3-dicyclohexylcarbodiimide (DCC)) in a compound of formula (s) and an inert organic solvent; Ester reaction with -ethyl-3-3- (dimethylamino) furophyll] carboxyimide (EDC); 2-chloro-1-methylpyridinium iodine or the like) to easily obtain the compound of formula (p). Examples of the compound (p) include t-butylglycinate (p-1), cyanoethylglycinate (p-2) or 2,2,2-trichloroethylglycinate (p-3). Can be.
이하, 동결 건조 제제의 제조 방법에 대해서 설명한다.Hereinafter, the manufacturing method of a lyophilized formulation is demonstrated.
상기와 같이 실시하여 유리된 화학 구조식 (Ⅱ)를 얻은 다음, 유효성분 함량에 대한 바이알 사이즈가 작은 고용량 제제를 제조하기 위해 다음과 같이 실시한다. 일반적으로 동결 건조 제품은 제조 공정 중 투명한 용액 상태를 만든다. 만약 상태가 현탁이거나 유탁이라면 약물의 함유량이 일정치가 않기 때문이다. 따라서 고용량(80 mg/ml)을 유지하면서 제제로써 사용시 녹일 때 맑은 액상을 갖도록 최대한의 용해도 조건을 맞춰 제제를 할 필요가 있다.As described above, the free chemical formula (II) is obtained, and then, to prepare a high-dose formulation having a small vial size for the active ingredient content, the following procedure is performed. In general, lyophilized products produce a clear solution during the manufacturing process. If the condition is suspended or emulsion, the drug content is not constant. Therefore, it is necessary to prepare the formulation so that the maximum solubility condition is maintained so as to have a clear liquid when dissolved as a formulation while maintaining a high dose (80 mg / ml).
화학식 (Ⅱ) 화합물은 물(0.4 mg/ml) 에탄올(6.0 mg/ml)에 대한 용해도가 극히 낮기 때문에 일반적으로 사용하는 용매를 가지고서는 고용량의 동결 건조 제제를 만들기가 어려우며 때문에 맑은 조제액을 제조하기가 곤란한 이유가 된다.The compound of formula (II) has very low solubility in water (0.4 mg / ml) and ethanol (6.0 mg / ml), making it difficult to prepare a high dose lyophilized formulation with a commonly used solvent. Thus, a clear preparation is prepared. It is a difficult reason to do so.
일본특허 공개 제9-40692호 화학식 (Ⅱ) 화합물을 물과 에탄올 혼합용매에 현탁하여 가성소다액을 가해 가열 용해 후 냉각시켜 화학식 (Ⅰ) 화합물을 제조하는 방법이 개시되어 있다. 일본 공개특허 평성 제5-194366호에는 탄산나트륨 및 물을 이용하여 화학식 (Ⅰ)의 동결 건조 제제를 제조하는 방법이 예시되어있다. 그러나 이 방법도 용해도 80 mg/ml을 달성하기에는 부족하다. Japanese Patent Application Laid-Open No. 9-40692 discloses a method for preparing a compound of formula (I) by suspending a compound of formula (II) in a mixed solvent of water and ethanol, adding a caustic soda solution, heating, dissolving, and cooling. Japanese Laid-Open Patent Publication No. 5-194366 exemplifies a method for preparing a lyophilized formulation of formula (I) using sodium carbonate and water. However, this method is also insufficient to achieve a solubility of 80 mg / ml.
일본 공개특허 평성 제14-80361호에는 인산 3나트륨수화물, 가성소다 또는 KOH로부터 선택한 염기로 화학식 (Ⅰ) 화합물을 수용액 중에서 pH를 7.0-8.5로 조정 후 동결 건조하여 고농도의 제제를 제조하는 방법이 예시되어 있다. Japanese Patent Application Laid-Open No. 14-80361 discloses a method for preparing a high concentration formulation of a compound of formula (I) with a base selected from trisodium phosphate trihydrate, caustic soda or KOH in an aqueous solution by adjusting the pH to 7.0-8.5 and lyophilizing. Is illustrated.
이상의 방법에 의해 제조한 동결건조 제제는 동결 건조 후 제제의 pH값이 상승함에 따라 화학식 (Ⅰ)의 화합물이 분해되는 문제가 있기 때문에 바람직한 방법이 될 수는 없다. The lyophilized preparation prepared by the above method cannot be a preferred method because there is a problem in that the compound of formula (I) is decomposed as the pH value of the preparation increases after freeze drying.
이러한 단점을 보완하여 난용성 약물인 화학식 (Ⅰ) 화합물의 용해도를 향상시켜 고용량 동결 건조 제제를 제공하는 방법을 다음과 같이 예시한다. The method of improving the solubility of the compound of formula (I), which is a poorly soluble drug, by supplementing these disadvantages is illustrated as follows.
화학식 (Ⅰ)의 화합물의 용해성을 향상시켜 고용량의 동결 건조 제제를 얻기 위해 여러 가지로 연구해본 결과, 화학식 (Ⅰ) 화합물을 최소량의 물에 현탁시킨 후 0 ℃~실온에서 소디움에톡시드로 pH를 7.5~8.5로 조절하여 맑은 용액으로 만든 후 동결 건조하여 줌으로써 난용성인 화학식 (Ⅰ) 화합물의 용해도가 대폭 향상되고 그 결과 고용량의 동결 건조 제제를 제조할 수 있는 것을 발견하여 본 발명을 완성할 수가 있었다. Various studies have been conducted to improve the solubility of the compound of formula (I) to obtain a high-dose lyophilized formulation, and then, after suspending the compound of formula (I) in a minimum amount of water, the pH of Is adjusted to 7.5 ~ 8.5 to make a clear solution and then lyophilized to significantly improve the solubility of the poorly soluble compound of formula (I), and as a result, it is possible to complete the present invention by discovering that a high capacity freeze-dried formulation can be prepared. there was.
즉, 상기의 제조 방법에 따라 제조한 화학식 (Ⅰ) 화합물 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신을 공지의 방법으로 모노나트륨염ㆍ4 수화물을 제조하고, 이것을 물에 현탁시켜 소디움에톡시드로 pH 7.5~8.5 조정 투명한 액으로 만든 후 동결 건조시켜 목적하는 이용성 N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신 모노나트륨염ㆍ4 수화물을 얻는 제조 방법이다. That is, monosodium salt tetrahydrate is prepared by a known method using the compound of formula (I) N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine prepared according to the above-mentioned production method. This was suspended in water to make a pH 7.5-8.5 transparent solution with sodium ethoxide, followed by freeze-drying to obtain the desired usable N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt. It is a manufacturing method to obtain tetrahydrate.
보다 상세히 설명하면, 화학식 (Ⅰ) 화합물을 물에 현탁한 후 필요하면 부형제를 첨가하여 소디움 에톡시드로 pH를 7.5~8.5로 조정한다. 그리고 통상 이용되는 동결 건조기의 냉각 온도 -50 ℃ 부근에서 동결 건조시켜 동결건조 제제를 제조한다. In more detail, the compound of formula (I) is suspended in water and, if necessary, an excipient is added to adjust the pH to 7.5-8.5 with sodium ethoxide. And lyophilized formulation is prepared by freeze-drying in the vicinity of the cooling temperature -50 ℃ of the commonly used freeze dryer.
이때 물과 에탄올 혼합 용매를 사용할 때 발생하는 비등 현상이나 동결이 안되는 현상을 막을 수 있고 물만을 이용하기 때문에 동결 건조 후 매우 안정하고 동결건조 제제를 재 용해한 용액도 대단히 안정하여 사용의 편의성 및 안정성을 제공한다. At this time, it is possible to prevent the boiling or freezing phenomenon that occurs when using water and ethanol mixed solvent, and because only water is used, it is very stable after freeze-drying, and the solution which re-dissolves the lyophilized formulation is very stable for convenience and stability of use. to provide.
또한 보존 시간도 장기간에 걸쳐 우수한 용해성과 안정성을 유지한다.
The retention time also maintains good solubility and stability over a long period of time.
본 발명에 따르면 화학식 (II) 화합물을 고수율로 제조할 수 있을 뿐만 아니라, 화학식 (I)의 안정한 동결건조를 제조할 수 있다는 특장점이 있다.
According to the present invention, not only can the compound of formula (II) be produced in high yield, but also a stable freeze-drying of formula (I) can be prepared.
이하 실시예에 의해 본 발명을 상세히 설명하지만 본 발명은 이들에 한정되지 않는다.EXAMPLES Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.
<참고예 1-3><Reference Example 1-3>
1. t-부틸글리시네이트의 제조(p-1).1. Preparation of t-butylglycinate (p-1).
건조한 다이옥산 100 ml을 가하고 0~5 ℃로 냉각한다. 이용액에 진한 황산 10 ml을 가하고 동온도를 유지하면서 글리신 3.0 g (F.W 75.07, 0.04 M), 이소부틸렌 액체 50 ml을 차례로 가하고 이 혼합물을 가압 반응부내에서 28~30 ℃를 유지하면서 2시간 동안 교반한다. 반응이 종료되었음을 확인한 후 반응액에 차가운 중조 수용액 200 ml를 적가하고 이 혼합물을 초산에틸 200 ml로 2회에 걸쳐 추출한다. 추출액을 물, 포화식염수액, 물 순으로 각각 100 ml씩 세척해준다. 유기층을 무수망초로 건조하고 여과하여 여액을 감압에 의해 용매를 제거한다. 얻어진 물질은 정제 없이 다음 반응에 이용한다. Add 100 ml of dry dioxane and cool to 0-5 ° C. 10 ml of concentrated sulfuric acid was added to the solution, and 3.0 g of glycine (FW 75.07, 0.04 M) and 50 ml of isobutylene liquid were added sequentially while maintaining the same temperature, and the mixture was maintained for 28 hours in a pressurized reaction section for 2 hours. Stir. After confirming that the reaction was completed, 200 ml of cold aqueous sodium bicarbonate solution was added dropwise to the reaction solution, and the mixture was extracted twice with 200 ml of ethyl acetate. The extract is washed with 100 ml each of water, saturated saline solution and then water. The organic layer is dried over anhydrous forget-me-not and filtered to remove the solvent by distillation under reduced pressure. The obtained material is used for the next reaction without purification.
수율: 4.48 g(99 %)Yield: 4.48 g (99%)
H+NMR(CDCl3) : δ 1.40(9H.S)H + NMR (CDCl 3 ): δ 1.40 (9H.S)
3.61(2H,S) 3.61 (2H, S)
2.0 (2H,S)
2.0 (2H, S)
2. 시아노에틸글리시네이트의 제조(p-2).2. Preparation of cyanoethylglycinate (p-2).
글리신 0.75 g(F.W 75.07, 10 mM)을 메틸렌클로라이드/디메틸아미노피리딘을 가하고 여기에 시아노에탄올 1.42 g(F.W 71.08, 20 mM)을 가한다. 상기 용액에 DCC 2.3 g(F.W 206.33, 11 mM)을 메틸렌크로라이드 50 ml에 가해 용해 후 실온에서 적가해 준다. 적가가 끝난 후 동온도에서 하룻밤 동안 교반한다. 생성된 DCU(Dicyclohexylurea)를 여과에 의해 제거하고 여액을 감압 농축하여 제거한다. 잔사를 초산에틸 50 ml에 가해 용해한 후 물, 포화식염수, 물 순으로 각각 30 ml씩 세척한다. 유기층을 무수망초로 건조하고 여과하여 여액을 감압에 의해 제거한다. 얻어진 물질은 정제 없이 다음 반응에 이용한다. 0.75 g (F.W 75.07, 10 mM) of glycine is added to methylene chloride / dimethylaminopyridine and 1.42 g (C.W 71.08, 20 mM) of cyanoethanol is added thereto. To the solution, 2.3 g of DCC (F.W 206.33, 11 mM) was added to 50 ml of methylene chloride, dissolved and added dropwise at room temperature. After the addition, the mixture is stirred overnight at the same temperature. The resulting DCU (Dicyclohexylurea) is removed by filtration and the filtrate is removed by concentration under reduced pressure. The residue was added to 50 ml of ethyl acetate and dissolved, followed by washing with 30 ml of water, saturated brine and water. The organic layer is dried over anhydrous forget-me-not and filtered to remove the filtrate by reduced pressure. The obtained material is used for the next reaction without purification.
수율: 1.26 g(96 %)Yield: 1.26 g (96%)
H+NMR(CDCl3): δ 2.0(S,2H), 2.69(S.2H)H + NMR (CDCl 3 ): δ 2.0 (S, 2H), 2.69 (S.2H)
3.61(S.2H) 3.61 (S.2 H)
4.45(S.2H)
4.45 (S.2H)
3. 2.2.2-트리클로로에틸글리시네이트의 제조(p-3).3. Preparation of 2.2.2-trichloroethylglycinate (p-3).
글리신 0.75 g(F.W 75.07, 10 mM)을 메틸렌클로라이드/디메틸포름아미드 용액 100 ml에 가하고 촉매량의 디메틸 아미노피리딘을 가하고 여기에 2.2.2-트리클로로에탄올 2.98 g(F.W 149.10, 20 mM)을 가한다. 이하 실시 예 2와 동일한 방법으로 처리하여 표제화합물 1.98 g(수율 96 %)을 얻는다. 0.75 g of glycine (FW 75.07, 10 mM) is added to 100 ml of methylenechloride / dimethylformamide solution and a catalytic amount of dimethyl aminopyridine is added thereto and 2.98 g of 2.2.2-trichloroethanol (FW 149.10, 20 mM) is added. . In the same manner as in Example 2 below, 1.98 g (yield 96%) of the title compound were obtained.
H+NMR(CDCl3): δ 2.0(S,2H)H + NMR (CDCl 3 ): δ 2.0 (S, 2H)
3.61(S,2H), 4.84(S,2H)
3.61 (S, 2H), 4.84 (S, 2H)
<실시예 1-11><Example 1-11>
1. t-부틸-N-(2-아미노벤조일)글리시네이트의 제조(q-1).1. Preparation of t-butyl-N- (2-aminobenzoyl) glycinate (q-1).
2-(아미노벤조산 1.37 g(F.W 137.14, 10 mM)을 메틸렌클로라이드 100 ml, t-부틸글리시네이트 1.2 g(F.W 113.8, 10.6 mM)을 차례로 가하고 균일한 용액으로 만든다. 상기 용액을 5~10 ℃로 냉각한 후 DCC 2.3 g을 서서히 30 ℃ 이하를 유지하면서 가해준다. 실온에서 하룻밤 교반한 다음 생성된 DCU를 여과에 의해 제거한다. 여액을 물, 포화식염수, 물 순으로 각각 50 mlTlr 세척을 한다. 세척된 유기층을 무수 망초로 건조하고 여과한 후 여액을 감압 유거하여 표제 화합물 2.28 g(98 %)을 얻는다.1.37 g of 2- (aminobenzoic acid (FW 137.14, 10 mM) is added to 100 ml of methylene chloride and 1.2 g of t-butylglycinate (FW 113.8, 10.6 mM) in order to make a homogeneous solution. After cooling to < RTI ID = 0.0 > C, < / RTI > 2.3 g of DCC are added slowly while maintaining below 30 [deg.] C. After stirring overnight at room temperature, the resulting DCU is removed by filtration The filtrate is washed 50 mlTlr each with water, saturated saline and then water. The washed organic layer is dried over anhydrous manganese, filtered and the filtrate is distilled off under reduced pressure to give 2.28 g (98%) of the title compound.
H+NMR(CDCl3) : δ1.40(9H.S), 4.0(2H.S)H + NMR (CDCl 3 ): δ 1.40 (9H.S), 4.0 (2H.S)
4.16(2H.S), 6.64(1H.S) 4.16 (2H.S), 6.64 (1H.S)
6.80(1H.S), 7.26(1H.S) 6.80 (1 H.S), 7.26 (1 H.S)
7.70(1H.S), 8.0 (1H.S)
7.70 (1 H.S), 8.0 (1 H.S)
2. 시아노에틸-N-(2-아미노벤조일)글리시네이트의 제조(q-2).2. Preparation of cyanoethyl-N- (2-aminobenzoyl) glycinate (q-2).
2-아미노벤조산 1.37 g(F.W 137.14, 10 mM)을 메틸렌클로라이드 100 ml, 시아노에틸글리시네이트 1.41 g(F.W 128.15, 11 mM)을 차례로 가하고 실온에서 균일한 용액으로 만든다. 상기용액을 5~10 ℃로 냉각한 후 DCC 2.3 g을 서서히 30 ℃ 이하를 유지하면서 가해준다. 이하 실시 예 1에서의 방법과 동일하게 처리하여 표제 화합물 2.35 g(95 %)을 얻는다.1.37 g of 2-aminobenzoic acid (F.W 137.14, 10 mM) are added in sequence to 100 ml of methylene chloride, 1.41 g of cyanoethylglycinate (F.W 128.15, 11 mM) and made into a homogeneous solution at room temperature. After cooling the solution to 5 ~ 10 ℃ to the DCC 2.3 g is slowly added while maintaining below 30 ℃. The same procedure as in Example 1 hereinafter gives 2.35 g (95%) of the title compound.
H+NMR(CDCl3) : δ 2.69(2H.S), 4.0(2H.S)H + NMR (CDCl 3 ): δ 2.69 (2H.S), 4.0 (2H.S)
4.16(2H.S), 4.45(2H.S) 4.16 (2H.S), 4.45 (2H.S)
6.64(1H.S), 6.80(1H.S) 6.64 (1 H.S), 6.80 (1 H.S)
7.26(1H.S), 7.70(1H.S) 7.26 (1 H.S), 7.70 (1 H.S)
8.0 (1H.S)
8.0 (1H.S)
3. 2.2.2-트리클로로에틸-N-(2-아미노벤조일)글리시네이트의 제조(q-3).3. Preparation of 2.2.2-trichloroethyl-N- (2-aminobenzoyl) glycinate (q-3).
2-아미노벤조산 1.37 g(F.W 137.14, 10 mM)을 메틸렌클로라이드 100 ml, 2.2.2-트리클로로에틸글리시네이트 2.27 g(F.W 206.47, 11 mM)을 차례로 가하고 실온에서 균일한 용액으로 만든다. 상기 용액을 5~10 ℃로 냉각한 후 DCC 2.3 g을 서서히 30 ℃이하를 유지하면서 가해준다. 이하 실시예 1과 동일한 방법으로 처리하여 표제 화합물 3.19 g(98 %)을 얻는다.1.37 g of 2-aminobenzoic acid (F.W 137.14, 10 mM) are added in sequence to 100 ml of methylene chloride, 2.27 g of 2.2.2-trichloroethylglycinate (F.W 206.47, 11 mM) and made into a homogeneous solution at room temperature. After cooling the solution to 5 ~ 10 ℃ the DCC 2.3 g is slowly added while maintaining below 30 ℃. 3.19 g (98%) of the title compound are obtained by the same method as in Example 1 below.
H+NMR(CDCl3) : δ 4.0(2H.S), 4.16(2H.S)H + NMR (CDCl 3 ): δ 4.0 (2H.S), 4.16 (2H.S)
4.84(2H.S) 4.84 (2H.S)
6.64(1H.S) 6.64 (1 H.S)
6.80(1H.S) 6.80 (1 H.S)
7.26(1H.S) 7.26 (1 H.S)
7.70(1H.S) 7.70 (1 H.S)
8.0 (1H.S)
8.0 (1H.S)
4. t-부틸-N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리시네이트의 제조(r-1).4. Preparation of t-butyl-N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycinate (r-1).
t-부틸-N-(2-아미노벤조일)글리시네이트 2.3 g(F.W 232.32, 10 mM), P-피바로일옥시벤젠술포닐클로라이드 3.6 g(F.W 276.75, 13 mM), 피리딘 25 ml을 실온에서 가하고 하룻밤 교반한다. 감압으로 피리딘을 제거한 후 잔사를 메틸렌클로라이드 50 ml에 가해 용해한 후 묽은 염산 수용액, 포화 식염수, 물 순으로 각각 20 ml씩 세척한다. 유기층을 무수망초로 건조한 다음 여과하고 감압 농축하여 유기층을 제거하여 표제 화합물 4.5 g(95 %)를 얻는다. 2.3 g of t-butyl-N- (2-aminobenzoyl) glycinate (FW 232.32, 10 mM), 3.6 g of P-fibaroyloxybenzenesulfonylchloride (FW 276.75, 13 mM), 25 ml of pyridine Add and stir overnight. After removing pyridine under reduced pressure, the residue was dissolved in 50 ml of methylene chloride, and then washed 20 ml each with dilute aqueous hydrochloric acid solution, saturated brine and water. The organic layer was dried over anhydrous forget-me-not, filtered and concentrated under reduced pressure to remove the organic layer to obtain 4.5 g (95%) of the title compound.
H+NMR(CDCl3) : δ 1.19(9H.S), 1.40(9H.S)H + NMR (CDCl 3 ): δ 1.19 (9H.S), 1.40 (9H.S)
4.16(2H.S), 6.64~6.8(2H.m) 4.16 (2H.S), 6.64-6.8 (2H.m)
7.35(2H.m), 7.90(2H,m) 7.35 (2H.m), 7.90 (2H, m)
7.0 (1H.m), 7.26(1H.S)
7.0 (1 H.m), 7.26 (1 H.S)
5. 시아노에틸-N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리시네이트의 제조(r-2).5. Preparation of cyanoethyl-N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycinate (r-2).
시아노에틸-N-(2-아미노벤조일)글리시네이트 2.47 g(F.W 247.29, 10 mM), P-피발로일옥시벤젠술포닐클로라이드 3.6 g(F.W 276.75, 13 mM), 피리딘 25 ml을 실온에서 가하고 하룻밤 교반한다. 이하 실시예 4와 동일한 방법으로 처리하여 표제화합물 4.69 g(96 %)을 얻었다.2.47 g of cyanoethyl-N- (2-aminobenzoyl) glycinate (FW 247.29, 10 mM), 3.6 g of P-pivaloyloxybenzenesulfonylchloride (FW 276.75, 13 mM), 25 ml of pyridine Add and stir overnight. 4.69 g (96%) of the title compound were obtained by the same method as the Example 4 below.
H+NMR(CDCl3) : δ 1.19(9H.S), 2.69(2H.S)H + NMR (CDCl 3 ): δ 1.19 (9H.S), 2.69 (2H.S)
4.16(2H.S), 4.45(2H.S) 4.16 (2H.S), 4.45 (2H.S)
6.64~6.80(2H.m) 6.64 ~ 6.80 (2H.m)
7.26~7.35(3H.m) 7.26 ~ 7.35 (3H.m)
7.70~7.90(3H.m)
7.70 ~ 7.90 (3H.m)
6. 2.2.2-트리클로로에틸-N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리시네이트의 제조(r-3).6. Preparation of 2.2.2-trichloroethyl-N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycinate (r-3).
2.2.2-트리클로로에틸-N-(2-아미노벤조일)글리시네이트 3.3 g(F.W 325.61, 10 mM), P-피발로일옥시벤젠술포닐클로라이드 3.6 g(F.W 276.75, 13 mM), 피리딘 25 ml을 실온에서 가하고 하룻밤 교반한다. 이하 실시예 4와 동일한 방법으로 처리하여 표제 화합물 5.4 g(97 %)을 얻었다. 2.2.2-trichloroethyl-N- (2-aminobenzoyl) glycinate 3.3 g (FW 325.61, 10 mM), P- pivaloyloxybenzenesulfonylchloride 3.6 g (FW 276.75, 13 mM), pyridine 25 ml are added at room temperature and stirred overnight. In the same manner as in Example 4 below, 5.4 g (97%) of the title compound were obtained.
H+NMR(CDCl3) : δ 1.19(9H.S), 4.16(2H.S)H + NMR (CDCl 3 ): δ 1.19 (9H.S), 4.16 (2H.S)
4.84(2H.S) 4.84 (2H.S)
6.64~6.80(2H.m) 6.64 ~ 6.80 (2H.m)
7.26~7.35(3H.m) 7.26 ~ 7.35 (3H.m)
7.70~7.90(3H.m) 7.70 ~ 7.90 (3H.m)
8.0 (1H.S)
8.0 (1H.S)
7. N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신의 제조(F.W 434.46).7. Preparation of N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine (F.W 434.46).
t-부틸-N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리시네이트 7.1 g(F.W 473.07, 15 mM)을 냉 트리플루오로초산 100 ml에 가하고 실온에서 30 분간 교반한다. 감압에 의해 트리플루오로초산을 제거한 후 잔사를 메탄올 200 ml에 가해 용해하고 pH를 3 으로 조정한다. 생성된 결정을 실온에서 3시간 교반한 다음 여과하여 모은다. 상기 표제 화합물 5.87 g(90 %)를 얻는다. 7.1 g (FW 473.07, 15 mM) of t-butyl-N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycinate was added to 100 ml of cold trifluoroacetic acid and stirred at room temperature for 30 minutes. do. After trifluoroacetic acid was removed by reduced pressure, the residue was added to 200 ml of methanol to dissolve and the pH was adjusted to 3. The resulting crystals are stirred at room temperature for 3 hours and then collected by filtration. 5.87 g (90%) of the title compound are obtained.
H+NMR(CDCl3) :δ 1.19(9H.S), 4.14(2H.S)H + NMR (CDCl 3 ): δ 1.19 (9H.S), 4.14 (2H.S)
6.64~6.8(2H.m) 6.64-6.8 (2H.m)
7.26~7.35(3H.m) 7.26 ~ 7.35 (3H.m)
7.70~7.90(3H.m) 7.70 ~ 7.90 (3H.m)
8.0 (1H.S) 8.0 (1H.S)
M.P : 219~223 ℃
MP: 219 ~ 223 ℃
8. N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신의 제조.8. Preparation of N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine.
시아노에틸-N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리시네이트 4.9 g(F.W 488.04, 10 mM)을 디메틸포름아미드 50 ml에 가하고 용해시킨다. 상기 용액에 테트라하이드로푸란 용액 내 포함된 1M 테트라부틸암모늄플루오라이드 용액 10 ml(10 mM)를 가하고 실온에서 10 분간 교반한다. 반응 혼합물을 정제수 50 ml를 가하고 메틸렌클로라이드 200 ml로 추출한다. 유기층을 물, 포화 식염수 용액, 물 순으로 각각 50 ml로 세척 후 무수망초로 건조한다. 여과하고 유기층을 감압 유거하여 메탄올 20 ml로 결정화하여 상기 표제 화합물 3.9 g(90 %)을 얻는다.
4.9 g (FW 488.04, 10 mM) of cyanoethyl-N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycinate is added to 50 ml of dimethylformamide and dissolved. To the solution was added 10 ml (10 mM) of 1M tetrabutylammonium fluoride solution contained in tetrahydrofuran solution and stirred at room temperature for 10 minutes. 50 ml of purified water is added and the reaction mixture is extracted with 200 ml of methylene chloride. The organic layer was washed with 50 ml each of water, saturated saline solution, and then dried over anhydrous forget-me-not. Filtration and distillation of the organic layer under reduced pressure and crystallization with 20 ml of methanol gave 3.9 g (90%) of the title compound.
9. N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신의 제조.9. Preparation of N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine.
2.2.2-트리클로로에틸-N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리시네이트 21 g(F.W 566.36, 37 mM)을 실온에서 테트라하이드로푸란 100 ml에 가해 용해시킨다.21.2 g of 2.2.2-trichloroethyl-N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycinate (FW 566.36, 37 mM) was added to 100 ml of tetrahydrofuran at room temperature for dissolution. Let's do it.
이용액에 Zn분말 20 g, 1M 포타시움 디하이드로젼 포스페이트 용액 20 ml을 빠르게 교반하면서 가해준다. 이렇게 형성된 현탁물을 10 분간 교반한 후 온도를 서서히 28 ℃까지 상승시킨다. 그리고나서 여과에 의해 아연을 제거하고 여액을 감압에 의해 제거한다. 잔사에 메탄올 70 ml로 결정화하여 상기 표제 화합물 14.8 g(92 %)을 얻는다.
To the solution was added 20 g of Zn powder and 20 ml of 1M Potassium Dihydrogen Phosphate solution with rapid stirring. The suspension thus formed is stirred for 10 minutes and then the temperature is gradually raised to 28 ° C. The zinc is then removed by filtration and the filtrate is removed by reduced pressure. Crystallize the residue with 70 ml of methanol to afford 14.8 g (92%) of the title compound.
10. N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신 모노나트륨ㆍ4 수화물의 제조.10. Preparation of N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium tetrahydrate.
N-[O-(P-피발로일옥시벤젠술포닐아미노)벤조일]글리신 227 g, 에탄올 3.989 ml, 정제수 2.850 ml을 가해 현탁하고 수산화나트리움 215 g을 정제수 1.059 ml에 가해 용해한 액을 20~30 ℃에서 가하고 40~60 ℃로 가온하여 용해한다. 불용물질을 여과하여 제거하고 에탄올/정제수 혼액(1:1)으로 세척하고 냉각하여 5 ℃에서 1~3 일간 방치한다. 생성된 결정을 여과해 모아 에탄올/물 (1:1) 혼합액으로 세척하고 결정을 감압 건조하였다. 에탄올이 잔존하지 않는 것을 확인 후 감압 건조기 중에서 정제수에 노출시켜 2~3 일간 방치해 준다. 이렇게 하여 표제 화합물을 얻는다. 227 g of N- [O- (P-pivaloyloxybenzenesulfonylamino) benzoyl] glycine, 3.989 ml of ethanol, and 2.850 ml of purified water were added and suspended. Add at 30 ° C, warm to 40 ~ 60 ° C to dissolve. Insoluble materials are removed by filtration, washed with ethanol / purified water mixture (1: 1), cooled and left to stand at 5 ° C for 1-3 days. The resulting crystals were collected by filtration, washed with an ethanol / water (1: 1) mixture, and the crystals were dried under reduced pressure. After confirming that ethanol does not remain, it is exposed to purified water in a reduced pressure dryer and allowed to stand for 2-3 days. This gives the title compound.
H+NMR : δ 1.32 (S. 9H), 3.80(2H.S)H + NMR: δ 1.32 (S. 9H), 3.80 (2H.S)
7.2(1H.t.j=8.5HZ), D.15(2H,d) 7.2 (1H.t.j = 8.5HZ), D.15 (2H, d)
j=8.5HZ), 7.41(1H, t.j=8.5HZ) j = 8.5HZ), 7.41 (1H, t.j = 8.5HZ)
7.62(1H, d,j=8.5HZ) 7.62 (1H, doublet, j = 8.5HZ)
7.67(1H,d,j=8.5HZ) 7.67 (1H, d, j = 8.5 HZ)
7.75(2H,d,j=8.5HZ) 7.75 (2Hd, j = 8.5HZ)
IR(Cm-1) : γ2979, 1750, 1628, 1588, 1401, 1216, 574IR (Cm- 1 ): γ2979, 1750, 1628, 1588, 1401, 1216, 574
T.L.C : Rf 0.3(클로로포름:메탄올:초산 = 30:3:1)T.L.C: Rf 0.3 (chloroform: methanol: acetic acid = 30: 3: 1)
M.P : 190~193 ℃
MP: 190 ~ 193 ℃
11. 동결 건조 제품의 제조.11. Preparation of lyophilized products.
화학식 II 화합물 100 g, 만니톨 25 g, 정제수 1 ℓ에 가하고 현탁시킨 후 그 용액을 -50 ℃에서 소디움 에톡시드를 가해 pH를 8.5로 조정하여 맑은 용액으로 만든후 필요하면 여과를 한다. 이 용액을 -50 ℃에서 10 기압 압력하에서 20 시간 동결 건조시켜 동결 건조 제제를 제조한다.
100 g of the compound of formula II, 25 g of mannitol, and 1 l of purified water were suspended and the solution was added to sodium ethoxide at -50 ° C to adjust the pH to 8.5 to make a clear solution, and then filtered if necessary. The solution is lyophilized at −50 ° C. under 10 atm for 20 hours to prepare a lyophilized formulation.
본 발명에 따르면, 화학식 (II) 화합물을 고수율로 얻을 수 있고, 화학식 (I)의 안정한 동결 건조 제제를 제공할 수 있다는 특장점이 있다.According to the present invention, the compound of formula (II) can be obtained in high yield and a stable freeze-dried preparation of formula (I) can be provided.
Claims (4)
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