KR100845383B1 - Process for preparing torsemide modification? - Google Patents
Process for preparing torsemide modification? Download PDFInfo
- Publication number
- KR100845383B1 KR100845383B1 KR1020040112307A KR20040112307A KR100845383B1 KR 100845383 B1 KR100845383 B1 KR 100845383B1 KR 1020040112307 A KR1020040112307 A KR 1020040112307A KR 20040112307 A KR20040112307 A KR 20040112307A KR 100845383 B1 KR100845383 B1 KR 100845383B1
- Authority
- KR
- South Korea
- Prior art keywords
- variant
- torsemide
- water
- present
- room temperature
- Prior art date
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/83—Thioacids; Thioesters; Thioamides; Thioimides
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyridine Compounds (AREA)
Abstract
본 발명은 이뇨제로 사용되는 다음 구조식⑴로 표시되는 토르세미드 변형체(I)의 제조 방법에 관한 것이다.The present invention relates to a process for preparing torsemide variant (I) represented by the following structural formula VII used as a diuretic.
본 발명의 방법은 물과 유기용매를 혼합한 혼합용매를 이용하여 반응 부산물 없이 효과적이고 경제적인 방법을 통하여 고수율 및 고순도로 목적하는 화합물을 합성하는 개량된 방법이다. The method of the present invention is an improved method of synthesizing a desired compound in high yield and purity through an effective and economical method without reaction by-products using a mixed solvent mixed with water and an organic solvent.
N-[[(1-메틸에틸)아미노]카르보닐]-4-[(3-메틸페닐)아미노]-3-피리딘설폰아미드, 토르세미드, 변형체N-[[(1-methylethyl) amino] carbonyl] -4-[(3-methylphenyl) amino] -3-pyridinesulfonamide, torsemide, variant
Description
도면 1 은 토르세미드 변형체(II)의 IR 스펙트럼을 나타낸다.1 shows the IR spectrum of the torsemide variant (II).
도면 2 는 실시예 1에 따라 제조된 토르세미드 변형체(I)의 IR 스펙트럼을 나타낸다.2 shows the IR spectrum of the torsemide variant (I) prepared according to Example 1. FIG.
도면 3 은 토르세미드 변형체(II) 의 X선 분말 회절 스펙트럼을 나타낸다.3 shows the X-ray powder diffraction spectrum of the torsemide variant (II).
도면 4 는 실시예 1에 따라 제조된 토르세미드 변형체(I)의 X선 분말 회절 스펙트럼을 나타낸다.4 shows the X-ray powder diffraction spectrum of the torsemide variant (I) prepared according to Example 1. FIG.
본 발명은 토르세미드의 변형체(I)의 제조 방법에 대한 것으로, 토르세미드 변형체(I)을 토르세미드 변형체(II)로부터 고수율 및 고순도로 변형시킬 수 있는 방법에 관한 것 이다.The present invention relates to a method for producing a torsemide variant (I), and to a method capable of transforming a torsemide variant (I) from a torsemideide (II) in high yield and high purity.
하기 [구조식 1]의 구조를 갖는 토르세미드는 독일 특허 제 25 15 025 호의 실시예 71에 기재되어 있는 소위 '고리 이뇨제(loop diuretic)' 계열의 신규한 효력 있는 이뇨제이다. 구조적으로, 이는 푸로세미드, 부메타니드 및 아조세미드와 같은 동일 계열의 이뇨제와 완전히 상이한 콩팥 세관고리(Henle's loop)의 이뇨제로,
Torcemide having the structure of [Formula 1] is a novel effective diuretic of the so-called 'loop diuretic' family described in Example 71 of German Patent 25 15 025. Structurally, it is a diuretic of the Henle's loop, which is completely different from the same class of diuretics such as furosemide, bumetanide and azosemide,
[구조식 1][Formula 1]
상기와 같은 토르세미드는 칼륨이온보다 물과 나트륨이온을 상대적으로 강하게 배출하게 되는 경우에 더욱 강한 이뇨작용을 가지며, 울혈성 심부전이나 간경화증 또는 신기능 이상에 의한 부종의 치료에 이용되며, 특히, 다른 항고혈압 약물과 함께 고혈압 치료를 목적으로 사용되기도 한다.Such torsemide has a stronger diuretic effect in the case of discharging water and sodium ions relatively stronger than potassium ions, and is used for the treatment of edema caused by congestive heart failure or cirrhosis or renal dysfunction. Along with high blood pressure drugs, it can also be used to treat high blood pressure.
[구조식 1]의 토르세미드는 결정학적으로 서로 다른 결정형태를 가지는 변형체로 나타날 수 있다는 사실이 참고문헌에 알려져 있다. ; [참고문헌, Acta Cryst., 1978, pp. 2659-2662 및 Acta Cryst., 1978. pp. 1304-1310]. 이와 같이, 하나 이상의 결정형으로 존재할 수 있는 물질의 능력을 동질이상(polymorphism)으로 정의하며, 상기 상이한 결정형을 “다형체(polymorph) 변형물” 또는 “다형체”라고 부른다. 일반적으로, 동질이상은 물질의 분자가 그 구조를 변화시키거나, 상이한 분자간 또는 분자내 상호작용, 특히 수소 결합을 형성하는 능력에 의해 유도되며, 상이한 다형체의 결정 격자 중 상이한 원자 배열로 반영된다. 동질이상은 몇몇 유기 화합물에서 발견된다. 물질의 상이한 다형체는 상이한 결정 격자 에너지를 보유하므로, 이들은 약학 제형의 제조 가능성, 이들의 안전성, 용해도 및 생체 이용률에 영향을 미칠 수 있는, 결과적으로 이들의 작용에 영향을 미칠 수 있는 형태, 밀도, 융점, 색상, 안정성, 용해 속도, 제분 설비, 과립화, 압축 등과 같은 고체 상태의 상이한 물리적 특성을 나타낸다.It is known in the references that the torsemide of [Formula 1] may appear as a variant having crystallographically different crystal forms. ; [References, Acta Cryst., 1978, pp. 2659-2662 and Acta Cryst., 1978. pp. 1304-1310. As such, the ability of a substance to exist in one or more crystalline forms is defined as polymorphism, and the different crystalline forms are called "polymorph variants" or "polymorphs". Generally, homogeneity is induced by the ability of molecules of a substance to change its structure or to form different intermolecular or intramolecular interactions, in particular hydrogen bonds, and is reflected in different atomic arrangements in the crystal lattice of different polymorphs. . Homogeneity is found in some organic compounds. Since different polymorphs of materials have different crystal lattice energies, they can affect the manufacturability of pharmaceutical formulations, their safety, solubility and bioavailability, resulting in forms, densities that can affect their action Different physical properties of the solid state such as melting point, color, stability, dissolution rate, milling equipment, granulation, compaction and the like.
[구조식 1]의 토르세미드의 경우 보통의 제법에서 정상적인 정제 및 제조하는 경우에 얻어지는 변형체는 보통 다른 용매로 재결정화한 경우에 초래되는 변형체(II)이다. 순수한 활성물질을 보관하는 경우에 상기 형태가 변화되지 않고, 모든 정제실험의 경우에 지배적인 형태로 형성되기 때문에 변형체(II)도 또한 안정하다고 가정했다. 그러나 놀랍게도, 변형체(II)의 토르세미드가 세분화된 형태의 제약정제로 존재하는 경우, 물속으로 정제를 주입함에 따라 활성물질의 용해속도 및 결정의 크기가 중요하게 변화됨으로 인하여, 변형체(II)는 다소 빠르게 변형체(I)로 재배열 된다. 반면, 용해 속도가 투여의 약제학적 형태의 하나로 나타나므로, 용해속도는 재생적으로 투여될 수 있도록 한 정제에서 다른 정제에 이르기까지 달라야 한다. 따라서, 보관하는 동안 용해속도가 변화되지 않는 토르세미드의 투여형태를 발견해야 하는 문제가 존재하게 된다. 용해속도의 비조절적 변화가 변형체(II)를 변형체(I)로 재배열하는데 의존되므로, 최초부터 변형체(I)을 사용해야 한다는 것이 명백하다. 그 이유는 변형체(I)이 정제에서 안전하고 변형체(II)로 다시 되돌아가 재배열되지 않기 때문이다. 그런데 종래기술에 의한 제조 방법을 통하여 토르세미드를 제조하는 경우, 제약 정제 상태에서 불안정하여 물속에서 재배열되는 변형체(II)로 주로 합성되는 바, 이러한 종래 기술의 문제점을 해결 할 수 있는 제약 정제 상태에서 재배열되지 않으며 토르세미드의 안정변형체(I)을 고수율 및 고순도 로 제조 할 수 있는 방법이 절실히 요구되고 있다. 위에서 기술된 토르세미드 결정형 변환에 관한 내용으로 출원된 특허를 살펴보면, 국내 특허 특 1987-0002076은 시드(Seed) 형태로 촉매 양 만큼의 토르세미드 변형체(I)를 부가하여 결정형 변환을 하는 방법으로 이는 토르세미드 변형체(II)만으로는 결정형 변환이 되지 않는 단점이 있고, 또 다른 국내특허 특2002-0025217은 단일용매를 사용하여 토르세미드 변형체(I)을 제조하는 방법이 기재되어 있는데 이 방법은 반응수율이 저조한 단점이 있다.In the case of the torsemide of [Formula 1], the variant obtained in the case of normal purification and preparation in the usual manufacturing method is the variant (II) which is usually caused when recrystallized with another solvent. Variant (II) was also assumed to be stable because the morphology did not change when the pure actives were stored, and formed in the dominant form for all purification experiments. Surprisingly, however, when the torsemide of variant (II) is present in the granular form of the pharmaceutical tablet, variant (II) due to the significant change in the dissolution rate and crystal size of the active substance as the tablet is injected into water. Is rearranged somewhat more quickly into variant (I). On the other hand, since the rate of dissolution appears as one of the pharmaceutical forms of administration, the rate of dissolution must vary from one tablet to another so that it can be regenerated. Thus, there is a problem of finding a dosage form of torsemide that does not change the dissolution rate during storage. Since uncontrolled changes in dissolution rate depend on rearranging variant (II) to variant (I), it is clear that variant (I) should be used from the beginning. This is because variant (I) is safe in tablets and does not revert back to variant (II). By the way, in the case of preparing torsemide through the manufacturing method according to the prior art, it is mainly synthesized as a variant (II) that is unstable in the pharmaceutical purification state and rearranged in water, pharmaceutical tablets that can solve the problems of the prior art There is an urgent need for a method that can produce stable variants of torsemide (I) in high yield and high purity without being rearranged in the state. Looking at the patent filed with the content of the torsemide crystalline conversion described above, Korean Patent No. 1987-0002076 is a method of performing a crystalline conversion by adding the amount of the torsemide variant (I) in the form of seed (Seed) As a result, there is a disadvantage in that the crystalline conversion is not performed only by the torsemide variant (II), and another Korean Patent Publication No. 2002-0025217 describes a method of preparing the torsemide variant (I) using a single solvent. The disadvantage is that the reaction yield is poor.
따라서, 본 발명은 상기와 같은 종래 기술의 문제점을 해소하고 물과 유기용매를 혼합한 혼합용매를 이용하여 반응 부산물 없이 반응을 효율적으로 수행하고 경제적인 공업적 제조 방법을 통하여 고수율 및 고순도로 얻을 수 있는 새로운 방법을 제공하고자 한다. 기존의 방법 중 토르세미드 변형체(II)에 토르세미드 변형체(I)을 촉매 양 만큼 부가하여 물에서 교반하여 결정형 변환을 시켜 얻는 방법은 변환 전에 토르세미드 변형체(I)형이 있어야 하는 단점이 있으며, 한 가지 단일 용매 또는 두 가지의 유기용매의 혼합용매를 이용하여 실험을 수행하였을 경우에는 결정형 변환이 이루어지지 않거나, 매우 저조한 수율을 나타내는 단점이 있었다. 이에 토르세미드 변형체(I)의 사용 없이 새로운 혼합용매를 이용한 결정형 변환을 통하여 토르세미드 변형체(I)을 얻을 수 있는 새로운 합성방법을 도출하게 되었다.Therefore, the present invention solves the problems of the prior art as described above, using a mixed solvent mixed with water and an organic solvent to perform the reaction efficiently without reaction by-products and obtain high yield and high purity through an economical industrial production method We want to provide a new way to do this. The conventional method of adding torcemide variant (I) to the torcemide variant (II) by the amount of the catalyst and stirring it in water to obtain the crystalline conversion has the disadvantage of having the torcemide variant (I) before conversion In this case, when the experiment was performed using a single solvent or a mixed solvent of two organic solvents, there was a disadvantage in that the crystalline conversion was not performed or the yield was very low. Thus, a new synthetic method for obtaining the torsemide variant (I) was obtained through the crystalline conversion using a new mixed solvent without using the tosemide variant (I).
본 발명은 유기 용매 중 아세톤과 물 또는 메탄올과 물을 혼합한 혼합용매에 촉매량의 토르세미드 변형체(I)없이, 토르세미드 변형체(II)만을 부가하여 환류교 반 후, 상온 교반시켜 목적하는 토르세미드 변형체(I)을 고수율로 얻을 수 있는 놀라운 사실을 발견하여 본 발명을 완성하였다.The present invention is added to a mixed solvent of acetone and water or methanol and water in an organic solvent, without the catalytic amount of torsemide variant (I), only by adding torsemid variant (II) and stirring at reflux, followed by stirring at room temperature. The present invention has been completed by discovering the surprising fact that the torsemide variant (I) can be obtained in high yield.
본 발명은 기존 특허방법과 비교하여 토르세미드 변형체(I) 없이 반응을 진행하여 결정형 변환이 완료되고 반응부산물도 거의 없이 정량적으로 목적하는 화합물을 얻을 수 있는, 순수한 토르세미드 변형체(I)의 제조를 위한 보다 효율적이고 경제적인 방법을 제공한다.Compared to the conventional patent method, the present invention proceeds the reaction without the torsemide variant (I) to complete the crystalline conversion and obtain the desired compound quantitatively with little reaction byproduct. It provides a more efficient and economic way for manufacturing.
본 발명은 N-[[(1-메틸에틸)아미노]카르보닐]-4-[(3-메틸페닐)아미노]-3-피리딘설폰아미드(이하 토르세미드) 변형체(II)를 유기용매와 물의 혼합용매에서 교반하여 토르세미드 변형체(I)로 결정형이 변환됨을 특징으로 한다. 토르세미드 변형체(I)은 톱프마이어 선언서 도 1의 X-선 분말 회절 패턴을 특징으로 하는 토르세미드로서 정의되며, 2θ=5.7±0.2° 에서의 강한 피크를 특징으로 하는 고유의 X-ray 분말 회절 패턴을 나타낸다.
The present invention provides N-[[(1-methylethyl) amino] carbonyl] -4-[(3-methylphenyl) amino] -3-pyridinesulfonamide (hereinafter torcemide) variant (II) of an organic solvent and water. It is characterized in that the crystalline form is converted to the torsemide modified product (I) by stirring in a mixed solvent. The torsemide variant (I) is defined as torsemide, which is characterized by the X-ray powder diffraction pattern of the Topmeier Declaration Figure 1, inherent X-rays characterized by strong peaks at 2θ = 5.7 ± 0.2 °. The powder diffraction pattern is shown.
[구조식 1][Formula 1]
본 발명을 보다 구체적으로 설명하면 다음과 같다.The present invention will be described in more detail as follows.
본 발명은 토르세미드 변형체(II)를 유기용매와 물의 혼합용매에 가하고 환 류교반 시킨 후, 상온 교반하여 반응을 완결시킨다. 상기 유기용매는 아세톤과 메탄올로, 그 중 아세톤과 물을 2:1 또는 1:1로 바람직하게는 1:1로 혼합한 혼합용매에 토르세미드 변형체(II)를 부가하여 환류교반 후 상온 교반시키는 것이 바람직하다. 상온 교반시간은 3시간 내지 20시간동안 이며, 바람직하게는 10시간 이상 진행시킨다.The present invention is added to the mixed solution of the torsemide (II) to a mixed solvent of an organic solvent and water and stirred under reflux, and then stirred at room temperature to complete the reaction. The organic solvent is acetone and methanol, in which a mixed solution of acetone and water in a mixed solvent of 2: 1 or 1: 1, preferably 1: 1, adds the torsemide modified (II) and stirred at room temperature after reflux stirring It is preferable to make it. Room temperature stirring time is for 3 to 20 hours, preferably 10 hours or more.
놀랍게도, 상기한 바와 같은 조건에서 상기 [구조식 1]의 토라세미드를 결정형 변환을 진행시켰을때, 결정형 변환 과정에서 높은 수율과 고순도의 토라세미드 변형체(I)을 얻을 수 있었다. 이와는 달리 유기용매를 단독으로 사용하여 상기 실험을 수행하였을 경우에는 저조한 수율을 보였다.Surprisingly, when the torasemide of [formula 1] was subjected to crystalline conversion under the above conditions, it was possible to obtain high yield and high purity torasemide variant (I) in the crystalline conversion process. On the contrary, when the experiment was performed using an organic solvent alone, the yield was low.
이하, 본 발명을 다음의 실시예에 의거하여 더욱 상세히 설명하는 바, 이는 하나의 예시로 제시된 것으로, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples, which are presented as an example and the present invention is not limited thereto.
실시예 1
Example 1
토르세미드 변형체(I)의 제조
Preparation of Torsemide Variant (I)
토르세미드 변형체(II) 200g을 아세톤 1,000ml와 물 1,000ml 의 혼합용액에 넣고, 이 혼합물을 환류교반 하였다. 이것을 상온으로 냉각한 후, 상온에서 일야 교반 하였다. 이것을 여과하여 2,000ml의 물로 세척하고, 건조하여 186g의 토르세미드 변형체(I)을 얻었다.200 g of torcide modified substance (II) was put into a mixed solution of 1,000 ml of acetone and 1,000 ml of water, and the mixture was stirred under reflux. After cooling to room temperature, the mixture was stirred at room temperature overnight. This was filtered, washed with 2,000 ml of water and dried to give 186 g of torsemide variant (I).
수율 93.0%
Yield 93.0%
토르세미드 변형체(I)을 확인하기 위하여 적외선 분광기, X-ray로 확인하고, 상기 적외선 분광기를 통해 얻어진 토르세미드 변형체(I)의 적외선 흡수 스펙트럼을 도면 2에 도시하고, X-ray 분말 회절 스펙트럼을 도면 4에 도시하였다.
In order to confirm the torsemide variant (I), it was confirmed by an infrared spectrometer and X-ray, and the infrared absorption spectrum of the torsemid variant (I) obtained through the infrared spectrometer is shown in FIG. 2, and the X-ray powder diffraction The spectrum is shown in FIG.
실시예 2
Example 2
토르세미드 변형체(I)의 제조
Preparation of Torsemide Variant (I)
토르세미드 변형체(II) 200g을 메탄올 1,000ml와 물 1,000ml 의 혼합용액에 넣고, 이 혼합물을 환류교반 하였다. 이것을 상온으로 냉각한 후, 상온에서 일야 교반 하였다. 이것을 여과하여 2,000ml의 물로 세척하고, 건조하여 168g의 토르세미드 변형체(I)을 얻었다. 200 g of torcide modified substance (II) was put into a mixed solution of 1,000 ml of methanol and 1,000 ml of water, and the mixture was stirred under reflux. After cooling to room temperature, the mixture was stirred at room temperature overnight. This was filtered, washed with 2,000 ml of water and dried to give 168 g of torsemide variant (I).
수율 84.0%
Yield 84.0%
이렇게 수득한 시료의 IR, X-ray 스펙트럼은 실시예 1 에서 수득한 토르세미드 변형체(I)의 IR, X-ray 스펙트럼에 상응하였다.
The IR, X-ray spectra of the samples thus obtained corresponded to the IR, X-ray spectra of the torsemide variant (I) obtained in Example 1.
참고예 1
Reference Example 1
토르세미드 변형체(I)의 제조
Preparation of Torsemide Variant (I)
토르세미드 변형체(II) 200g을 아세톤 2,000ml 에 넣고, 이 혼합물을 환류교반 하였다. 이것을 상온으로 냉각한 후, 상온에서 일야 교반 하였다. 이것을 여과하여 2,000ml의 아세톤으로 세척하고, 건조하여 160g의 토르세미드 변형체(I)을 얻었다. 수율 80.0%200 g of torcide modified (II) was put in 2,000 ml of acetone, and the mixture was stirred under reflux. After cooling to room temperature, the mixture was stirred at room temperature overnight. This was filtered, washed with 2,000 ml of acetone, and dried to obtain 160 g of torsemide variant (I). Yield 80.0%
이렇게 수득한 시료의 IR, X-ray 스펙트럼은 실시예 1 에서 수득한 토르세미드 변형체(I)의 IR, X-ray 스펙트럼에 상응하였다.The IR, X-ray spectra of the samples thus obtained corresponded to the IR, X-ray spectra of the torsemide variant (I) obtained in Example 1.
본 발명에 따르면, 촉매량의 토르세미드 변형체(I) 없이 물과 유기용매를 혼합한 혼합용매를 이용하여 반응 부산물 없이 고수율 및 고순도로 목적하는 화합물을 얻을 수 있으며 또한 저렴하고 경제적인 방법을 통하여 공업적인 대량생산에 적용이 가능한 우수한 발명이다.According to the present invention, the target compound can be obtained in high yield and purity without reaction by-products by using a mixed solvent in which water and an organic solvent are mixed without a catalytic amount of torsemide variant (I), and through an inexpensive and economical method. It is an excellent invention that can be applied to industrial mass production.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020040112307A KR100845383B1 (en) | 2004-12-24 | 2004-12-24 | Process for preparing torsemide modification? |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020040112307A KR100845383B1 (en) | 2004-12-24 | 2004-12-24 | Process for preparing torsemide modification? |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20060073865A KR20060073865A (en) | 2006-06-29 |
| KR100845383B1 true KR100845383B1 (en) | 2008-07-09 |
Family
ID=37166735
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020040112307A KR100845383B1 (en) | 2004-12-24 | 2004-12-24 | Process for preparing torsemide modification? |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR100845383B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115417810B (en) * | 2022-09-22 | 2023-10-10 | 南京正科医药股份有限公司 | Refining method of torsemide crystal form I |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20020025217A (en) * | 1999-08-11 | 2002-04-03 | 추후보정 | Torsemide polymorphs |
| KR20040081236A (en) * | 2003-03-14 | 2004-09-21 | 보령제약 주식회사 | Purification method of crystal form i of torasemide |
-
2004
- 2004-12-24 KR KR1020040112307A patent/KR100845383B1/en active IP Right Grant
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20020025217A (en) * | 1999-08-11 | 2002-04-03 | 추후보정 | Torsemide polymorphs |
| KR20040081236A (en) * | 2003-03-14 | 2004-09-21 | 보령제약 주식회사 | Purification method of crystal form i of torasemide |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20060073865A (en) | 2006-06-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7046968B2 (en) | 2- (Substituted Phenyl Hetero) Aromatic Carboxylic Acid FTO Inhibitor, Its Production Method and Its Use | |
| KR20200086385A (en) | Cap-dependent endonuclease inhibitors | |
| DE69523298T2 (en) | AMINO STYLE BAZOLE DERIVATIVES AND MEDICINE | |
| WO2016131431A1 (en) | Solid forms of empagliflozin | |
| AU759291B2 (en) | New crystal modification N of torasemide | |
| KR20060090245A (en) | 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]-methyl piperidine oxalate (donepezil oxalate) and its polymorphs | |
| CN108794412B (en) | Preparation method of 4, 5-diaryl-2H-1, 2, 3-triazole compound | |
| TWI772424B (en) | Crystalline form of free alkali of benzofuran derivative and preparation method thereof | |
| CN113214223B (en) | Preparation method of Voranolan fumarate impurity | |
| KR100845383B1 (en) | Process for preparing torsemide modification? | |
| WO2022000265A1 (en) | Cocrystals of axitinib and glutaric acid, and preparation method therefor | |
| Tague et al. | Diastereoselective Pd‐catalyzed Decarboxylative (4+ 2) Cycloaddition Reactions of 4‐Vinylbenzoxazinanones and 2‐Nitro‐1, 3‐enynes | |
| KR102207333B1 (en) | Novel Production Method for Quadruple Cyclic Compounds | |
| JP2003527425A (en) | New production method of torsemide intermediate | |
| CN110437125A (en) | A kind of preparation method of Tezacaftor intermediate II | |
| CN103910676B (en) | A kind of synthetic method of polysubstituted tetrahydro isoquinoline derivative | |
| JPH11501007A (en) | Lamotrigine production method | |
| CN114773176A (en) | Chlorpheniramine maleate impurity, and preparation method and application thereof | |
| JP2003528083A (en) | Amorphous torasemide transformation | |
| Neumann et al. | Preparation of 5-(cyclohexylmethyl) barbituric acid derivatives by acid-catalyzed reductive cyclohexylmethylation of barbituric acids with p-hydroxy or p-methoxybenzaldehydes | |
| CA3191714A1 (en) | Benzylamine derivative, preparation method therefor and use thereof | |
| JP2022109444A (en) | Method of producing nitrile oxide compound | |
| Ingle et al. | Synthesis, crystal structure and Hirshfeld surface analysis of the hydrated form of N’, N-(1, 4-phenylenebis (methanylylidene) di (iso-nicotinic hydrazide) | |
| JP2707012B2 (en) | Crystal polymorph of N-tert-butyl-1-methyl-3,3-diphenylpropylamine hydrochloride and method for producing the same | |
| CN106279144B (en) | Method for preparing pioglitazone impurity C by one-pot method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E90F | Notification of reason for final refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20130624 Year of fee payment: 6 |
|
| FPAY | Annual fee payment |
Payment date: 20140617 Year of fee payment: 7 |
|
| FPAY | Annual fee payment |
Payment date: 20150626 Year of fee payment: 8 |
|
| FPAY | Annual fee payment |
Payment date: 20160704 Year of fee payment: 9 |
|
| FPAY | Annual fee payment |
Payment date: 20170620 Year of fee payment: 10 |
|
| FPAY | Annual fee payment |
Payment date: 20180625 Year of fee payment: 11 |
|
| FPAY | Annual fee payment |
Payment date: 20190620 Year of fee payment: 12 |