KR101837488B1 - Optically pure benzyl-4-chlorophenyl-c-glucoside derivative - Google Patents
Optically pure benzyl-4-chlorophenyl-c-glucoside derivative Download PDFInfo
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- KR101837488B1 KR101837488B1 KR1020140037632A KR20140037632A KR101837488B1 KR 101837488 B1 KR101837488 B1 KR 101837488B1 KR 1020140037632 A KR1020140037632 A KR 1020140037632A KR 20140037632 A KR20140037632 A KR 20140037632A KR 101837488 B1 KR101837488 B1 KR 101837488B1
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- South Korea
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- rti
- diabetes
- chlorophenyl
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- 238000000034 method Methods 0.000 claims abstract description 36
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- 150000003839 salts Chemical class 0.000 claims abstract description 26
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
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Abstract
본 발명은 약학 기술 분야에 속하며, 보다 구체적으로 하기 화학식 II 및 III에 의해 나타낸 광학적으로 순수한 벤질-4-클로로페닐-C-글루코사이드 유도체 또는 그의 약학적으로 허용 가능한 염, 상기 화합물 및 그의 중간체의 제조 방법, 상기 화합물을 함유하는 약학 제형 및 약학 조성물, 및 당뇨병(인슐린 의존성 당뇨병 및 비-인슐린 의존성 당뇨병 포함) 또는 당뇨병-관련된 질병(인슐린 내성 질병 및 비만증)의 치료 및/또는 예방을 위한 약제의 제조에서 나트륨 글루코스 공동수송체(SGLT) 억제제로서 상기 광학적으로 순수한 벤질-4-클로로페닐-C-글루코사이드 유도체의 용도에 관한 것이다:
화학식 II
화학식 III
(II)
(III)
Description
본 발명은 약학 기술 분야에 속하며, 보다 구체적으로 광학적으로 순수한 벤질-4-클로로페닐-C-글루코사이드 유도체 또는 그의 약학적으로 허용 가능한 염, 상기 화합물 및 그의 중간체의 제조 방법, 상기 화합물을 함유하는 약학 제형 및 약학 조성물, 및 당뇨병(인슐린 의존성 당뇨병 및 비-인슐린 의존성 당뇨병 포함) 또는 당뇨병-관련된 질병(인슐린 내성 질병 및 비만증)의 치료 및/또는 예방을 위한 약제의 제조에서 나트륨 글루코스 공동수송체(SGLT) 억제제로서 상기 광학적으로 순수한 벤질-4-클로로페닐-C-글루코사이드 유도체 또는 그의 약학적으로 허용 가능한 염의 용도에 관한 것이다.The present invention belongs to the field of pharmacy, and more particularly to an optically pure benzyl-4-chlorophenyl-C-glucoside derivative or a pharmaceutically acceptable salt thereof, a process for the preparation of said compound and its intermediates, Formulations and pharmaceutical compositions for the manufacture of medicaments for the treatment and / or prevention of diabetes (including insulin dependent diabetes and non-insulin dependent diabetes) or diabetes-related diseases (insulin resistant disease and obesity), and sodium glucose co- 4-chlorophenyl-C-glucoside derivative or a pharmaceutically acceptable salt thereof as an < RTI ID = 0.0 > pharmaceutically < / RTI >
전세계적으로 대략 100,000,000 명의 사람들이 II형 당뇨병에 걸려 있으며, 상기 당뇨병은 과도한 간 글루코스 생산 및 말초 인슐린 내성에 의해 야기되는 고혈당증을 특징으로 한다. 상기 고혈당증은 당뇨 합병증을 형성하는데 중요한 위험 인자인 것으로 간주되며, 어쩌면 II형 당뇨병의 말기 단계에서 인슐린 분비 장애와 직접 관련되는 것으로 생각된다. 따라서, 인슐린의 정상화가 II형 당뇨병이 있는 환자에게서 혈당을 개선시킬 수 있을 것으로 예상할 수 있다. 현재 공지된 당뇨병 치료제들은 대개 인슐린 분비 촉진제 또는 혈당정상화제, 예를 들어 설포닐유레아, 글리나이드, 티아졸리딘다이온 및 다이메틸 바이구아나이드이고, 이들은 체중을 증가시키기 쉬운 성향, 저혈당증 및 락테이트 산증과 같은 잠재적인 부작용들을 가지며, 따라서 새로운 작용 기전을 갖는 안전하고 유효한 당뇨병 치료 약물의 개발을 촉구할 필요가 있다.Approximately 100,000,000 people worldwide are afflicted with type II diabetes, which is characterized by hyperglycemia caused by excessive hepatic glucose production and peripheral insulin resistance. The hyperglycemia is considered to be an important risk factor for the development of diabetic complications and is likely to be directly related to insulin secretory disturbances in the late stage of type II diabetes. Thus, normalization of insulin may be expected to improve blood glucose in patients with type II diabetes. Currently known diabetes therapeutic agents are usually insulin secretagogues or blood glucose normalizers such as sulfonylureas, glynides, thiazolidinediones and dimethylbiguanides, which tend to increase body weight, hypoglycemia and lactate acidosis And therefore there is a need to urge the development of safe and effective diabetic therapeutic drugs with new mechanisms of action.
신장에서, 글루코스는 신사구체(약 180 g/d)를 통해 자유롭게 여과되지만 근위 곡세뇨관에서 거의 능동적으로 수송되어 재흡수될 수 있다. 다른 것들 중에서도, 2 개의 나트륨-글루코스 수송체, 즉 SGLT-1 및 SGLT-2, 특히 SGLT-2는 글루코스 재흡수에 중요한 영향을 미친다. SGLT-2는 근위 세뇨관의 S1 섹션에서만 오직 특이적으로 발현되는 막관통 단백질이다. 그의 주요 생리학적 기능들 중 하나는 상기 신세뇨관을 통해 흐르는 혈중 글루코스를 흡수하는 것으로, 상기 재흡수의 90%를 차지한다. SGLT-2는 1:1 나트륨-글루코스의 비로 수송한다. 상기 SGLT-2 억제제는 다량의 글루코스가 소변을 통해 배설되도록 상기 신세뇨관에서의 혈당의 흡수를 억제할 수 있다. SGLT-1은 주로 원위 곡세뇨관에서 발현되며, 상기 재흡수의 10%를 차지한다. SGLT-1은 2:1 나트륨-글루코스의 비로 수송한다. 또한, SGLT-1은 장관 및 다른 조직들에서도 발견된다. 이들 수송체는 Na+/ATPase 펌프를 통해 그들의 기능을 발휘하며 글루코스 수송체-2(GLUT2)를 통해 혈액으로 수송한다. 이는, 한편으로 글루코스에 대한 절대적인 재흡수 및 다른 한편으로 단지 신장에서의 발현으로 인해, 가장 잠재적인 약물 표적이 SGLT-2 수송체임을 가리킨다. 가족성 형태의 신장증으로부터의 뇨당에 대한 연구에서, 상기 경로의 가능성이 확인되었다. 상기 가족형의 신장증으로부터의 뇨당은 주로 비-정량적인 뇨당(약 10 내지 120 g/d)으로서 나타나지만, 환자들은 양호한 일반적인 상태를 가지며 건강에 대한 만성적인 부작용은 발견되지 않는다. 이러한 양성 뇨당은 주로 상기 SGLT-2 수송체의 유전자 돌연변이에 의해 야기되며, 이는 SGLT-2에 대한 선택적인 약물학적 억제가 뇨당의 유도를 제외하고 부작용을 생성시키지 않을 것임을 가리킨다. 상기 SGLT-2 억제제에 대한 한 가지 중요한 임상적 장점은 낮은 저혈당증 가능성임이 입증되었다. 그러나, SGLT-1의 억제는 글루코스-갈락토스 흡수불량 증후군을 유발할 것이며, 이는 탈수를 발생시킬 수도 있다. 또한, 상기 SGLT-1 억제제는 탄수화물의 흡수를 지연시키고 개인에게 허용되기에 어려운 위장 증상을 유발할 것임이 또한 입증되었다. 고도로 선택성인 SGLT-2 억제제는 장관 수송에서 상기 글루코스를 흡수하는 SGLT-1의 작용을 차단하지 않을 것이며, 따라서 위장 증상을 유발하기 쉽지 않다. 또한, SGLT-1은 인체의 심근 조직에서도 고도로 발현되며, SGLT-1의 차단이 어쩌면 심장 기능에 있어서 새롭거나 구조적인 질병을 유발할 것이다. 따라서, SGLT-2에 대해 높은 선택성을 갖는 화합물의 개발이 당뇨병 치료 약물 연구에 중대한 의미를 갖는다.In the kidney, glucose is freely filtered through the gonadal sphere (approximately 180 g / d), but can be transported and resorbed almost proactively in the proximal tubule. Among other things, two sodium-glucose transporters, SGLT-1 and SGLT-2, in particular SGLT-2, have a significant effect on glucose reabsorption. SGLT-2 is a transmembrane protein that is specifically expressed only in the S1 section of proximal tubules. One of his main physiological functions is to absorb blood glucose flowing through the renal tubules, accounting for 90% of the reabsorption. SGLT-2 transports at a ratio of 1: 1 sodium-glucose. The SGLT-2 inhibitor may inhibit the absorption of blood glucose in the renal tubule so that a large amount of glucose is excreted through the urine. SGLT-1 is expressed mainly in distal gut tubules, accounting for 10% of the reabsorption. SGLT-1 transports at a ratio of 2: 1 sodium-glucose. SGLT-1 is also found in ministers and other organizations. These transporters exert their function through Na + / ATPase pumps and transport them to the blood via Glucose transporter-2 (GLUT2). This indicates that the most potent drug target is the SGLT-2 transporter, on the one hand due to absolute reabsorption of glucose and on the other hand only in the kidney. In studies of urinary glucose from familial forms of nephropathy, the possibility of this pathway has been confirmed. Although urinary sugars from the familial nephrotic syndrome appear primarily as non-quantitative urinary glucose (about 10 to 120 g / d), patients have a good general condition and no chronic side effects to health are found. Such benign prostatic hyperplasia is mainly caused by genetic mutation of the SGLT-2 transporter, indicating that selective pharmacologic inhibition of SGLT-2 will not produce side effects except induction of urine sugar. One significant clinical benefit of the SGLT-2 inhibitor has been demonstrated to be low hypoglycemia potential. However, inhibition of SGLT-1 will lead to glucose-galactose uptake syndrome, which may also cause dehydration. It has also been demonstrated that the SGLT-1 inhibitor will delay the absorption of carbohydrates and induce gastrointestinal symptoms that are difficult for individuals to tolerate. Highly selective adult SGLT-2 inhibitors will not block the action of SGLT-1 that absorbs the glucose in intestinal transit and are therefore not prone to gastrointestinal symptoms. In addition, SGLT-1 is highly expressed in human myocardial tissue, and blockade of SGLT-1 may induce new or structural disease in cardiac function. Thus, the development of compounds with a high selectivity for SGLT-2 has significant implications for diabetes therapeutic drug studies.
상기 SGLT-2 억제제는 SGLT-2 수송체에 작용하여 신장 글루코스의 재흡수를 억제하여 고혈당을 치료하기 때문에, 당뇨병의 새로운 치료 경로를 제공한다. 상기 경로는 II형 당뇨병의 병태생리학에 직접적으로 작용할 수 없지만, 신장에서 글루코스 배출을 증가시킴에 의한 혈당의 감소는 순 에너지의 결손을 유발하여 체중 손실을 촉진하고 비만 상태를 간접적으로 개선시킬 수 있다. 상기 연구에서 이들 약물은 기존의 혈당 또는 인슐린 감소 약물과 함께 사용되는 경우 낮은 저혈당증의 위험성과 체중 손실의 잠재적인 효과를 갖는 것으로 밝혀졌다. 상기 SGLT-2 억제제는 β-세포의 작용 및 인슐린 내성에 무관하며, 따라서 일반적인 당뇨병을 갖는 환자에게도 유효할 뿐만 아니라 바이구아나이드 및 DPP-4 억제제와 같은 약물 치료에 실패한 경험이 있는 환자에게 보다 양호한 치료 효과를 갖는다. 따라서, 장차 상기 SGLT-2 억제제를 혈당강하 약물, 예를 들어 바이구아나이드 및 DPP-4 억제제와 함께 사용할 수 있다.The inhibitor of SGLT-2 acts on SGLT-2 transporter to inhibit reabsorption of renal glucose to treat hyperglycemia, thus providing a new therapeutic pathway for diabetes. Although this pathway can not act directly on the pathophysiology of type II diabetes, a decrease in blood glucose by increasing glucose excretion in the kidney may induce a net energy deficit, thereby promoting weight loss and indirectly improving obesity status . In these studies, these drugs have been found to have the potential effects of low hypoglycemia and weight loss when used in combination with existing blood glucose or insulin-reducing drugs. The SGLT-2 inhibitor is independent of the action of? -Cells and insulin resistance, and is therefore also effective in patients with general diabetes as well as in patients with experience of failing drug treatment such as beta-guanidine and DPP-4 inhibitors It has a therapeutic effect. Thus, the SGLT-2 inhibitor may be used in combination with a hypoglycemic drug such as a biguanide and a DPP-4 inhibitor in the future.
다른 것들 중에서도, WO 0127128 및 US 2005209166과 같은 특허 문헌들은 SGLT-2 억제제로서 일련의 화합물들을 개시한다.Among other things, patent documents such as WO 0127128 and US 2005209166 disclose a series of compounds as SGLT-2 inhibitors.
본 출원인은 또한 PCT 출원 WO2013/000275A1에서 SGLT-2 억제제로서 일련의 C-글루코사이드 유도체들을 개시하였으며, 여기에서 화합물 4는 SGLT-2에 대한 양호한 억제 효과 및 양호한 선택성을 가졌고 하기의 구조를 가졌다:Applicants also disclosed a series of C-glucoside derivatives as SGLT-2 inhibitors in PCT application WO2013 / 000275A1, wherein compound 4 had a good inhibitory effect on SGLT-2 and good selectivity and had the following structure:
상기 화합물 4는 입체이성체들의 혼합물이며 비대칭 중심을 갖는다. 따라서, 다수의 광학 이성체들이 존재한다. 종래 기술에서 다수의 키랄 혼합물 약물들이, 쉽게 발생되고 알려지지 않은 독성 및 부작용, 감소된 약물 유효성, 및 품질 조절의 어려움과 같은 잠재적인 문제들을 가짐을 고려한다면, 상기 키랄 혼합물 약물의 연구개발에 대한 위험성은 현저하게 증가할 것이다. 상기 키랄 혼합물과 비교 시, 광학적으로 순수한 입체이성체는 보다 안전하고, 독성 및 부작용의 보다 낮은 발생 확률, 보다 양호한 안정성, 및 품질 조절의 용이성과 같은 장점들을 가지며 상기 광학적으로 순수한 입체이성체는 또한 약역학, 약동학 및 독성학에 있어서 잠재적인 개선의 특징들을 갖기 때문에, SGLT-2에 대한 높은 선택성, 빠른 개시, 높은 유효성, 양호한 안전성 및 양호한 안정성을 갖는 단일 입체이성체의 개발은 후속의 약제 연구개발 및 시판 약물의 생산 시 품질 조절에 있어서 중요한 의미를 갖는다.The compound 4 is a mixture of stereoisomers and has an asymmetric center. Thus, there are a number of optical isomers. Considering that many chiral compound drugs in the prior art have potential problems such as easily generated and unknown toxicity and side effects, reduced drug effectiveness, and difficulty in controlling quality, the risk for research and development of such chiral compound drugs Will increase significantly. Compared to the above chiral mixtures, the optically pure stereoisomers have advantages such as safer safety, lower probability of occurrence of toxicity and side effects, better stability, and ease of quality control, , Pharmacokinetics and toxicology, the development of single stereoisomers with high selectivity for SGLT-2, rapid onset, high efficacy, good safety, and good stability has led to subsequent drug research and development, Which is important in the quality control of production.
본 발명은 광학적으로 순수한 벤질-4-클로로페닐-C-글루코사이드 유도체 또는 그의 약학적으로 허용 가능한 염, 상기 화합물 및 그의 중간체의 제조 방법, 상기 화합물을 함유하는 약학 제형 및 약학 조성물, 및 당뇨병(인슐린 의존성 당뇨병 및 비-인슐린 의존성 당뇨병 포함) 또는 당뇨병-관련된 질병(인슐린 내성 질병 및 비만증)의 치료 및/또는 예방을 위한 약제의 제조에서 나트륨 글루코스 공동수송체(SGLT) 억제제로서 상기 광학적으로 순수한 벤질-4-클로로페닐-C-글루코사이드 유도체 또는 그의 약학적으로 허용 가능한 염의 용도를 제공하고자 한다.The present invention relates to optically pure benzyl-4-chlorophenyl-C-glucoside derivatives or a pharmaceutically acceptable salt thereof, a process for the preparation of said compound and its intermediates, pharmaceutical formulations and pharmaceutical compositions containing said compound, (SGLT) inhibitor in the manufacture of a medicament for the treatment and / or prophylaxis of diabetes-related diseases (including insulin-dependent diseases and obesity), such as diabetes-related diabetes and non-insulin dependent diabetes mellitus, 4-chlorophenyl-C-glucoside derivative or a pharmaceutically acceptable salt thereof.
발명의 요약SUMMARY OF THE INVENTION
본 발명은 하기의 기술적 해법들을 제공한다:The present invention provides the following technical solutions:
1. 하기 화학식 I에 의해 나타낸 화합물의 입체이성체성 화합물 또는 그의 약학적으로 허용 가능한 염, 여기에서 상기 입체이성체성 화합물은 하기 화학식 II, III, IV 및 V 중에서 선택된다:1. A stereostructured compound of a compound represented by the formula (I): wherein the stereostructural compound is selected from the following formulas II, III, IV and V:
화학식 IFormula I
화학식 II(II)
(상기 화합물은 (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올이다)(The above compound is obtained by reacting (2S, 3R, 4R, 5S, 6R) -2- (3- (4- ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)
화학식 III(III)
(상기 화합물은 (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올이다)(This compound was synthesized in the same manner as (1S, 3R, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)
화학식 IVFormula IV
(상기 화합물은 (2R,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올이다)(This compound was synthesized in the same manner as (1R, 3S, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)
화학식 VFormula V
(상기 화합물은 (2R,3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올이다)(The compound was prepared from (2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3R, 5S) -bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)
2. 기술적 해법 1에서 정의된 바와 같은 화학식 II에 의해 나타낸 화합물의 제조 방법으로, 상기 방법은 하기의 단계들을 포함한다:2. A process for the preparation of a compound represented by formula (II) as defined in technical solution 1, said process comprising the steps of:
상기에서, In the above,
X는 플루오로, 클로로, 브로모 또는 요오도를 나타내고,X represents fluoro, chloro, bromo or iodo,
G는 트라이메틸실릴, 트라이에틸실릴, 벤질, 파라-메톡시벤질, 파라-나이트로벤질, 피발로일, 알릴, 메톡시메틸, 벤질옥시메틸, 트라이메틸실릴에틸 등 중에서 선택된 하이드록시 보호 그룹, 바람직하게는 트라이메틸실릴이다.G is a hydroxy protecting group selected from trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, Preferably trimethylsilyl.
상기 단계는The step
화학식 b의 화합물(즉 (1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일 메탄설포네이트)을 유기 용매(N-메틸피롤리돈, N,N-다이메틸폼아미드, 테트라하이드로퓨란, 다이옥산 및 아세토나이트릴 중에서 선택될 수 있다)에 용해시키고; 상기 생성 혼합물에 화학식 a의 화합물을 가하고; 이어서 상기 생성 혼합물을 0 ℃ 내지 70 ℃의 온도에서 반응시켜 화학식 c의 화합물을 생성시키고;(1R, 3r, 5S) -bicyclo [3.1.0] hexan-3-ylmethanesulfonate) in an organic solvent (N-methylpyrrolidone, N, N- dimethylformamide, ≪ / RTI > tetrahydrofuran, dioxane and acetonitrile); Adding the compound of formula a to the resulting mixture; The resulting mixture is then reacted at a temperature of from 0 캜 to 70 캜 to yield a compound of formula c;
상기 화학식 c의 화합물을
상기 화학식 d-2의 화합물을 -78 ℃ 내지 30 ℃의 온도에서 반응시켜 화학식 e의 화합물을 생성시키고;Reacting the compound of formula d-2 at a temperature between -78 [deg.] C and 30 [deg.] C to yield a compound of formula e;
상기 화학식 e의 화합물을 정제시켜 화학식 II에 의해 나타낸 화합물을 생성시킨다.The compound of formula e is purified to produce the compound represented by formula II.
상기 언급한 바와 같이, 화학식 e의 화합물을, 예를 들어 하기의 방법에 따라 정제하여 화학식 II에 의해 나타낸 화합물을 생성시킬 수 있다:As mentioned above, the compound of formula e can be purified, for example, according to the following method to produce the compound represented by formula II:
상기 화학식 e의 화합물에 하이드록시 보호 반응을 가하여 화학식 f의 화합물을 생성시키고;Subjecting the compound of formula e to a hydroxy protecting reaction to produce a compound of formula f;
상기 화학식 f의 화합물에 탈보호 반응을 가하여 화학식 II에 의해 나타낸 화합물을 생성시킨다:The compound of formula (f) is deprotected to give the compound represented by formula (II): < EMI ID =
화학식 fFormula f
상기 식에서,In this formula,
G'는 아세틸, 트라이메틸실릴, 트라이에틸실릴, 벤질, 파라-메톡시벤질, 파라-나이트로벤질, 피발로일, 알릴, 메톡시메틸, 벤질옥시메틸, 트라이메틸실릴에틸, 프로피오닐, 아이소부티릴, 벤조일 등으로부터 선택된 하이드록시 보호 그룹, 바람직하게는 아세틸, 피발로일, 프로피오닐, 아이소부티릴 또는 벤조일을 나타낸다.G 'is selected from the group consisting of acetyl, trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, Butyryl, benzoyl and the like, preferably acetyl, pivaloyl, propionyl, isobutyryl or benzoyl.
상기 화학식 II에 의해 나타낸 화합물을 상기 반응식에 예시된 바와 같은 방법에 따라 및/또는 당해 분야의 숙련가에게 널리 공지된 다른 기술에 따라 제조할 수 있으나, 상기 방법들이 독점적인 것은 아님을 알아야 한다.The compounds represented by formula II above may be prepared according to methods as illustrated in the above schemes and / or according to other techniques well known to those skilled in the art, but it should be noted that these methods are not exclusive.
3. 기술적 해법 1에서 정의된 바와 같은 화학식 III에 의해 나타낸 화합물의 제조 방법으로, 상기 방법은 하기의 단계들을 포함한다:3. A process for the preparation of a compound represented by formula (III) as defined in technical solution 1, said process comprising the steps of:
상기에서, In the above,
X는 플루오로, 클로로, 브로모 또는 요오도를 나타내고,X represents fluoro, chloro, bromo or iodo,
G는 트라이메틸실릴, 트라이에틸실릴, 벤질, 파라-메톡시벤질, 파라-나이트로벤질, 피발로일, 알릴, 메톡시메틸, 벤질옥시메틸, 트라이메틸실릴에틸 등 중에서 선택된 하이드록시 보호 그룹, 바람직하게는 트라이메틸실릴을 나타낸다.G is a hydroxy protecting group selected from trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, Preferably trimethylsilyl.
상기 단계는The step
화학식 a의 화합물을 유기 용매(톨루엔, N,N-다이메틸폼아미드, 테트라하이드로퓨란, 다이옥산 및 아세토나이트릴 중에서 선택될 수 있고, 바람직하게는 톨루엔이다)에 용해시키고; 상기 생성 혼합물에 화학식 b의 화합물을 가하고; 이어서 상기 생성 혼합물을 0 ℃ 내지 70 ℃의 온도에서 반응시켜 화학식 c'의 화합물을 생성시키고;Dissolving the compound of formula a in an organic solvent (toluene, N, N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile, preferably toluene); Adding the compound of formula b to the product mixture; The resulting mixture is then reacted at a temperature of 0 ° C to 70 ° C to yield a compound of formula c ';
상기 화학식 c'의 화합물을
상기 화학식 d'-2의 화합물을 -78 ℃ 내지 30 ℃의 온도에서 반응시켜 화학식 e'의 화합물을 생성시키고;Reacting said compound of formula (D-2) at a temperature of from -78 [deg.] C to 30 [deg.] C to give a compound of formula e ';
상기 화학식 e'의 화합물을 정제시켜 화학식 III에 의해 나타낸 화합물을 생성시킨다.The compound of formula e ' is purified to produce the compound represented by formula III.
상기 언급한 바와 같이, 화학식 e'의 화합물을, 예를 들어 하기의 방법에 따라 정제하여 화학식 III에 의해 나타낸 화합물을 생성시킬 수 있다:As mentioned above, the compound of formula e 'can be purified, for example, according to the following method to produce the compound represented by formula III:
상기 화학식 e'의 화합물에 하이드록시 보호 반응을 가하여 화학식 f'의 화합물을 생성시키고;Subjecting the compound of formula e 'to a hydroxy protecting reaction to produce a compound of formula f';
상기 화학식 f'의 화합물에 탈보호 반응을 가하여 화학식 III에 의해 나타낸 화합물을 생성시킨다:The compound of formula f 'is deprotected to give the compound represented by formula III:
화학식 f'The formula f '
상기 식에서,In this formula,
G'는 아세틸, 트라이메틸실릴, 트라이에틸실릴, 벤질, 파라-메톡시벤질, 파라-나이트로벤질, 피발로일, 알릴, 메톡시메틸, 벤질옥시메틸, 트라이메틸실릴에틸, 프로피오닐, 아이소부티릴, 벤조일 등으로부터 선택된 하이드록시 보호 그룹, 바람직하게는 아세틸, 피발로일, 프로피오닐, 아이소부티릴 또는 벤조일을 나타낸다.G 'is selected from the group consisting of acetyl, trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, Butyryl, benzoyl and the like, preferably acetyl, pivaloyl, propionyl, isobutyryl or benzoyl.
상기 화학식 III에 의해 나타낸 화합물을 상기 반응식에 예시된 바와 같은 방법에 따라 및/또는 당해 분야의 숙련가에게 널리 공지된 다른 기술에 따라 제조할 수 있으나, 상기 방법들이 독점적인 것은 아님을 알아야 한다.The compounds represented by formula III above may be prepared according to methods as illustrated in the above schemes and / or according to other techniques well known to those skilled in the art, but it should be noted that these methods are not exclusive.
4. 화학식 II에 의해 나타낸 화합물에 대한 중간체로, 여기에서 상기 중간체는 하기와 같다:4. An intermediate for a compound represented by formula II, wherein said intermediate is:
5. 화학식 II에 의해 나타낸 화합물에 대한 중간체로, 여기에서 상기 중간체는 하기와 같다:5. An intermediate for a compound represented by formula II, wherein said intermediate is:
상기 식에서, X는 브로모 또는 요오도를 나타낸다.In the above formula, X represents bromo or iodo.
6. 화학식 III에 의해 나타낸 화합물에 대한 중간체로, 여기에서 상기 중간체는 하기와 같다:6. An intermediate for a compound represented by formula III, wherein said intermediate is:
7. 화학식 III에 의해 나타낸 화합물에 대한 중간체로, 여기에서 상기 중간체는 하기와 같다:7. An intermediate for a compound represented by formula III, wherein said intermediate is:
상기 식에서, X는 브로모 또는 요오도를 나타낸다.In the above formula, X represents bromo or iodo.
본 발명에 사용된 바와 같이, 상기 "약학적으로 허용 가능한 염"은 알칼리 금속염, 예를 들어 Na 염, K 염, Li 염 등; 알칼리 토금속 염, 예를 들어, Ca 염, Mg 염 등; 다른 금속 염, 예를 들어 Al 염, Fe 염, Zn 염, Cu 염, Ni 염, Co 염 등; 무기 염기염, 예를 들어 암모늄 염; 유기 염기염, 예를 들어 3급-옥틸아민 염, 다이벤질아민 염, 모폴린 염, 글루코스아민 염, 페닐 글리신 알킬 에스터 염, 에틸렌 다이아민 염, N-메틸글루코스아민 염, 구아니딘 염, 다이에틸아민 염, 트라이에틸아민 염, 다이사이클로헥실 아민 염, N,N'-다이벤질에틸렌 다이아민 염, 클로로프로카인 염, 프로카인 염, 다이에탄올 아민 염, N-벤질-페닐에틸 아민 염, 피페라진 염, 테트라메틸 아민 염, 트리스(하이드록시메틸)아미노메탄 염 등; 할로겐산 염, 예를 들어 불화수소산 염, 하이드로클로라이드, 하이드로브로마이드, 하이드로요오데이트 등; 무기산 염, 예를 들어 나이트레이트, 퍼클로레이트, 설페이트, 포스페이트 등; 저급 알칸설포네이트, 예를 들어 메실레이트, 트라이플루오로메실레이트, 에탄설포네이트 등; 아릴설포네이트, 예를 들어 벤젠설포네이트, 파라-벤젠설포네이트 등; 유기산 염, 예를 들어 아세테이트, 말레이트, 퓨마레이트, 숙시네이트, 시트레이트, 타르트레이트, 옥살레이트, 말리에이트 등; 아미노산 염, 예를 들어 글리신 염, 트라이메틸 글리신 염, 아르기닌 염, 오르니틴 염, 글루타메이트 염, 아스파테이트 염 등을 포함한다.As used herein, the "pharmaceutically acceptable salts" are alkali metal salts such as Na salts, K salts, Li salts and the like; Alkaline earth metal salts such as Ca salts, Mg salts and the like; Other metal salts such as Al salts, Fe salts, Zn salts, Cu salts, Ni salts, Co salts and the like; Inorganic base salts such as ammonium salts; Organic base salts such as tertiary-octylamine salts, dibenzylamine salts, morpholine salts, glucamineamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethyl Amine salts, triethylamine salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenylethylamine salts, Tetramethylammonium salts, tris (hydroxymethyl) aminomethane salts and the like; Halides, such as hydrofluoride, hydrochloride, hydrobromide, hydroiodate and the like; Inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate and the like; Lower alkanesulfonates such as mesylate, trifluoromesylate, ethanesulfonate and the like; Aryl sulfonates such as benzene sulfonate, para-benzene sulfonate and the like; Organic acid salts such as acetate, maleate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc .; Amino acid salts such as glycine salts, trimethylglycine salts, arginine salts, ornithine salts, glutamate salts, aspartate salts and the like.
본 발명은 또한 약학 조성물을 포함하며, 상기 조성물은 화학식 II에 의해 나타낸 화합물 및/또는 화학식 III에 의해 나타낸 화합물 또는 그의 약학적으로 허용 가능한 염, 및 하나 이상의 약학적으로 허용 가능한 담체 및/또는 희석제를 함유하고, 임의의 약학적으로 허용 가능한 투여형으로 제조될 수 있다. 상기 약학 조성물을 경구, 비경구, 직장 또는 폐로 상기 조성물이 필요한 환자에게 투여할 수 있다. 경구 투여의 경우, 상기 조성물을 통상적인 고체 제형, 예를 들어 정제, 캡슐, 환제, 과립 등으로; 또는 경구 액체 제형, 예를 들어 경구 용액, 경구 현탁액, 시럽 등으로 제조할 수 있다. 경구 제형으로 제조 시, 적합한 충전제, 결합제, 붕해제, 윤활제 등을 첨가할 수 있다. 비경구 투여의 경우, 상기 조성물을 주사성 제제, 예를 들어 주사액, 멸균 주사 분말 및 농축된 주사액으로 제조할 수 있다. 주사성 제제의 제조를 위해서, 약물의 성질에 따라 첨가제를 임의로 첨가할 수 있다. 직장 투여의 경우, 상기 조성물을 좌약 등으로 제조할 수 있다. 폐 투여의 경우, 상기 조성물을 흡입제, 분무제 등으로 제조할 수 있다. 상기 제형의 단위당 생리학적으로 유효한 양, 예를 들어 0.005g-10g, 예를 들어 0.005g, 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 10 g 등의 화학식 II에 의해 나타낸 화합물 및/또는 화학식 III에 의해 나타낸 화합물 또는 그의 약학적으로 허용 가능한 염을 함유한다.The invention also encompasses a pharmaceutical composition comprising a compound represented by formula (II) and / or a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or diluents , And may be prepared in any pharmaceutically acceptable dosage form. The pharmaceutical composition may be administered orally, parenterally, rectally, or pulmonally to a patient in need of such a composition. For oral administration, the compositions may be presented in conventional solid dosage forms, such as tablets, capsules, pills, granules, and the like; Or oral liquid formulations, for example, oral solutions, oral suspensions, syrups, and the like. In preparing the oral dosage form, suitable fillers, binders, disintegrants, lubricants, and the like may be added. In the case of parenteral administration, the composition may be formulated into a injectable preparation, for example, as an injection, as a sterile injectable powder, and as a concentrated injection. For the preparation of injectable preparations, additives may optionally be added depending on the nature of the drug. For rectal administration, the composition may be prepared as a suppository or the like. For pulmonary administration, the composition may be formulated as an inhalant, a spray, or the like. A physiologically effective amount per unit of the formulation, for example, 0.005g-10g, such as 0.005g, 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g And / or a compound represented by formula (III), such as a compound represented by formula (III), such as, for example, Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salts.
본 발명은 또한 화학식 II에 의해 나타낸 화합물 및/또는 화학식 III에 의해 나타낸 화합물 또는 그의 약학적으로 허용 가능한 염, 및 다른 약학적으로 활성인 성분(들)을 함유하는 약학 조합을 포함한다. 상기 다른 약학적으로 활성인 성분은 하나 이상의 혈당강하제일 수 있다. 상기 혈당강하제는 시타글립틴 포스페이트, 빌다글립틴, 삭사글립틴, 알로글립틴 벤조에이트, 리나글립틴, 테넬리글립틴, 제미글립틴, 메트포르민, 펜포르민, 엑세나타이드, 리라글루티드 등 중에서 선택될 수 있다.The present invention also encompasses a pharmaceutical combination comprising a compound represented by formula (II) and / or a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, and another pharmaceutically active ingredient (s). The other pharmaceutically active ingredient may be one or more hypoglycemic agents. The hypoglycemic agent may be selected from the group consisting of citagliptine phosphate, valdagliptin, saxagliptin, allogliptin benzoate, linagliptin, teneligliptin, gemigliptin, metformin, penformin, exenatide, ≪ / RTI >
본 발명은 또한 당뇨병 또는 당뇨병 관련된 질병의 치료 및/또는 예방을 위한 약제의 제조에서 화학식 II에 의해 나타낸 화합물 및/또는 화학식 III에 의해 나타낸 화합물 또는 그의 약학적으로 허용 가능한 염의 용도를 포함한다. 상기 당뇨병은 인슐린 의존성 당뇨병(I형) 및 비-인슐린 의존성 당뇨병(II형)을 포함한다. 상기 당뇨병 관련된 질병은 인슐린 내성 질병, 비만증 등을 포함한다.The present invention also encompasses the use of a compound represented by formula (II) and / or a compound represented by formula (III) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of diabetes or a diabetes related disease. The diabetes includes insulin-dependent diabetes mellitus (type I) and non-insulin dependent diabetes mellitus (type II). The diabetes-related diseases include insulin-resistant diseases, obesity, and the like.
본 발명은 또한 당뇨병(인슐린 의존성 당뇨병 및 비-인슐린 의존성 당뇨병 포함) 또는 당뇨병 관련된 질병(인슐린 내성 질병 및 비만증 포함)의 치료 및/또는 예방이 필요한 포유동물(인간 포함)에 있어서 상기 질병의 치료 및/또는 예방 방법을 포함하며, 상기 방법은 상기와 같은 포유동물에게 치료 유효량의 화학식 II에 의해 나타낸 화합물 및/또는 화학식 III에 의해 나타낸 화합물 또는 그의 약학적으로 허용 가능한 염을 투여함을 포함한다.The present invention also relates to the use of the compounds of formula I in the treatment and / or prophylaxis of such diseases in mammals (including humans) which require the treatment and / or prevention of diabetes (including insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus) or diabetes related diseases (including insulin resistant diseases and obesity) Comprising administering to such mammal a therapeutically effective amount of a compound represented by formula (II) and / or a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.
본 발명의 화합물은 하기의 특징들을 갖는다:The compounds of the present invention have the following characteristics:
(1) 본 발명의 화합물은 SGLT-2에 대한 높은 선택성을 가지며, 당뇨병 또는 당뇨병 관련된 질병의 치료 및/또는 예방이 필요한 포유동물(인간 포함)에 있어서 상기 치료 및/또는 예방에 안전하게 사용될 수 있다.(1) The compounds of the present invention have a high selectivity for SGLT-2 and can be safely used for the above treatment and / or prophylaxis in mammals (including humans) in need of treatment and / or prevention of diabetes or diabetes related diseases .
(2) 본 발명의 화합물은 SGLT-2에 대한 매우-유효한 억제 및 현저한 혈당강하 활성, 빠른 개시, 낮은 독성 및 낮은 부작용, 및 높은 안전성을 갖는다.(2) The compounds of the present invention have very-effective inhibition and significant hypoglycemic activity, rapid onset, low toxicity and low side effects, and high safety for SGLT-2.
(3) 본 발명의 화합물은 양호한 물리-화학적 성질, 높은 순도, 양호한 안정성 및 쉽게 조절 가능한 품질을 가지며, 산업적으로 대규모로 제조되기 쉽다.(3) The compounds of the present invention have good physical-chemical properties, high purity, good stability and easily adjustable quality, and are industrially large-scale productions.
(1) 본 발명의 화합물은 SGLT-2에 대한 높은 선택성을 가지며, 당뇨병 또는 당뇨병 관련된 질병의 치료 및/또는 예방이 필요한 포유동물(인간 포함)에 있어서 상기 치료 및/또는 예방에 안전하게 사용될 수 있다.(1) The compounds of the present invention have a high selectivity for SGLT-2 and can be safely used for the above treatment and / or prophylaxis in mammals (including humans) in need of treatment and / or prevention of diabetes or diabetes related diseases .
(2) 본 발명의 화합물은 SGLT-2에 대한 매우-유효한 억제 및 현저한 혈당강하 활성, 빠른 개시, 낮은 독성 및 낮은 부작용, 및 높은 안전성을 갖는다.(2) The compounds of the present invention have very-effective inhibition and significant hypoglycemic activity, rapid onset, low toxicity and low side effects, and high safety for SGLT-2.
(3) 본 발명의 화합물은 양호한 물리-화학적 성질, 높은 순도, 양호한 안정성 및 쉽게 조절 가능한 품질을 가지며, 산업적으로 대규모로 제조되기 쉽다.(3) The compounds of the present invention have good physical-chemical properties, high purity, good stability and easily adjustable quality, and are industrially large-scale productions.
편의성을 위해서, 본 명세에 사용된 널리 공지된 약어들을 포함한다:For convenience, well-known abbreviations used in this specification are included:
Me: 메틸;Me: methyl;
Et: 에틸;Et: ethyl;
Ms: 메틸설포닐;Ms: methylsulfonyl;
Ac: 아세틸;Ac: acetyl;
TBS: 3급-부틸다이메틸실릴;TBS: tert-butyldimethylsilyl;
THF: 테트라하이드로퓨란;THF: tetrahydrofuran;
DMAP: 4-다이메틸아미노피리딘;DMAP: 4-dimethylaminopyridine;
DIPEA: N,N-다이아이소프로필에틸아민;DIPEA: N, N-diisopropylethylamine;
n-BuLi: n-부틸 리튬;n-BuLi: n-butyllithium;
TMS: 트라이메틸실릴.TMS: trimethylsilyl.
본 발명에서, 실온은 10 ℃ 내지 30 ℃의 온도를 의미한다.In the present invention, room temperature refers to a temperature of from 10 캜 to 30 캜.
이후부터, 본 발명 화합물들의 이로운 효과를 약물학적 활성에 대한 분석으로 예시할 것이다. 그러나, 상기 본 발명의 이로운 효과가 하기에 예시되는 효과들로 제한되지 않음은 물론이다.Hereinafter, the beneficial effects of the compounds of the present invention will be illustrated by analysis of pharmacological activity. However, it goes without saying that the beneficial effects of the present invention are not limited to the effects illustrated below.
분석 1: 본 발명 화합물들의 약물학적 활성에 대한 시험관 내 분석Analysis 1: In vitro analysis of the pharmacological activity of the compounds of the present invention
분석 샘플:Analysis sample:
본 발명에서 앞서 정의되고, 실험실-제조된 바와 같은 화학식 II, III, IV 및 V에 의해 나타낸 화합물들, 그들의 화학명 및 제조 방법들을 하기의 제조예에 개시한다.Compounds represented by formulas (II), (III), (IV) and (V) as defined above in the present invention and as lab-produced, their chemical names and methods of preparation are disclosed in the following preparations.
비교 화합물 1: 실험실-제조된(PCT 출원 WO2013/000275A1을 참조하여), PCT 출원 WO2013/000275A1에 개시된 바와 같은 화합물 4, 그의 구조는 하기와 같다:Comparative compound 1: Laboratory-prepared (with reference to PCT application WO2013 / 000275A1), compound 4 as disclosed in PCT application WO2013 / 000275A1, the structure of which is as follows:
화합물 4, 즉 화학식 I에 의해 나타낸 화합물.Compound 4, i.e. a compound represented by formula I.
하기의 분석에 사용된 약어(들)는 하기의 의미를 갖는다:The abbreviation (s) used in the following analysis has the following meanings:
NMG N-메틸-글루코스아민NMG N-methyl-glucoseamine
KRH 크렙스-링거-헨셀라이트(Krebs-Ringer-Henseleit)KRH Krebs-Ringer-Henseleit
본 발명 화합물들의 약물학적 활성에 대한 시험관 내 분석에서, 인간 SGLT-2 및 SGLT-1 서열을 중국 햄스터 난소 세포에 형질감염시켜 안정하게 발현시켰다. [14C]-표지된 R-메틸-D-글루코피라노사이드(AMG)의 세포 내로의 나트륨 의존성 흡착의 억제를 측정함으로써, 절반-억제 농도 IC50를 측정하였다.In in vitro analysis of the pharmacological activity of the compounds of the present invention, human SGLT-2 and SGLT-1 sequences were stably transfected into Chinese hamster ovary cells. The half-inhibitory concentration IC 50 was determined by measuring the inhibition of sodium-dependent adsorption of [ 14 C] -labeled R-methyl-D-glucopyranoside (AMG) into cells.
완충제 A (KRH-Na+): 120 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl2, 2.2 mM CaCl2, 10 mM HEPES (1 mM 트리스에 의해 pH 7.4). Buffer A (KRH-Na +): 120 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl 2, 2.2 mM CaCl 2, 10 mM HEPES (1 pH 7.4 by tris mM).
완충제 A- (KRH-NMG): 120 mM NMG, 4.7 mM KCl, 1.2 mM MgCl2, 2.2 mM CaCl2, 10 mM HEPES (1 mM 트리스에 의해 pH 7.4). Buffer A- (KRH-NMG): 120 mM NMG, 4.7 mM KCl, 1.2 mM MgCl 2, 2.2 mM CaCl 2, 10 mM HEPES (1 pH 7.4 by tris mM).
완충제 D: 120 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl2, 2.2 mM CaCl2, 10 mM HEPES, 0.5 mM (1 mM 트리스에 의해 pH 7.4).Buffer D: 120 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl 2, 2.2 mM CaCl 2, 10 mM HEPES, 0.5 mM (1 pH 7.4 by tris mM).
분석 방법: 인간 SGLT-2 및 SGLT-1 서열을 CHO 세포에서 안정하게 발현시켰다. 상기 세포 배양을 96-웰 플레이트에서 12 시간 동안 수행하였다. 상기 플레이트를 KRH-Na+(완충제 A) 또는 KRH-NMG(완충제 A-) 완충 용액으로 3 회, 200 ㎕/웰로 세척하였다. 이어서 상기 플레이트에 완충제 A 또는 완충제 A- 플러스 [14C]-AMG(10 μCi/㎖), 100 ㎕/웰을 함유하는 완충 용액을 가하였다. 상기 세포 배양을 37 ℃에서 1 시간 동안 수행하였다. 이어서, 100 ㎕의 얼음 예냉시킨 완충 용액(완충제 D)을 가하여 상기 분석을 종결시켰다. 상기 플레이트를 5 회 세척하였다. 이어서 얼음 예냉시킨 용해 완충 용액(100 mM NaOH 용액, 20 ㎕/웰)을 가하고, 600 rpm에서 원심분리를 5 분간 수행하였다. 이어서 마이크로신트(Microscint) 40 용액(80 ㎕/웰)을 가하고, 600 rpm에서 원심분리를 5 분간 수행하였다. 최종적으로, [14C]-AMG의 방사성을 섬광 카운팅 방법에 따라 마이크로베타 트릴룩스(MicroBeta Trilux)(퍼킨엘머 캄파니 리미티드(PerkinElmer Co. Ltd.)로부터 구입함)로 검출하고, 절반-억제 농도 IC50를 계산하였다.Assay: Human SGLT-2 and SGLT-1 sequences were stably expressed in CHO cells. The cell culture was performed in a 96-well plate for 12 hours. The plate was washed three times with KRH-Na + (Buffer A) or KRH-NMG (Buffer A-) buffer, 200 μl / well. Buffer A or Buffer A-plus [ 14 C] -AMG (10 μCi / ml), buffer solution containing 100 μl / well was then added to the plate. The cell culture was performed at 37 캜 for 1 hour. The assay was then terminated by adding 100 [mu] l ice-cold buffer (Buffer D). The plate was washed five times. Followed by ice-cold lysis buffer (100 mM NaOH solution, 20 [mu] l / well) and centrifugation at 600 rpm for 5 minutes. Subsequently, a solution of Microscint 40 (80 [mu] l / well) was added, and centrifugation was performed at 600 rpm for 5 minutes. Finally, the radioactivity of [< 14 > C] -AMG was detected with MicroBeta Trilux (purchased from PerkinElmer Co. Ltd.) according to the flash counting method and the half- IC 50 was calculated.
분석 결과 및 결론:Results and Conclusion:
상기 표 1로부터 본 발명에 따른 화학식 II에 의해 나타내는 화합물은 비교 화합물 1보다 양호한 SGLT-2에 대한 억제 효과뿐만 아니라 양호한 선택성을 가지며 현저한 이점을 나타냄을 알았다.From the above Table 1, it was found that the compound represented by the formula (II) according to the present invention has a remarkable advantage with good selectivity as well as an inhibitory effect on SGLT-2 better than the comparative compound 1.
분석 2: 본 발명 화합물들에 대한 래트 생체 내 약동학 분석Analysis 2: In vivo pharmacokinetic analysis of the compounds of the invention in vivo
분석 동물: 6 내지 8 주된 수컷 SD 래트(바이탈 리버 레보라토리즈(Vital River Laboratories)로부터 구입), 화합물당 3 마리 래트, 중량 200 내지 240 g.Anal animal: 6-8 week old male SD rats (purchased from Vital River Laboratories), 3 rats per compound, weight 200-240 g.
분석 샘플:Analysis sample:
본 발명에서 앞서 정의되고, 실험실-제조된 바와 같은 화학식 II에 의해 나타낸 화합물, 그의 화학명 및 제조 방법을 하기의 실시예 1에 개시한다.The compounds, as previously defined herein and as lab-produced, represented by formula II, their chemical names and methods of preparation are set forth in Example 1 below.
비교 화합물 1: 실험실-제조된(PCT 출원 WO2013/000275A1을 참조하여), PCT 출원 WO2013/000275A1에 개시된 바와 같은 화합물 4, 그의 구조는 하기와 같다:Comparative compound 1: Laboratory-prepared (with reference to PCT application WO2013 / 000275A1), compound 4 as disclosed in PCT application WO2013 / 000275A1, the structure of which is as follows:
화합물 4, 즉 화학식 I에 의해 나타낸 화합물.Compound 4, i.e. a compound represented by formula I.
비교 화합물 2: 실험실-제조된(PCT 출원 WO2013/000275A1을 참조하여), PCT 출원 WO2013/000275A1에 개시된 바와 같은 화합물 22, 그의 구조는 하기와 같다:COMPARATIVE COMPOUND 2: LABORATORY - COMPOUND 22 (as described in PCT Application WO2013 / 000275A1), PCT Application WO2013 / 000275A1, the structure of which is as follows:
화합물 22.Compound 22.
용매: 0.5% MC(메틸 셀룰로스) 용액 + 0.1% SDS(나트륨 도데실 설페이트).Solvent: 0.5% MC (methylcellulose) solution + 0.1% SDS (sodium dodecyl sulfate).
분석 방법:Analysis method:
위내 투여(PO): 표 2 참조Intragastric (PO): See Table 2
채혈: 각각 200 ㎕의 전혈을 0.17hr, 0.5hr, 1hr, 2hr, 4hr, 6hr, 8hr, 24hr, 30hr, 48hr, 54hr 및 72hr째에 채혈하였다. 상기 채혈된 혈액 샘플을 저온 고속 원심분리기(5415R, 에펜도르프)에서 8000 rpm에서 6 분간 4 ℃에서 원심분리시켜 혈장을 분리하였다. 상기 분리된 혈장을 냉장고에서 -80 ℃에서 보존하였다.Blood collection: 200 쨉 l of whole blood was collected at 0.17 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hr, 30 hr, 48 hr, 54 hr and 72 hr. The collected blood samples were centrifuged at 8000 rpm for 6 minutes at 4 DEG C in a low-temperature high-speed centrifuge (5415R, Eppendorf) to separate plasma. The separated plasma was stored in a refrigerator at -80 占 폚.
혈장 샘플 분석:Plasma Sample Analysis:
20 ㎕의 혈장을 조심스럽게 취하고, 여기에 600 ㎕의 내부 표준 MTBE(메틸 3급-부틸 에테르) 용액(내부 표준 다파글리플로진 25 ng/㎖ 함유)을 가하였다. 상기 혈장에 1500 rpm에서 10 분간 와동을 가하고, 이어서 12000 rpm에서 5 분간 원심분리를 수행하였다. 400 ㎕의 상등액을 취하고 질소 기체로 송풍-건조시켰다. 상기 건조된 물질을 200 ㎕의 재용해 용액(아세토나이트릴:물 = 7:3)으로 재용해시켰다. 상기 용액에 10 분간 와동을 가하고, LC-MS/MS(API4000, 어플라이드 바이오시스템스(Applied Biosystems)로 분석하였다.20 [mu] l of plasma was carefully taken and 600 [mu] l of an internal standard MTBE (methyl tert-butyl ether) solution (containing 25 ng / ml of internal standard dipalmitoylphosphate) was added. The plasma was vortexed at 1500 rpm for 10 minutes and then centrifuged at 12000 rpm for 5 minutes. 400 [mu] l of the supernatant was taken and blown-dried with nitrogen gas. The dried material was redissolved in 200 [mu] l of redissolving solution (acetonitrile: water = 7: 3). The solution was vortexed for 10 minutes and analyzed by LC-MS / MS (API4000, Applied Biosystems).
(h)T 1/2
(h)
(h)Tmax
(h)
(ng/㎖)Cmax
(ng / ml)
(h*ng/㎖)AUC last
(h * ng / ml)
(h*ng/㎖)AUC inf
(h * ng / ml)
T1/2는 반감기를 나타낸다.T 1/2 represents half-life.
Tmax는 혈장 중 최대 농도까지의 시간을 나타낸다.Tmax represents the time to maximum plasma concentration.
Cmax는 혈장 중 최대 농도를 나타낸다.Cmax represents the maximum concentration in plasma.
AUClast는 시간 = 0 → t 투여 시 곡선 아래 면적을 나타낸다.AUC last represents the area under the curve at time = 0 → t.
AUCinf는 시간 = 0 → ∞ 투여 시 곡선 아래 면적을 나타낸다.AUC inf shows the area under the curve when time = 0 → ∞.
결론: 표 3에 나타낸 결과로부터 본 발명에 따른 화학식 II에 의해 나타낸 화합물은 짧은 혈장 중 최대 농도까지의 시간 및 빠른 개시를 가짐을 알았다. 비교 화합물 1 및 비교 화합물 2와 비교시, 본 발명에 따른 화학식 II에 의해 나타낸 화합물은 보다 높은 노출을 나타내고 상당한 차이를 가졌으며, 이는 본 발명에 따른 화학식 II에 의해 나타낸 화합물이 현저한 진보를 가짐을 입증하였다.Conclusion: From the results shown in Table 3, it was found that the compound represented by Formula II according to the present invention had time to maximum concentration in short plasma and fast onset. Compared with the comparative compound 1 and the comparative compound 2, the compound represented by the formula II according to the present invention exhibited higher exposure and had a considerable difference, indicating that the compound represented by formula II according to the present invention has remarkable improvement .
하기의 제조예들은 본 발명을 예시하고자 하는 것이며 본 발명에 대한 제한인 것으로 해석되지 않는다. 상기 명세를 기본으로 수행될 수 있는 모든 기술적 해법들은 본 발명의 범위 내에 있다.The following preparations are intended to illustrate the invention and are not to be construed as limitations thereof. All technical solutions that can be performed on the basis of the above specification are within the scope of the present invention.
제조예에서, 사용된 출발 물질들은 상업적으로, 예를 들어 알파 에이사 차이나(텐진) 캄파니 리미티드(Alfa Aesar China (Tianjin) Co., Ltd.), 시노팜 케미칼 리에이전트 캄파니 리미티드(Sinopharm Chemical Reagent Co., Ltd.), 텐진 후유 파인 케미칼 캄파니 리미티드(Tianjin Fuyu Fine Chemical Co., Ltd.), 상하이 뱅켄 케미칼 캄파니 리미티드(Shanghai Bangchen Chemical Co. Ltd.), 텐진 광쳉 케미칼 리에이전트 캄파리 리미티드(Tianjin Guangcheng Chemical Reagent Co., Ltd.), 텐진 광푸 파인 케미칼 캄파니 리미티드(Tianjin Guangfu Fine Chemical Co., Ltd.), 텐진 케미오우 케미칼 리에이전트 캄파니 리미티드(Tianjin Kemiou Chemical Reagent Co., Ltd.)로부터 입수할 수 있었다.In the preparation examples, the starting materials used are commercially available, for example, from Alfa Aesar China (Tianjin) Co., Ltd., Sinopharm Chemical Co., Reagent Co., Ltd., Tianjin Fuyu Fine Chemical Co., Ltd., Shanghai Bangchen Chemical Co. Ltd., Ltd., Tianjin Guangxi Chemical Reagent Co., Ltd., Tianjin Guangfu Fine Chemical Co., Ltd., Tianjin Kemiou Chemical Reagent Co., Ltd. ). ≪ / RTI >
실시예 1: (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올(화학식 II)의 제조Example 1: Preparation of (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S) -bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (Formula II)
(1) 5-브로모-2-클로로벤조일 클로라이드의 제조(1) Preparation of 5-bromo-2-chlorobenzoyl chloride
5-브로모-2-클로로벤조산(270 g, 1.15 mol)을 염화 메틸렌(2700 ㎖)에 현탁시켰다. 상기 생성 혼합물에 N,N-다이메틸폼아미드(1 ㎖)를 가하고, 이어서 0 ℃에서 염화 옥살릴(288 ㎖, 3.46 mol)을 적가하였다. 상기 적가의 완료 후에, 상기 혼합물을 20 ℃로 가온하고 3 시간 동안 반응시켰다. 상기 반응 혼합물은 등명해졌으며, TLC(박층 크로마토그래피)는 반응의 완료를 가리켰다. 상기 반응 혼합물을 30 내지 35 ℃에서 회전에 의해 증발시켜 생성물을 생성시켰으며, 이를 다음 반응에 직접 사용하였다.5-Bromo-2-chlorobenzoic acid (270 g, 1.15 mol) was suspended in methylene chloride (2700 mL). To the resulting mixture was added N, N-dimethylformamide (1 mL), followed by dropwise addition of oxalyl chloride (288 mL, 3.46 mol) at 0 ° C. After completion of the dropwise addition, the mixture was warmed to 20 < 0 > C and reacted for 3 hours. The reaction mixture became clear and TLC (thin layer chromatography) indicated the completion of the reaction. The reaction mixture was evaporated by rotation at 30-35 [deg.] C to give the product which was used directly in the next reaction.
(2) (5-브로모-2-클로로페닐)(4-메톡시페닐)메탄온의 제조(2) Preparation of (5-bromo-2-chlorophenyl) (4-methoxyphenyl)
무수 알루미늄 트라이클로라이드(155 g, 1.16 mol)를 질소 보호 하에서 염화 메틸렌(2050 ㎖)에 현탁시켰다. 상기 생성 혼합물에 -5 ℃에서 아니솔(125 ㎖, 1.15 mol)을 하나의 배치로 가하였다. 20 분간 교반 후에, 상기 혼합물에 염화 메틸렌(300 ㎖) 중의 5-브로모-2-클로로벤조일 클로라이드의 용액을 적가하였다. 상기 생성 혼합물을 -5 ℃에서 3 시간 동안 반응시켰다. TLC는 반응의 완료를 가리켰다. 상기 반응 혼합물에 2N 염산을 부었다. 상기 생성 혼합물을 유기상과 수성상으로 분리시켰다. 상기 유기상을 포화된 나트륨 바이카보네이트 용액으로 2 회 및 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 회전에 의해 증발시켜 고체를 생성시켰다. 상기 고체에 에탄올(150 ㎖)을 가하고, 생성 혼합물을 세척하고 30 분간 녹말화하고 여과하였다. 상기 필터 케이크를 오븐 건조시켜 265 g의 생성물을 71%의 수율로 생성시켰다.Anhydrous aluminum trichloride (155 g, 1.16 mol) was suspended in methylene chloride (2050 mL) under nitrogen protection. To the resulting mixture was added anisole (125 mL, 1.15 mol) in one batch at -5 ° C. After stirring for 20 min, a solution of 5-bromo-2-chlorobenzoyl chloride in methylene chloride (300 mL) was added dropwise to the mixture. The resulting mixture was allowed to react at -5 DEG C for 3 hours. TLC indicated completion of the reaction. The reaction mixture was poured into 2N hydrochloric acid. The product mixture was separated into an organic phase and an aqueous phase. The organic phase was washed twice with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to give a solid. Ethanol (150 mL) was added to the solid, and the resulting mixture was washed, starved for 30 minutes, and filtered. The filter cake was oven dried to yield 265 g of product in 71% yield.
(3) 4-브로모-1-클로로-2-(4-메톡시벤질)벤젠의 제조(3) Preparation of 4-bromo-1-chloro-2- (4-methoxybenzyl) benzene
(5-브로모-2-클로로페닐)(4-메톡시페닐)메탄온(265 g, 0.81 mol)을 염화 메틸렌(515 ㎖) 및 아세토나이트릴(1030 ㎖)에 용해시켰다. 상기 생성 혼합물에 트라이에틸 실란(352 ㎖, 2.22 mol)을 가하였다. 이어서 상기 생성 혼합물에 질소 보호 하에서 0 ℃에서 붕소 트라이플루오라이드-다이에틸 에테레이트(273 ㎖, 2.22 mol)를 적가하였다. 적가의 완료 후에, 생성 혼합물을 20 분간 교반하고, 실온으로 가온하고 2 시간 동안 반응시켰다. TLC는 반응의 완료를 가리켰다. 상기 반응 혼합물에 메틸 3급-부틸 에테르(1.5 L) 및 포화된 나트륨 바이카보네이트 용액(1.5 L)을 가하였다. 상기 혼합물을 30 분간 교반하였다. 유기상을 분리시키고, 포화된 나트륨 바이카보네이트 용액으로 4 회 세척하고, 포화된 염화 나트륨 용액으로 1 회 세척하고, 무수 황산 나트륨 상에서 건조시키고, 회전에 의해 증발시켜 유질 물질을 생성시켰다. 상기 유질 물질에 에탄올을 가하였다. 생성 혼합물을 실온에서 30 분간 교반하고 빙욕에서 30 분간 교반하였다. 다량의 고체가 분리되고 여과되었다. 상기 필터 케이크를 건조시켜 226 g의 생성물을 89%의 수율로 생성시켰다.Methoxyphenyl) methanone (265 g, 0.81 mol) was dissolved in methylene chloride (515 mL) and acetonitrile (1030 mL). To the resultant mixture was added triethylsilane (352 mL, 2.22 mol). Boron trifluoride-diethyl etherate (273 mL, 2.22 mol) was then added dropwise to the resulting mixture at 0 < 0 > C under nitrogen protection. After completion of the dropwise addition, the resulting mixture was stirred for 20 minutes, allowed to warm to room temperature and reacted for 2 hours. TLC indicated completion of the reaction. Methyl tertiary-butyl ether (1.5 L) and saturated sodium bicarbonate solution (1.5 L) were added to the reaction mixture. The mixture was stirred for 30 minutes. The organic phase was separated, washed four times with saturated sodium bicarbonate solution, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to give an oily material. Ethanol was added to the oily material. The resulting mixture was stirred at room temperature for 30 minutes and then in an ice bath for 30 minutes. A large amount of solid was separated and filtered. The filter cake was dried to yield 226 g of product in 89% yield.
(4) 4-(5-브로모-2-클로로벤질)페놀의 제조(4) Preparation of 4- (5-bromo-2-chlorobenzyl) phenol
4-브로모-1-클로로-2-(4-메톡시벤질)벤젠(226 g, 0.73 mol)을 질소 보호 하에서 빛을 차단시켜 염화 메틸렌(2240 ㎖)에 용해시켰다. 상기 생성 혼합물을 -78 ℃에서 염화 메틸렌(1416 ㎖) 중의 붕소 트라이브로마이드(357 g, 1.42 mol)의 용액을 서서히 적가하였다. 상기 적가의 완료 후에, 상기 반응 혼합물을 실온으로 가온하고 2 시간 동안 반응시켰다. TLC는 반응의 완료를 가리켰다. 상기 반응 혼합물에 빙-수욕에서 물을 서서히 적가하였다. 염화 메틸렌 상을 수거하였다. 잔류 수성상을 염화 메틸렌(1 L)으로 2 회 추출하였다. 유기상들을 합하고, 물로 3 회 및 포화된 염화 나트륨 용액으로 1 회 세척하고, 무수 황산 나트륨 상에서 건조시키고, 회전에 의해 증발시켜 210 g의 생성물을 97%의 수율로 생성시켰다.4-Bromo-1-chloro-2- (4-methoxybenzyl) benzene (226 g, 0.73 mol) was dissolved in methylene chloride (2240 mL) under nitrogen protection with interception of light. The resulting mixture was slowly added dropwise to a solution of boron tribromide (357 g, 1.42 mol) in methylene chloride (1416 mL) at -78 <0> C. After completion of the dropwise addition, the reaction mixture was allowed to warm to room temperature and reacted for 2 hours. TLC indicated completion of the reaction. Water was slowly added dropwise to the reaction mixture in an ice-water bath. The methylene chloride phase was collected. The residual aqueous phase was extracted twice with methylene chloride (1 L). The organic phases were combined, washed three times with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to yield 210 g of product in 97% yield.
(5) (1R,3r,5S)-바이사이클로[3.1.0]헥산-3-올의 제조(5) Preparation of (lR, 3r, 5S) -bicyclo [3.1.0] hexan-3-ol
다이에틸 아연(7.16 L, 7.14 mol)을 0 ℃에서 염화 메틸렌(9 L)에 적가하였다. 상기 적가의 완료 후에 백색 증기가 사라졌을 때, 상기 생성 혼합물에 염화 메틸렌(1 L) 중의 트라이플루오로아세트산(816 g, 7.16 mol)의 용액을 서서히 적가하였다. 상기 적가의 완료 후에, 생성 혼합물을 30 분 동안 교반하였다. 상기 혼합물에 염화 메틸렌(1 L) 중의 메틸렌 요오다이드(1918 g, 7.14 mol)의 용액을 적가하였다. 상기 적가의 완료 후에, 생성 혼합물을 30 분 동안 교반하였다. 상기 혼합물에 염화 메틸렌(800 ㎖) 중의 사이클로펜트-3-엔-1-올(200 g, 2.38 mol)의 용액을 적가하였다. 상기 적가의 완료 후에, 생성 혼합물을 실온으로 가온하고 30 분간 반응시켰다. TLC는 반응의 완료를 가리켰다. 상기 반응 혼합물을 포화된 염화 암모늄에 부었다. 10 분간 교반 후에, 상기 혼합물은 유기상과 수성상으로 분리되었다. 수성상을 염화 메틸렌(2 L)으로 1 회 추출하였다. 유기상을 포화된 나트륨 설파이트, 포화된 나트륨 바이카보네이트, 및 포화된 염화 나트륨으로 세척하고, 무수 황산 나트륨 상에서 건조시켰다. 잔사를 컬럼 크로마토그래피에 의해 정제시켜 112 g의 생성물을 48%의 수율로 생성시켰다.Diethylzinc (7.16 L, 7.14 mol) was added dropwise at 0 < 0 > C to methylene chloride (9 L). When the white vapors disappeared after completion of the dropwise addition, a solution of triflu or o acetic acid (816 g, 7.16 mol) in methylene chloride (1 L) was slowly added dropwise to the resulting mixture. After completion of the dropwise addition, the resulting mixture was stirred for 30 minutes. To this mixture was added dropwise a solution of methylene iodide (1918 g, 7.14 mol) in methylene chloride (1 L). After completion of the dropwise addition, the resulting mixture was stirred for 30 minutes. To this mixture was added dropwise a solution of cyclopent-3-en-1-ol (200 g, 2.38 mol) in methylene chloride (800 mL). After completion of the dropwise addition, the resulting mixture was allowed to warm to room temperature and reacted for 30 minutes. TLC indicated completion of the reaction. The reaction mixture was poured into saturated ammonium chloride. After stirring for 10 minutes, the mixture was separated into an organic phase and an aqueous phase. The aqueous phase was extracted once with methylene chloride (2 L). The organic phase was washed with saturated sodium sulphite, saturated sodium bicarbonate, and saturated sodium chloride and dried over anhydrous sodium sulfate. The residue was purified by column chromatography to give 112 g of product in 48% yield.
(6) (1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일 메탄설포네이트의 제조(6) Preparation of (lR, 3r, 5S) -bicyclo [3.1.0] hexan-3-ylmethanesulfonate
(1R,3r,5S)-바이사이클로[3.1.0]헥산-3-올(112 g, 1.14 mol)을 빙수욕에서 염화 메틸렌(1250 ㎖)에 용해시켰다. 상기 생성 혼합물에 트라이에틸아민(174 g, 1.69 mol)을 가하고, 이어서 메틸설포닐 클로라이드(197 g, 1.72 mol)를 서서히 적가하였다. 상기 적가의 완료 후에, 생성 혼합물을 0 ℃에서 30 분간 반응시켰다. TLC는 반응의 완료를 가리켰다. 상기 반응 혼합물을 물에 붓고 이는 유기상과 수성상으로 분리되었다. 유기상을 희석된 염산으로 1 회, 물로 2 회, 및 이어서 포화된 염화 나트륨으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 회전에 의해 증발시켜 138 g의 생성물을 68%의 수율로 생성시켰다.(112 g, 1.14 mol) was dissolved in methylene chloride (1250 mL) in an ice-water bath. To the resultant mixture was added triethylamine (174 g, 1.69 mol), followed by the slow addition of methylsulfonyl chloride (197 g, 1.72 mol). After completion of the dropwise addition, the resulting mixture was reacted at 0 占 폚 for 30 minutes. TLC indicated completion of the reaction. The reaction mixture was poured into water, which was separated into an organic phase and an aqueous phase. The organic phase was washed once with diluted hydrochloric acid, twice with water, and then with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to yield 138 g of product in 68% yield.
(7) (1R,3s,5S)-3-(4-(5-브로모-2-클로로벤질)페닐옥시)바이사이클로[3.1.0]헥산의 제조(7) Preparation of (lR, 3s, 5S) -3- (4- (5-bromo-2- chlorobenzyl) phenyloxy) bicyclo [3.1.0] hexane
(1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일 메탄설포네이트(138 g, 0.78 mol)를 N-메틸피롤리돈(2.1 L)에 용해시켰다. 상기 생성 혼합물에 4-(5-브로모-2-클로로벤질)페놀(210 g, 0.71 mol), 세슘 카보네이트(462 g, 1.42 mol) 및 벤질트라이에틸암모늄 클로라이드(5.46 g, 24 mmol)를 가하였다. 이어서 상기 생성 혼합물을 실온에서 10 분간 교반하고, 50 ℃까지 가온하고, 밤새 반응시켰다. TLC는 반응의 완료를 가리켰다. 상기 반응 혼합물에 물을 가하였다. 이어서 상기 생성 혼합물을 석유 에테르 및 메틸 3급-부틸 에테르의 혼합된 용액(석유 에테르:메틸 3급-부틸 에테르 = 1:1)으로 2 회 추출하였다. 유기상들을 합하고, 포화된 나트륨 바이카보네이트 용액으로 2 회 및 포화된 염화 나트륨으로 2 회 세척하고, 무수 황산 나트륨 상에서 건조시키고, 회전에 의해 증발시켰다. 잔사를 컬럼 크로마토그래피(석유 에테르:에틸 아세테이트 = 50:1)로 정제시켜 135 g의 생성물을 50%의 수율로 생성시켰다.(138 mg, 0.78 mol) was dissolved in N-methylpyrrolidone (2.1 L). To the resulting mixture was added 210 g (0.71 mol), cesium carbonate (462 g, 1.42 mol) and benzyltriethylammonium chloride (5.46 g, 24 mmol) Respectively. The resulting mixture was then stirred at room temperature for 10 minutes, warmed to 50 < 0 > C and allowed to react overnight. TLC indicated completion of the reaction. Water was added to the reaction mixture. The resulting mixture was then extracted twice with a mixed solution of petroleum ether and methyl tertiary-butyl ether (petroleum ether: methyl tert-butyl ether = 1: 1). The organic phases were combined, washed twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated by rotary evaporation. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 50: 1) to give 135 g of product in a yield of 50%.
화학식: C19H18BrClO;Mw:377.71 Formula: C 19 H 18 BrClO; Mw : 377.71
1H-NMR(400MHz,CDCl3)δ:7.28-7.21(m,3H),7.07-7.05(d,2H),6.82-6.78(m,2H),4.42-4.35(m,1H),3.98(s,2H),2.36-2.31(m,2H),1.96-1.90(m,2H),1.40-1.33(m,2H),0.47-0.44(m,1H),0.07-0.02(m,1H). 1 H-NMR (400MHz, CDCl 3) δ: 7.28-7.21 (m, 3H), 7.07-7.05 (d, 2H), 6.82-6.78 (m, 2H), 4.42-4.35 (m, 1H), 3.98 ( s, 2H), 2.36-2.31 (m, 2H), 1.96-1.90 (m, 2H), 1.40-1.33 (m, 2H), 0.47-0.44 (m, 1H), 0.07-0.02 (m,
(8) (3R,4S,5R,6R)-3,4,5-트라이((트라이메틸실릴)옥시)-6-(((트라이메틸실릴)옥시)메틸)테트라하이드로-2H-피란-2-온의 제조((Trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2 - Manufacture of onions
(3R,4S,5S,6R)-3,4,5-트라이하이드록시-6-(하이드록시메틸)테트라하이드로-2H-피란-2-온(85 g, 0.47 mol)을 THF(테트라하이드로퓨란)(932 ㎖)에 현탁시켰다. 상기 생성 혼합물에 N-메틸모폴린(405 ㎖, 4.78 mol)을 가하였다. 이어서 상기 생성 혼합물을 질소 보호 하에서 -5 ℃로 냉각시키고, TMSCl(트라이메틸실란 클로라이드)(360 ㎖, 4.78 mol)를 상기에 적가하였다. 상기 적가의 완료 후에, 생성 혼합물을 실온에서 1 시간 및 35 ℃에서 5 시간 동안 교반하였다. 이어서 상기 혼합물을, 온도를 25 ℃에서 유지시키면서 밤새 교반하였다. TLC는 반응의 완료를 가리켰다. 상기 반응 혼합물에 톨루엔(200 ㎖)을 가하고 빙수욕에서 물(1 L)을 적가하였다. 유기상을 수거하고, 나트륨 이수소 포스페이트로 1 회, 물로 1 회, 및 포화된 염화 나트륨 용액으로 1 회 세척하고, 건조시키고 농축시켜 218 g의 생성물을 100% 수율로 생성시켰다.(85 g, 0.47 mol) was dissolved in THF (tetrahydrofuran) in tetrahydrofuran (10 mL) at -78 < 0 > ) (932 mL). To the resulting mixture was added N-methylmorpholine (405 mL, 4.78 mol). The resulting mixture was then cooled to -5 [deg.] C under nitrogen protection and TMSCl (trimethylsilane chloride) (360 mL, 4.78 mol) was added dropwise thereto. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 1 hour and at 35 DEG C for 5 hours. The mixture was then stirred overnight while maintaining the temperature at 25 < 0 > C. TLC indicated completion of the reaction. Toluene (200 mL) was added to the reaction mixture, and water (1 L) was added dropwise in an ice-water bath. The organic phase was collected, washed once with sodium hydrogenphosphate, once with water and once with saturated sodium chloride solution, dried and concentrated to yield 218 g of product in 100% yield.
(9) (3R,4S,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올의 제조(9R) -4S, 5S, 6R) -2- (3- (4 - (((1R, 3S, 5S) -Bicyclo [3.1.0] -Chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol
(1R,3s,5S)-3-(4-(5-브로모-2-클로로벤질)페닐옥시)바이사이클로[3.1.0]헥산(135 g, 0.358 mol)을 질소 보호 하에서 테트라하이드로퓨란(813 ㎖) 및 톨루엔(813 ㎖)에 용해시켰다. 상기 생성 혼합물을 -78 ℃로 냉각시키고, n-부틸 리튬(194 ㎖, 0.465 mol)을 상기에 적가하였다. 적가의 완료 후에, 상기 반응 혼합물을 2 시간 동안 교반하고, 주입기로 흡입하고, 이어서 톨루엔(950 ㎖) 중의 (3R,4S,5R,6R)-3,4,5-트라이((트라이메틸실릴)옥시)-6-(((트라이메틸실릴)옥시)메틸)테트라하이드로-2H-피란-2-온(218 g, 0.47 mol)의 용액에 주입하였다. 생성 혼합물을 1 시간 동안 교반하고, 메탄올(1.2 L) 중의 메틸설폰산(44.9 ㎖, 2.15 mol)의 용액을 상기에 가하였다. 상기 혼합물을 -78 ℃에서 1 시간 동안 교반하고, 실온으로 가온하고, 밤새 반응시켰다. TLC는 반응의 완료를 가리켰다. 상기 반응 혼합물을 포화된 나트륨 바이카보네이트 용액으로 급냉시키고 에틸 아세테이트(2 L)로 추출하였다. 유기상을 물 및 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 회전에 의해 증발시켜 173 g의 생성물을 98%의 수율로 생성시켰다.(135 g, 0.358 mol) was added dropwise to a solution of (1R, 3S, 5S) -3- (4- (5- bromo-2- chlorobenzyl) phenyloxy) bicyclo [3.1.0] hexane 813 ml) and toluene (813 ml). The resulting mixture was cooled to -78 < 0 > C and n-butyllithium (194 mL, 0.465 mol) was added dropwise thereto. After completion of the dropwise addition, the reaction mixture was stirred for 2 hours, sucked into the syringe and subsequently treated with (3R, 4S, 5R, 6R) -3,4,5-tri ((trimethylsilyl) Oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-one (218 g, 0.47 mol). The resulting mixture was stirred for 1 hour and a solution of methyl sulfonic acid (44.9 mL, 2.15 mol) in methanol (1.2 L) was added thereto. The mixture was stirred at -78 < 0 > C for 1 hour, warmed to room temperature and allowed to react overnight. TLC indicated completion of the reaction. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 L). The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to yield 173 g of product in 98% yield.
(10) (3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)-테트라하이드로-2H-피란-3,4,5-트라이올의 제조(10) (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3S, 5S) -Bicyclo [3.1.0] -Chlorophenyl) -6- (hydroxymethyl) -tetrahydro-2H-pyran-3,4,5-triol
(3R,4S,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올(173 g, 0.352 mol) 및 트라이에틸 실란(180 ㎖, 1.05 mol)을 질소 보호 하에서 -78 ℃에서 염화 메틸렌(2 L)에 용해시켰다. 상기 생성 혼합물에 붕소 트라이플루오라이드-다이에틸 에테레이트(134 ㎖, 1.05 mol)를 서서히 적가하였다. 적가의 완료 후에, 상기 혼합물을 -78 ℃에서 1 시간 동안 반응시켰다. 상기 반응 혼합물을 실온으로 서서히 가온하고 1 시간 동안 반응시켰다. HPLC는 반응의 완료를 가리켰다. 상기 반응 혼합물에 포화된 나트륨 바이카보네이트 용액을 적가하였다. 생성 혼합물을 에틸 아세테이트(1 L)로 추출하였다. 유기상을 물 및 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 회전에 의해 증발시켜 143 g의 생성물을 88%의 수율로 생성시켰다.(3R, 4S, 5S, 6R) -2- (3- (4 - ((lR, 3s, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) Pyrrol-3,4,5-triol (173 g, 0.352 mol) and triethylsilane (180 mL, 1.05 mol) were added to a solution of 2- In methylene chloride (2 L) at -78 < 0 > C. To the resulting mixture was slowly added dropwise boron trifluoride-diethyl etherate (134 mL, 1.05 mol). After completion of the dropwise addition, the mixture was reacted at -78 ° C for 1 hour. The reaction mixture was slowly warmed to room temperature and allowed to react for 1 hour. HPLC indicated completion of the reaction. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture. The resulting mixture was extracted with ethyl acetate (1 L). The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to yield 143 g of product in 88% yield.
(11) (2R,3R,4R,5S,6S)-2-(아세톡시메틸)-6-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-테트라하이드로-2H-피란-3,4,5-트라이일 트라이아세테이트의 제조(11R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4 - ((lR, 3s, 5S) -bicyclo [3.1.0] hexane- Yl) oxy) benzyl) -4-chlorophenyl) -tetrahydro-2H-pyran-3,4,5-triyl triacetate
(3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올(143 g, 0.311 mol)을 염화 메틸렌(720 ㎖)에 용해시켰다. 상기 생성 혼합물에 피리딘(252 ㎖, 3.11 mol) 및 DMAP(4-다이메틸아미노피리딘)(1.9 g, 15.6 mmol)을 가하고, 이어서 빙수욕 중에서 아세트산 무수물(292 ㎖, 3.11 mol)을 적가하였다. 상기 반응 혼합물을 실온에서 3 시간 동안 교반하고, 물로 급냉시키고, 에틸 아세테이트(1.5 L)로 추출하였다. 유기층을 희석된 염산으로 3 회, 포화된 나트륨 바이카보네이트로 1 회, 물, 및 포화된 염화 나트륨으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 회전에 의해 증발시켰다. 상기 잔사를 에탄올로 재결정화하여 81 g의 생성물을 42%의 수율로 생성시켰다.(3R, 4R, 5S, 6R) -2- (3- (4 - ((lR, 3s, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) ) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (143 g, 0.311 mol) was dissolved in methylene chloride (720 mL). To the resulting mixture was added pyridine (252 mL, 3.11 mol) and DMAP (4-dimethylaminopyridine) (1.9 g, 15.6 mmol) followed by dropwise addition of acetic anhydride (292 mL, 3.11 mol) in an ice bath. The reaction mixture was stirred at room temperature for 3 hours, quenched with water and extracted with ethyl acetate (1.5 L). The organic layer was washed three times with diluted hydrochloric acid, once with saturated sodium bicarbonate, with water, and with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated by rotary evaporation. The residue was recrystallized from ethanol to give 81 g of product in 42% yield.
(12) (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-(6-하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올의 제조(12) (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3S, 5S) -Bicyclo [3.1.0] -4-chlorophenyl) - (6-hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol
(2R,3R,4R,5S,6S)-2-(아세톡시메틸)-6-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)테트라하이드로-2H-피란-3,4,5-트라이일 트라이아세테이트(81 g, 0.129 mol)를 테트라하이드로퓨란(313 ㎖), 메탄올(470 ㎖) 및 물(156 ㎖)의 혼합된 용매에 용해시켰다. 상기 생성 혼합물에 리튬 하이드록사이드 모노하이드레이트(6.32 g, 150 mmol)를 가하였다. 상기 혼합물을 실온에서 밤새 교반하였다. TLC는 반응의 완료를 가리켰다. 용매를 회전 증발에 의해 반응 혼합물로부터 제거하였다. 잔류 반응 혼합물을 에틸 아세테이트(400 ㎖)로 용해시켰다. 유기상을 수성 포화된 염화 나트륨 용액, 수성 KHSO4 용액, 및 물로 2 회 세척하고, 무수 황산 나트륨 상에서 건조시키고, 회전에 의해 증발시켰다. 잔사를 C18 역상 예비 크로마토그래피에 의해 정제시켜 54.2 g의 최종 생성물을 91%의 수율로 생성시켰다.(2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4 - ((lR, 3s, 5S) -bicyclo [3.1.0] (81 g, 0.129 mol) was dissolved in tetrahydrofuran (313 ml), methanol (470 ml), and methanol (470 ml) Was dissolved in a mixed solvent of water (156 ml). To the resultant mixture was added lithium hydroxide monohydrate (6.32 g, 150 mmol). The mixture was stirred at room temperature overnight. TLC indicated completion of the reaction. The solvent was removed from the reaction mixture by rotary evaporation. The residual reaction mixture was dissolved in ethyl acetate (400 mL). The organic phase was washed twice with aqueous saturated sodium chloride solution, aqueous KHSO 4 solution and water, dried over anhydrous sodium sulfate and evaporated by rotary evaporation. The residue was purified by C18 reverse phase preparative chromatography to yield 54.2 g of the final product in 91% yield.
화학식: C25H29ClO6 Mw: 460.95 LC-MS(m/z): 478.3 [M+NH4]+ Formula: C 25 H 29 ClO 6 Mw : 460.95 LC-MS (m / z): 478.3 [M + NH 4] +
1H-NMR (400MHz, MeOD) δ:7.35-7.26(m,3H),7.08-7.06(d,2H),6.76-6.74(d,2H),4.45-4.41(m,1H),4.10-4.00(m,3H),3.89-3.88(d,1H),3.71-3.69(m,1H),3.45-3.38(m,3H),3.31-3.26(m,1H),2.34-2.29(m,2H),1.87-1.81(m,2H),1.37-1.33(m,2H),0.43-0.42(m,1H),0.11-0.10(m,1H). 1 H-NMR (400MHz, MeOD ) δ: 7.35-7.26 (m, 3H), 7.08-7.06 (d, 2H), 6.76-6.74 (d, 2H), 4.45-4.41 (m, 1H), 4.10-4.00 (m, 3H), 3.31-3. 26 (m, 1H), 2.34-2.29 (m, 2H) , 1.87-1.81 (m, 2H), 1.37-1.33 (m, 2H), 0.43-0.42 (m, 1H), 0.11-0.10 (m, 1H).
실시예 2: (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올(화학식 III)의 제조Example 2: Preparation of (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3R, 5S) -Bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (Formula III)
(1) (1R,3r,5S)-3-(4-(5-브로모-2-클로로벤질)페닐옥시)바이사이클로[3.1.0]헥산의 제조Preparation of (1R, 3R, 5S) -3- (4- (5-bromo-2-chlorobenzyl) phenyloxy) bicyclo [3.1.0] hexane
4-(5-브로모-2-클로로벤질)페놀(실시예 1의 단계(1) 내지 (4)에 따라 제조됨)(29.7 g, 0.10 mol)을 톨루엔(450 ㎖)에 용해시켰다. 상기 생성 혼합물에 수산화 나트륨(8 g, 0.20 mol), 물(27 ㎖), (1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일 메탄설포네이트(실시예 1의 단계(5)-(6)에 따라 제조됨)(17.6 g, 0.10 mol), 및 벤질트라이에틸암모늄 클로라이드(1.05 g, 4.61 mmol)를 연속적으로 가하였다. 상기 혼합물을 70 ℃에서 2 시간 동안 반응시켰다. TLC는 반응의 완료를 가리켰다. 상기 반응 혼합물을 에틸 아세테이트(500 ㎖)로 추출하였다. 유기상을 건조시키고, 용매를 회전 증발에 의해 추출하였다. 잔사를 실리카젤 컬럼 크로마토그래피(석유 에테르:에틸 아세테이트 = 50:1)에 의해 정제시켜 10.1 g의 생성물을 27%의 수율로 생성시켰다.(29.7 g, 0.10 mol) was dissolved in toluene (450 mL) at room temperature under nitrogen atmosphere. To the resulting mixture was added sodium hydroxide (8 g, 0.20 mol), water (27 mL), (lR, 3r, 5S) -bicyclo [3.1.0] hexane- 3- yl methanesulfonate (step 5) - (6) (17.6 g, 0.10 mol) and benzyltriethylammonium chloride (1.05 g, 4.61 mmol) were successively added. The mixture was reacted at 70 DEG C for 2 hours. TLC indicated completion of the reaction. The reaction mixture was extracted with ethyl acetate (500 mL). The organic phase was dried and the solvent was extracted by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to give 10.1 g of product in 27% yield.
화학식: C19H18BrClO Mw:377.71C 19 H 18 BrClO Mw: 377.71
1H-NMR (400MHz, CDCl3)δ:7.28-7.21(m,3H),7.07-7.05(d,2H),6.76-6.72(d,2H),4.79-4.76(m,1H),3.98(s,2H),2.22-2.16(m,2H),2.05-2.01(m,2H),1.35-1.31(m,2H),0.62-0.58(m,1H),0.51-0.46(m,1H). 1 H-NMR (400MHz, CDCl 3) δ: 7.28-7.21 (m, 3H), 7.07-7.05 (d, 2H), 6.76-6.72 (d, 2H), 4.79-4.76 (m, 1H), 3.98 ( s, 2H), 2.22-2.16 (m, 2H), 2.05-2.01 (m, 2H), 1.35-1.31 (m, 2H), 0.62-0.58 (m, 1H), 0.51-0.46 (m,
(2) (3R,4S,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올의 제조(3R, 4S, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -Chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol
(1R,3r,5S)-3-(4-(5-브로모-2-클로로벤질)페닐옥시)바이사이클로[3.1.0]헥산(1.5 g, 3.97 mmol)을 테트라하이드로퓨란(100 ㎖)에 용해시켰다. 상기 생성 혼합물을 질소 보호 하에서 -78 ℃로 냉각시켰다. 상기 혼합물에 n-부틸 리튬(2 ㎖, 4.8 mmol)을 적가하였다. 적가의 완료 후에, 상기 생성 혼합물을 -78 ℃에서 1 시간 동안 교반하였다. 상기 혼합물에 톨루엔(25 ㎖) 중의 (3R,4S,5R,6R)-3,4,5-트라이((트라이메틸실릴)옥시)-6-(((트라이메틸실릴)옥시)메틸)테트라하이드로-2H-피란-2-온(3.0 g, 6.4 mmol)의 용액을 적가하였다. 상기 생성 혼합물을, 상기 온도를 -78 ℃에서 유지시키면서 1 시간 동안 반응시켰다. 이어서 상기 반응 혼합물에 메탄올(50 ㎖) 중의 메탄설폰산(3.8 g, 39.6 mmol)의 용액을 적가하였다. 상기 생성 혼합물을, 상기 온도를 -78 ℃에서 유지시키면서 0.5 시간 동안 반응시키고, 이어서 실온에서 18 시간 동안 반응시켰다. 상기 반응 혼합물을 수성 포화된 나트륨 바이카보네이트 용액(100 ㎖)으로 급냉시키고, 에틸 아세테이트(100 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 무수 황산 나트륨 상에서 건조시키고, 여과하였다. 상기 여액을 감압 하에서 농축시켜 용매를 제거하고 1.5 g의 생성물을 77%의 수율로 생성시켰다.(1.5 g, 3.97 mmol) was dissolved in tetrahydrofuran (100 ml) and the mixture was stirred at room temperature for 3 hours. ≪ / RTI > The resulting mixture was cooled to -78 < 0 > C under nitrogen protection. To the mixture was added n-butyllithium (2 mL, 4.8 mmol) dropwise. After completion of the dropwise addition, the resulting mixture was stirred at -78 < 0 > C for 1 hour. To this mixture was added a solution of (3R, 4S, 5R, 6R) -3,4,5-tri ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro -2H-pyran-2-one (3.0 g, 6.4 mmol). The resulting mixture was allowed to react for 1 hour while maintaining the temperature at -78 占 폚. A solution of methanesulfonic acid (3.8 g, 39.6 mmol) in methanol (50 mL) was then added dropwise to the reaction mixture. The resultant mixture was allowed to react for 0.5 hour while maintaining the temperature at -78 占 폚, followed by reaction at room temperature for 18 hours. The reaction mixture was quenched with an aqueous saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent and yield 1.5 g of product in 77% yield.
(3) (3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올의 제조(3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -Chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol
(3R,4S,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올(1.40 g, 2.86 mmol)을 염화 메틸렌(40 ㎖) 및 아세토나이트릴(40 ㎖)의 혼합된 용액에 용해시켰다. 상기 생성 혼합물에 트라이에틸 실란(1.0 g, 8.6 mmol)을 가하였다. 상기 혼합물을 실온에서 교반하였으며, 붕소 트라이플루오라이드-다이에틸 에테레이트(1.2 g, 8.45 mmol)를 상기에 적가하였다. 첨가의 완료 후에, 상기 생성 혼합물을 실온에서 16 시간 동안 반응시켰다. 상기 반응 혼합물에 수성 포화된 나트륨 바이카보네이트 용액(100 ㎖)을 가하였다. 상기 생성 혼합물을 에틸 아세테이트(100 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 무수 황산 나트륨 상에서 건조시키고, 여과하였다. 상기 여액을 감압 하에서 농축시켜 용매를 제거하고 1.0 g의 조 생성물을 76%의 수율로 생성시켰다.(3R, 4S, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) (1.40 g, 2.86 mmol) was dissolved in methylene chloride (40 mL) and acetonitrile (40 mL) at 0 < 0 & ). ≪ / RTI > To the resultant mixture was added triethylsilane (1.0 g, 8.6 mmol). The mixture was stirred at room temperature and boron trifluoride-diethyl etherate (1.2 g, 8.45 mmol) was added dropwise thereto. After completion of the addition, the resulting mixture was allowed to react at room temperature for 16 hours. To the reaction mixture was added an aqueous saturated sodium bicarbonate solution (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent and yield 1.0 g of crude product in 76% yield.
(4) (2R,3R,4R,5S,6S)-2-(아세톡시메틸)-6-(3-(4-((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)테트라하이드로-2H-피란-3,4,5-트라이일 트라이아세테이트의 제조(4R, 3R, 5S) -Bicyclo [3.1.0] hexane-3 (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- -Yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate
(3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올(1.0 g, 2.2 mmol)을 염화 메틸렌(40 ㎖)에 용해시켰다. 상기 생성 혼합물에 피리딘(1.78 ㎖) 및 DMAP(13 ㎎)를 가하고, 빙욕에서 아세트산 무수물(2.07 ㎖)을 적가하였다. 상기 반응 혼합물을 실온에서 3 시간 동안 교반하고, 물(10 ㎖)로 급냉시키고, 유기상과 수성상으로 분리시켰다. 상기 수성상을 에틸 아세테이트(50 ㎖ x 2)로 추출하였다. 유기상들을 합하고, 무수 황산 나트륨 상에서 건조시키고, 실리카젤 컬럼 크로마토그래피(석유 에테르:에틸 아세테이트 = 2:1)에 의해 정제시켜 400 ㎎의 생성물을 29%의 수율로 생성시켰다.(3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) ) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (1.0 g, 2.2 mmol) was dissolved in methylene chloride (40 mL). Pyridine (1.78 mL) and DMAP (13 mg) were added to the resulting mixture, and acetic anhydride (2.07 mL) was added dropwise in an ice bath. The reaction mixture was stirred at room temperature for 3 hours, quenched with water (10 mL) and separated into an organic and an aqueous phase. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to yield 400 mg of product in 29% yield.
(5) (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올의 제조(5S, 3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol
(2R,3R,4R,5S,6S)-2-(아세톡시메틸)-6-(3-(4-((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)테트라하이드로-2H-피란-3,4,5-트라이일 트라이아세테이트(400 ㎎, 0.64 mmol)를 테트라하이드로퓨란(5 ㎖), 물(5 ㎖) 및 메탄올(5 ㎖)의 혼합된 용매에 용해시켰다. 상기 생성 혼합물에 리튬 하이드록사이드 모노하이드레이트(107.5 ㎎, 2.56 mmol)를 가하였다. 상기 반응 혼합물을 실온에서 2 시간 동안 교반하였다. TLC는 반응의 완료를 가리켰다. 용매를 회전 증발에 의해 수거하였다. 잔사를 실리카젤 컬럼 크로마토그래피(염화 메틸렌:메탄올 = 10:1)에 의해 정제시켜 200 ㎎의 최종 생성물을 68%의 수율로 생성시켰다.(3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4- (400 mg, 0.64 mmol) was dissolved in tetrahydrofuran (5 mL), water (5 mL), and methanol (5 mL) (5 mL) in a mixed solvent. To the resultant mixture was added lithium hydroxide monohydrate (107.5 mg, 2.56 mmol). The reaction mixture was stirred at room temperature for 2 hours. TLC indicated completion of the reaction. Solvent was collected by rotary evaporation. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give 200 mg of the final product in a yield of 68%.
화학식: C25H29ClO6 Mw:460.95The formula: C 25 H 29 ClO 6 Mw: 460.95
1H-NMR (400MHz, MeOD) d:7.23-7.38(m,3H),7.07(m,2H),6.69(m,2H),4.79(m,1H),4.06-4.11(m,1H),3.94-4.05(m,2H),3.87(m,1H),3.64-3.73(m,1H),3.36-3.24(m,4H),2.19(m,2H),1.88-2.02(m,2H),1.26-1.41(m,2H),0.52-0.60(m,1H),0.39-0.50(m,1H). 1 H-NMR (400MHz, MeOD ) d: 7.23-7.38 (m, 3H), 7.07 (m, 2H), 6.69 (m, 2H), 4.79 (m, 1H), 4.06-4.11 (m, 1H), 2H), 3.94 (m, 2H), 3.87 (m, 1H), 3.64-3.73 (m, 1.26-1.41 (m, 2H), 0.52-0.60 (m, 1H), 0.39-0.50 (m, 1H).
실시예 3: (2R,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올(화학식 IV)의 제조Example 3: (2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S) -Bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (IV)
(1) (3R,4S,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올의 제조(1R, 3R, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl) -4 -Chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol
(1R,3s,5S)-3-(4-(5-브로모-2-클로로벤질)페닐옥시)바이사이클로[3.1.0]헥산(5 g, 13.3 mmol)을 테트라하이드로퓨란(100 ㎖)에 용해시켰다. 생성 혼합물을 질소 보호 하에서 -78 ℃로 냉각시켰다. 상기 혼합물에 n-BuLi(6.7 ㎖, 15.8 mmol)을 적가하였다. 적가의 완료 후에, 상기 생성 혼합물을 -78 ℃에서 1 시간 동안 교반하였다. 상기 혼합물에 톨루엔(50 ㎖) 중의 (3R,4S,5R,6R)-3,4,5-트라이((트라이메틸실릴)옥시)-6-(((트라이메틸실릴)옥시)메틸)테트라하이드로-2H-피란-2-온(10 g, 21.4 mmol)의 용액을 적가하였다. 상기 생성 혼합물을, 상기 온도를 -78 ℃에서 유지시키면서 1 시간 동안 반응시켰다. 이어서 상기 반응 혼합물에 메탄올(60 ㎖) 중의 메탄설폰산(12.7 g, 132 mmol)의 용액을 가하였다. 상기 생성 혼합물을 실온에서 18 시간 동안 반응시켰다. 상기 반응 혼합물을 수성 포화된 나트륨 바이카보네이트 용액(100 ㎖)으로 급냉시키고, 에틸 아세테이트(100 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 무수 황산 나트륨 상에서 건조시키고, 여과하였다. 상기 여액을 감압 하에서 농축시켜 용매를 제거하고 4.5 g의 생성물을 69%의 수율로 생성시켰다.(5 g, 13.3 mmol) was dissolved in tetrahydrofuran (100 ml) and the mixture was stirred at room temperature for 3 hours. ≪ / RTI > The resulting mixture was cooled to -78 < 0 > C under nitrogen protection. N-BuLi (6.7 mL, 15.8 mmol) was added dropwise to the mixture. After completion of the dropwise addition, the resulting mixture was stirred at -78 < 0 > C for 1 hour. To this mixture was added a solution of (3R, 4S, 5R, 6R) -3,4,5-tri ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro -2H-pyran-2-one (10 g, 21.4 mmol) in dichloromethane was added dropwise. The resulting mixture was allowed to react for 1 hour while maintaining the temperature at -78 占 폚. To the reaction mixture was then added a solution of methanesulfonic acid (12.7 g, 132 mmol) in methanol (60 mL). The resulting mixture was allowed to react at room temperature for 18 hours. The reaction mixture was quenched with an aqueous saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent and yield 4.5 g of product in 69% yield.
(2) (3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올의 제조(3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -Chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol
(3R,4S,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올(4 g, 8.16 mmol)을 염화 메틸렌(30 ㎖) 및 아세토나이트릴(30 ㎖)의 혼합된 용액에 용해시켰다. 상기 생성 혼합물에 트라이에틸 실란(2.86 g, 24.6 mmol)을 가하였다. 상기 혼합물을 실온에서 교반하였으며, 붕소 트라이플루오라이드-다이에틸 에테레이트(3.43 g, 24.2 mmol)를 상기에 적가하였다. 첨가의 완료 후에, 상기 생성 혼합물을 실온에서 16 시간 동안 반응시켰다. 상기 반응 혼합물에 수성 포화된 나트륨 바이카보네이트 용액(50 ㎖)을 가하였다. 상기 생성 혼합물을 에틸 아세테이트(50 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 무수 황산 나트륨 상에서 건조시키고, 여과하였다. 상기 여액을 감압 하에서 농축시켜 용매를 제거하였다. 생성된 조 생성물을 실리카젤 컬럼 크로마토그래피(염화 메틸렌:메탄올 = 10:1)로 정제시켜 2 ㎎의 생성물을 53%의 수율로 생성시켰다.(3R, 4S, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) Yl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol (4 g, 8.16 mmol) was dissolved in methylene chloride (30 mL) and acetonitrile ). ≪ / RTI > To the resultant mixture was added triethylsilane (2.86 g, 24.6 mmol). The mixture was stirred at room temperature and boron trifluoride-diethyl etherate (3.43 g, 24.2 mmol) was added dropwise thereto. After completion of the addition, the resulting mixture was allowed to react at room temperature for 16 hours. To the reaction mixture was added an aqueous saturated sodium bicarbonate solution (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting crude product was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give 2 mg of product in 53% yield.
(3) (2R,3R,4R,5S,6R)-2-(아세톡시메틸)-6-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)테트라하이드로-2H-피란-3,4,5-트라이일 트라이아세테이트의 제조(3R, 3R, 4R, 5S, 6R) -2- (acetoxymethyl) -6- (3- (4- Yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate
(3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올(1.0 g, 2.17 mmol)을 염화 메틸렌(20 ㎖)에 용해시켰다. 상기 생성 혼합물에 N,N-다이아이소프로필에틸아민(2.8 g, 21.7 mmol), 아세트산 무수물(2.2 g, 21.7 mmol) 및 촉매량의 4-다이메틸아미노피리딘(25 ㎎)을 가하였다. 상기 반응 혼합물을 실온에서 2 시간 동안 교반하고, 1N 염산(15 ㎖)으로 세척하고, 유기상과 수성상으로 분리시켰다. 유기상을 무수 황산 나트륨 상에서 건조시키고 여과하였다. 상기 여액을 감압 하에서 농축시켜 용매를 제거하였다. 상기 생성되는 조 생성물을 실리카젤 컬럼 크로마토그래피(석유 에테르:에틸 아세테이트 = 5:1)에 의해 정제시켜 0.55 g의 생성물을 40%의 수율로 생성시켰다.(3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) ) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (1.0 g, 2.17 mmol) was dissolved in methylene chloride (20 mL). N, N-Diisopropylethylamine (2.8 g, 21.7 mmol), acetic anhydride (2.2 g, 21.7 mmol) and a catalytic amount of 4-dimethylaminopyridine (25 mg) were added to the resulting mixture. The reaction mixture was stirred at room temperature for 2 hours, washed with 1 N hydrochloric acid (15 mL) and separated into an organic and an aqueous phase. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 0.55 g of product in 40% yield.
(4) (2R,3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올의 제조(4R, 3R, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl) -2,3- -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol
(2R,3R,4R,5S,6R)-2-(아세톡시메틸)-6-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)테트라하이드로-2H-피란-3,4,5-트라이일 트라이아세테이트(0.55 g, 0.87 mmol)를 물, 메탄올 및 테트라하이드로퓨란의 혼합된 용매(25 ㎖, 2:2:1)에 용해시켰다. 상기 생성 혼합물에 리튬 하이드록사이드 모노하이드레이트(0.37 g, 8.7 mmol)를 가하였다. 상기 반응 혼합물을 실온에서 밤새 교반하였다. 용매를 회전 증발에 의해 수거하였다. 생성 혼합물을 에틸 아세테이트(10 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 무수 황산 나트륨 상에서 건조시키고, 여과하였다. 상기 여액을 감압 하에서 농축시켜 용매를 제거하였다. 상기 생성되는 조 생성물을 실리카젤 컬럼 크로마토그래피(염화 메틸렌:메탄올 = 10:1)에 의해 정제시켜 0.27 ㎎의 최종 생성물을 67.5%의 수율로 생성시켰다.(2R, 3R, 4R, 5S, 6R) -2- (acetoxymethyl) -6- (3- (4- (0.55 g, 0.87 mmol) was dissolved in a mixed solvent of water, methanol and tetrahydrofuran (25 mL), and the mixture was stirred at room temperature for 2 hours. , 2: 2: 1). To the resultant mixture was added lithium hydroxide monohydrate (0.37 g, 8.7 mmol). The reaction mixture was stirred overnight at room temperature. Solvent was collected by rotary evaporation. The resulting mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting crude product was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give 0.27 mg of the final product in a yield of 67.5%.
화학식: C25H29ClO6 Mw:460.95The formula: C 25 H 29 ClO 6 Mw: 460.95
1H-NMR (400MHz, MeOD) d: 7.21-7.31 (m, 3H), 6.93-7.09 (m, 2H), 6.74-6.79 (m, 2H), 4.53-4.63 (m, 1H), 4.39-4.48 (m, 1H), 4.14-4.20 (m, 1H), 3.89-4.11 (m, 5H), 3.82 (m, 1H), 3.67 (m, 1H), 2.32 (m, 2H), 1.84 (m, 2H), 1.34 (m, 2H), 0.43 (m, 1H), 0.10 (m, 1H). 1 H-NMR (400MHz, MeOD ) d: 7.21-7.31 (m, 3H), 6.93-7.09 (m, 2H), 6.74-6.79 (m, 2H), 4.53-4.63 (m, 1H), 4.39-4.48 (m, 2H), 1.84 (m, 2H), 3.84 (m, ), 1.34 (m, 2H), 0.43 (m, IH), 0.10 (m, IH).
실시예 4: (2R,3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올(화학식 V)의 제조Example 4: (2R, 3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -Bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (Formula V)
(1) 2-클로로-5-요오도벤조일 클로라이드의 제조(1) Preparation of 2-chloro-5-iodobenzoyl chloride
2-클로로-5-요오도벤조산(10.0 g, 35.3 mmol)을 염화 메틸렌(200 ㎖)에 현탁시켰다. 상기 생성 혼합물에 N,N-다이메틸폼아미드(0.05 ㎖)를 가하고, 이어서 0 ℃에서 염화 옥살릴(11.3 g, 89.0 mmol)을 적가하였다. 상기 적가의 완료 후에, 생성 혼합물을 실온으로 가온하고 4 시간 동안 교반하였다. 생성되는 등명한 용액을 회전에 의해 증발시켜 용매를 제거하였으며 10.7 g의 생성물을 100%의 수율로 생성시켰고, 이를 정제 없이 다음 반응에 직접 사용하였다.2-Chloro-5-iodobenzoic acid (10.0 g, 35.3 mmol) was suspended in methylene chloride (200 mL). N, N-Dimethylformamide (0.05 mL) was added to the resulting mixture, followed by dropwise addition of oxalyl chloride (11.3 g, 89.0 mmol) at 0 ° C. After completion of the dropwise addition, the resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting clear solution was evaporated by rotary evaporation to remove the solvent and yielded 10.7 g of the product in 100% yield, which was used directly in the next reaction without purification.
(2) (2-클로로-5-요오도페닐)(4-메톡시페닐)메탄온의 제조(2) Preparation of (2-chloro-5-iodophenyl) (4-methoxyphenyl) methanone
2-클로로-5-요오도벤조일 클로라이드(10.7 g, 35.5 mmol)를 염화 메틸렌(200 ㎖)에 용해시켰다. 생성 혼합물을 빙수욕에서 냉각시켰다. 상기 혼합물에 알루미늄 트라이클로라이드(10.4 g, 78.2 mmol)를 가하고, 이어서 염화 메틸렌(50 ㎖) 중의 아니솔(4.2 g, 38.9 mmol)의 용액을 적가하였다. 적가의 완료 후에, 생성 혼합물을 실온으로 가온하고 3 시간 동안 교반하였다. 반응 혼합물을 빙수에 붓고 급냉시켰다. 상기 반응 혼합물에 3 mol/L의 염산을 가하였다. 상기 생성 혼합물을 수성상과 유기상으로 분리시켰다. 수성상을 염화 메틸렌(150 ㎖ x 2)으로 추출하였다. 유기상들을 합하고, 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고 감압 하에서 농축시켰다. 생성된 조 생성물을 실리카젤 컬럼 크로마토그래피(에틸 아세테이트:석유 에테르 = 0-1:100)에 의해 정제시켜 12.0 g의 생성물을 91%의 수율로 생성시켰다.2-Chloro-5-iodobenzoyl chloride (10.7 g, 35.5 mmol) was dissolved in methylene chloride (200 mL). The resulting mixture was cooled in an ice-water bath. Aluminum trichloride (10.4 g, 78.2 mmol) was added to the mixture, followed by the dropwise addition of a solution of anisole (4.2 g, 38.9 mmol) in methylene chloride (50 mL). After completion of the dropwise addition, the resulting mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was poured into ice water and quenched. 3 mol / L hydrochloric acid was added to the reaction mixture. The product mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (150 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 100) to give 12.0 g of product in 91% yield.
(3) 1-클로로-4-요오도-2-(4-메톡시벤질)벤젠의 제조(3) Preparation of 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene
(2-클로로-5-요오도페닐)(4-메톡시페닐)메탄온(12.0 g, 32.2 mmol) 및 트라이에틸 실란(9.86 g, 84.8 mmol)을 아세토나이트릴(200 ㎖)에 용해시켰다. 상기 생성 혼합물에 붕소 트라이플루오라이드-다이에틸 에테레이트 복합체(13.7 g, 96.5 mmol)를 0 ℃에서 가하였다. 상기 적가의 완료 후에, 상기 혼합물을 70 ℃까지 가온하고 3 시간 동안 교반하였다. 이어서 상기 혼합물을 실온으로 냉각시켰다. 상기 혼합물을 포화된 나트륨 바이카보네이트 용액으로 급냉시키고 에틸 아세테이트(200 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 감압 하에서 농축시켰다. 생성되는 조 생성물을 실리카젤 컬럼 크로마토그래피(에틸 아세테이트:석유 에테르 = 0-1:100)에 의해 정제시켜 10.0 g의 생성물을 87%의 수율로 생성시켰다.Methoxyphenyl) methanone (12.0 g, 32.2 mmol) and triethylsilane (9.86 g, 84.8 mmol) were dissolved in acetonitrile (200 mL). To the resulting mixture was added boron trifluoride-diethyl etherate complex (13.7 g, 96.5 mmol) at 0 < 0 > C. After completion of the dropwise addition, the mixture was warmed to 70 DEG C and stirred for 3 hours. The mixture was then cooled to room temperature. The mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 100) to give 10.0 g of product in 87% yield.
(4) 4-(2-클로로-5-요오도벤질)페놀의 제조(4) Preparation of 4- (2-chloro-5-iodobenzyl) phenol
1-클로로-4-요오도-2-(4-메톡시벤질)벤젠(10.0 g, 27.9 mmol)을 염화 메틸렌(150 ㎖)에 용해시켰다. 상기 생성 혼합물에 붕소 트라이브로마이드(21 g, 83.7 mmol)를 빙수욕에서 냉각 하에 적가하였다. 상기 적가의 완료 후에, 상기 혼합물을 실온으로 가온하고, 3 시간 동안 교반하였다. 상기 혼합물을 포화된 나트륨 바이카보네이트 용액으로 급냉시키고, 수성상과 유기상으로 분리시켰다. 수성상을 염화 메틸렌(150 ㎖ x 2)으로 추출하였다. 유기상들을 합하고, 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고 감압 하에서 농축시켰다. 생성되는 조 생성물을 실리카젤 컬럼 크로마토그래피(에틸 아세테이트:석유 에테르 = 0-1:20)에 의해 정제시켜 8.5 g의 생성물을 88%의 수율로 생성시켰다.(10.0 g, 27.9 mmol) was dissolved in methylene chloride (150 mL). Boron tribromide (21 g, 83.7 mmol) was added dropwise to the resulting mixture under cooling in an ice-water bath. After completion of the dropwise addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was quenched with saturated sodium bicarbonate solution and separated into an aqueous and an organic phase. The aqueous phase was extracted with methylene chloride (150 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 20) to give 8.5 g of product in 88% yield.
(5) (4-(2-클로로-5-요오도벤질)페닐옥시)3급-부틸다이메틸실란의 제조(5) Preparation of (4- (2-chloro-5-iodobenzyl) phenyloxy) tert-butyldimethylsilane
4-(2-클로로-5-요오도벤질)페놀(8.5 g, 24.7 mmol) 및 트라이에틸아민(5.0 g, 49.5 mmol)을 염화 메틸렌(200 ㎖)에 용해시켰다. 상기 생성 혼합물에 0 ℃에서 3급-부틸다이메틸실란 클로라이드(5.6 g, 37.1 mmol) 및 4-(다이메틸아미노)피리딘(305 ㎎, 2.5 mmol)을 가하였다. 상기 첨가의 완료 후에, 상기 혼합물을 실온으로 가온하고 18 시간 동안 교반하였다. 상기 혼합물에 물(100 ㎖)을 가하였다. 생성 혼합물을 수성상과 유기상으로 분리시켰다. 상기 수성상을 염화 메틸렌(100 ㎖ x 2)으로 추출하였다. 유기상들을 합하고, 포화된 수성 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 감압 하에서 농축시켰다. 생성되는 조 생성물을 실리카젤 컬럼 크로마토그래피(에틸 아세테이트:석유 에테르 = 0-1:100)에 의해 정제시켜 10.0 g의 생성물을 88%의 수율로 생성시켰다.4- (2-Chloro-5-iodobenzyl) phenol (8.5 g, 24.7 mmol) and triethylamine (5.0 g, 49.5 mmol) were dissolved in methylene chloride (200 mL). To the resulting mixture was added tert-butyldimethylsilane chloride (5.6 g, 37.1 mmol) and 4- (dimethylamino) pyridine (305 mg, 2.5 mmol) at 0 ° C. After completion of the addition, the mixture was allowed to warm to room temperature and stirred for 18 hours. Water (100 mL) was added to the mixture. The resulting mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (100 mL x 2). The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 100) to give 10.0 g of product in 88% yield.
(6) (3R,4S,5S,6R)-2-(3-(4-((3급-부틸다이메틸실릴)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올의 제조(6) Synthesis of (3R, 4S, 5S, 6R) -2- (3- (4- ((tert- butyldimethylsilyl) oxy) benzyl) -4- chlorophenyl) -6- (hydroxymethyl) Preparation of 2-methoxytetrahydro-2H-pyran-3,4,5-triol
무수 테트라하이드로퓨란(80 ㎖) 및 톨루엔(80 ㎖) 중의 (4-(2-클로로-5-요오도벤질)페닐옥시)3급-부틸다이메틸실란(10.0 g, 21.8 mmol)의 용액을 -78 ℃로 냉각시켰다. 상기 용액에 n-헥산(2.4 mol/L, 13.6 ㎖, 32.6 mmol) 중의 n-부틸 리튬의 용액을 서서히 적가하였다. 상기 생성 혼합물을 -78 ℃에서 2 시간 동안 반응시키고, 이어서 -60 ℃까지 가온하였다. 상기 반응 혼합물에 톨루엔(60 ㎖) 중의 (3R,4S,5R,6R)-3,4,5-트라이((트라이메틸실릴)옥시)-6-(((트라이메틸실릴)옥시)메틸)테트라하이드로-2H-피란-2-온(15.3 g, 32.7 mmol)의 용액을 하나의 배치로 가하였다. 상기 생성 혼합물을 -60 ℃에서 2 시간 동안 반응시켰다. 상기 반응 혼합물에 메탄올(50 ㎖) 중의 메탄설폰산(14.6 g, 152.1 mmol)의 용액을 적가하였다. 상기 적가의 완료 후에, 상기 생성 혼합물을 실온에서 교반 하에 17 시간 동안 반응시켰다. 상기 반응 혼합물을 포화된 나트륨 바이카보네이트 용액으로 급냉시키고, 수성상과 유기상으로 분리시켰다. 상기 수성상을 에틸 아세테이트(200 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 감압 하에서 농축시켜 9.0 g의 조 생성물을 생성시켰으며, 이를 정제 없이 다음 반응에 직접 사용하였다.A solution of (4- (2-chloro-5-iodobenzyl) phenyloxy) tert-butyldimethylsilane (10.0 g, 21.8 mmol) in anhydrous tetrahydrofuran (80 mL) and toluene (80 mL) Gt; 78 C. < / RTI > To this solution was slowly added dropwise a solution of n-butyllithium in n-hexane (2.4 mol / L, 13.6 mL, 32.6 mmol). The resulting mixture was allowed to react at -78 < 0 > C for 2 hours and then warmed to -60 < 0 > C. To the reaction mixture was added a solution of (3R, 4S, 5R, 6R) -3,4,5-tri ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetra -2H-pyran-2-one (15.3 g, 32.7 mmol) was added in one batch. The resultant mixture was reacted at -60 DEG C for 2 hours. To the reaction mixture was added dropwise a solution of methanesulfonic acid (14.6 g, 152.1 mmol) in methanol (50 mL). After completion of the dropwise addition, the resulting mixture was reacted at room temperature for 17 hours with stirring. The reaction mixture was quenched with saturated sodium bicarbonate solution and separated into an aqueous and an organic phase. The aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 9.0 g of crude product which was used directly in the next reaction without purification.
(7) (3R,4S,5S,6R)-2-(4-클로로-3-(4-하이드록시벤질)페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올의 제조(7) Synthesis of (3R, 4S, 5S, 6R) -2- (4-chloro-3- (4- hydroxybenzyl) phenyl) -6- (hydroxymethyl) -2- methoxytetrahydro- -3,4,5-triol
조 (3R,4S,5S,6R)-2-(3-(4-((3급-부틸다이메틸실릴)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올(9.0 g)을 테트라하이드로퓨란(70 ㎖)에 용해시켰다. 상기 생성 용액에 테트라부틸 암모늄 플루오라이드 트라이하이드레이트(22.1 g, 70 mmol)를 가하였다. 상기 생성 혼합물을 실온에서 2 시간 동안 교반하고 감압 하에서 농축시켰다. 상기 혼합물에 에틸 아세테이트(400 ㎖) 및 물(200 ㎖)을 가하였다. 상기 생성 혼합물을 수성상과 유기상으로 분리시켰다. 상기 유기상을 물(200 ㎖ x 3) 및 포화된 염화 나트륨 용액으로 연속적으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 감압 하에서 농축시켜 6.5 g의 조 생성물을 생성시키고, 이를 정제 없이 다음 단계에 직접 사용하였다.Benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2- (4-methylpiperazin-1- Methoxytetrahydro-2H-pyran-3,4,5-triol (9.0 g) was dissolved in tetrahydrofuran (70 ml). Tetrabutylammonium fluoride trihydrate (22.1 g, 70 mmol) was added to the resulting solution. The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. Ethyl acetate (400 mL) and water (200 mL) were added to the mixture. The product mixture was separated into an aqueous phase and an organic phase. The organic phase was washed successively with water (200 mL x 3) and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 6.5 g of crude product which was used directly in the next step without purification Respectively.
(8) (3R,4R,5S,6R)-2-(4-클로로-3-(4-하이드록시벤질)페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올의 제조(8) (3R, 4R, 5S, 6R) -2- (4-Chloro-3- (4- hydroxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro- Preparation of 5-triol
조 (3R,4S,5S,6R)-2-(4-클로로-3-(4-하이드록시벤질)페닐)-6-(하이드록시메틸)-2-메톡시테트라하이드로-2H-피란-3,4,5-트라이올(6.5 g) 및 트라이에틸 실란(4.03 g, 34.7 mmol)을 염화 메틸렌(100 ㎖) 및 아세토나이트릴(100 ㎖)의 혼합된 용매에 용해시켰다. 상기 생성 혼합물에 0 ℃에서 붕소 트라이플루오라이드-다이에틸 에테레이트 복합체(5.6 g, 39.5 mmol)를 적가하였다. 상기 적가의 완료 후에, 생성 혼합물을 실온까지 가온하고 16 시간 동안 교반하였다. 상기 혼합물을 포화된 나트륨 바이카보네이트 용액으로 급냉시키고, 에틸 아세테이트(250 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 감압 하에서 농축시켰다. 생성되는 조 생성물을 실리카젤 컬럼 크로마토그래피(메탄올:염화 메틸렌 = 0-1:15)에 의해 정제시켜 3.8 g의 생성물을 46%의 수율(총 3 단계)로 생성시켰다.(4-chloro-3- (4-hydroxybenzyl) phenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran- , 4,5-triol (6.5 g) and triethylsilane (4.03 g, 34.7 mmol) were dissolved in a mixed solvent of methylene chloride (100 ml) and acetonitrile (100 ml). To the resulting mixture was added dropwise a boron trifluoride-diethyl etherate complex (5.6 g, 39.5 mmol) at 0 ° C. After completion of the dropwise addition, the resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (250 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (methanol: methylene chloride = 0-1: 15) to give 3.8 g of product in 46% yield (total of 3 steps).
(9) (3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올의 제조(9R) - (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3R, 5S) -Bicyclo [3.1.0] -Chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol
(3R,4R,5S,6R)-2-(4-클로로-3-(4-하이드록시벤질)페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올(3.8 g, 10 mmol) 및 (1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일 메탄설포네이트(3.5 g, 20 mmol)를 톨루엔(100 ㎖) 및 물(10 ㎖)에 현탁시켰다. 상기 생성 현탁액에 NaOH(1.0 g, 25 mmol) 및 벤질 트라이에틸암모늄 클로라이드(114 ㎎, 0.5 mmol)를 연속적으로 가하였다. 상기 생성 혼합물을 80 ℃로 가열하고 16 시간 동안 반응시켰다. 상기 반응 혼합물을 실온으로 냉각시켰다. 상기 반응 혼합물에 물(50 ㎖)을 가하였다. 상기 생성 혼합물을 수성상과 유기상으로 분리시켰다. 상기 수성상을 에틸 아세테이트(50 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 감압 하에서 농축시켜 5.0 g의 조 생성물을 생성시키고, 이를 정제 없이 다음 단계에 직접 사용하였다.(3R, 4R, 5S, 6R) -2- (4-chloro-3- (4- hydroxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro- (3.8 g, 10 mmol) and (lR, 3r, 5S) -bicyclo [3.1.0] hexan-3- yl methanesulfonate (3.5 g, 20 mmol) were dissolved in toluene (100 mL) ). NaOH (1.0 g, 25 mmol) and benzyltriethylammonium chloride (114 mg, 0.5 mmol) were successively added to the resulting suspension. The resulting mixture was heated to 80 < 0 > C and allowed to react for 16 hours. The reaction mixture was cooled to room temperature. Water (50 mL) was added to the reaction mixture. The product mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5.0 g of crude product which was used directly in the next step without purification.
(10) (2R,3R,4R,5S,6R)-2-(아세톡시메틸)-6-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)테트라하이드로-2H-피란-3,4,5-트라이일 트라이아세테이트의 제조(10) (2R, 3R, 4R, 5S, 6R) -2- (acetoxymethyl) -6- (3- (4- Yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate
조 (3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올(5.0 g)을 염화 메틸렌(50 ㎖)에 용해시켰다. 상기 생성 혼합물에 피리딘(7.9 g, 100 mmol) 및 4-(다이메틸아미노)피리딘(122 ㎎, 1 mmol)을 가하고, 이어서 빙욕에서 아세트산 무수물(10.2 g, 100 mmol)을 가하였다. 상기 혼합물을 실온까지 가온하고 4 시간 동안 교반하였다. 상기 혼합물에 물을 가하였다. 생성 혼합물을 에틸 아세테이트(150 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 1 mol/L 염산(150 ㎖ x 3), 포화된 나트륨 바이카보네이트 용액(150 ㎖) 및 포화된 염화 나트륨 용액으로 연속적으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 감압 하에서 농축시켰다. 상기 생성되는 조 생성물을 실리카젤 컬럼 크로마토그래피(에틸 아세테이트:석유 에테르 = 0-1:4)에 의해 정제시켜 350 ㎎의 생성물을 5.6%의 수율(총 2 단계)로 생성시켰다.(3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) Phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (5.0 g) was dissolved in methylene chloride (50 ml). To the resulting mixture was added pyridine (7.9 g, 100 mmol) and 4- (dimethylamino) pyridine (122 mg, 1 mmol) followed by acetic anhydride (10.2 g, 100 mmol) in an ice bath. The mixture was allowed to warm to room temperature and stirred for 4 hours. Water was added to the mixture. The resulting mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed successively with 1 mol / L hydrochloric acid (150 mL x 3), saturated sodium bicarbonate solution (150 mL) and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 4) to give 350 mg of the product in a yield of 5.6% (total of 2 steps).
(11) (2R,3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올의 제조(11R, 3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol
(2R,3R,4R,5S,6R)-2-(아세톡시메틸)-6-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)테트라하이드로-2H-피란-3,4,5-트라이일 트라이아세테이트(350 ㎎, 0.56 mmol)를 물, 메탄올 및 테트라하이드로퓨란(1:2:2, 25 ㎖)의 혼합된 용매에 용해시켰다. 상기 생성 혼합물에 LiOH·H2O(118 ㎎, 2.8 mmol)를 가하였다. 상기 반응 혼합물을 실온에서 16 시간 동안 교반하고, 감압 하에서 농축시켰다. 상기 생성되는 농축물에 물(20 ㎖)을 가하였다. 상기 생성 혼합물을 에틸 아세테이트(30 ㎖ x 3)로 추출하였다. 유기상들을 합하고, 포화된 염화 나트륨 용액으로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 감압 하에서 농축시켰다. 생성되는 조 생성물을 실리카젤 컬럼 크로마토그래피(메탄올:염화 메틸렌 = 0-1:15)에 의해 정제시켜 140 ㎎의 생성물을 54.7%의 수율로 생성시켰다.(2R, 3R, 4R, 5S, 6R) -2- (acetoxymethyl) -6- (3- (4- (350 mg, 0.56 mmol) was dissolved in water, methanol, and tetrahydrofuran (1: 2: 2, 25 ml) in a mixed solvent. To the resultant mixture was added LiOH 占2 2O (118 mg, 2.8 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. Water (20 mL) was added to the resulting concentrate. The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (methanol: methylene chloride = 0-1: 15) to give 140 mg of product in a yield of 54.7%.
화학식: C25H29ClO6 Mw:460.95The formula: C 25 H 29 ClO 6 Mw: 460.95
1H-NMR (400MHz, MeOD) δ: 7.29-7.31 (m, 3H), 7.04-7.07 (m, 2H), 6.68-6.71 (m, 2H), 4.77-4.81 (m, 1H), 4.57-4.61 (m, 1H), 4.15-4.19 (m, 1H), 3.98-4.05 (4H, m), 3.92-3.93 (m, 1H), 3.80-3.83 (m, 1H), 3.63-3.68 (m, 1H), 2.16-2.21 (m, 2H), 1.94-1.97 (m, 2H), 1.24-1.34 (m, 2H), 0.54-0.56 (m, 1H), 0.39-0.49(m, 1H). 1 H-NMR (400MHz, MeOD ) δ: 7.29-7.31 (m, 3H), 7.04-7.07 (m, 2H), 6.68-6.71 (m, 2H), 4.77-4.81 (m, 1H), 4.57-4.61 (m, 1 H), 3.63-3.68 (m, 1H), 4.15-4.19 (m, 1H), 3.98-4.05 (4H, m), 3.92-3.93 , 2.16-2.21 (m, 2H), 1.94-1.97 (m, 2H), 1.24-1.34 (m, 2H), 0.54-0.56 (m, 1H), 0.39-0.49 (m, 1H).
Claims (21)
화학식 II
(상기 화합물은 (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올이다).Claims 1. A compound represented by the formula < RTI ID = 0.0 > (II) < / RTI &
(II)
(The above compound is obtained by reacting (2S, 3R, 4R, 5S, 6R) -2- (3- (4- ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol.
(상기 화합물은 (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올이다)
화학식 b의 화합물을 유기 용매에 용해시키고; 상기 생성 혼합물에 화학식 a의 화합물을 가하고; 이어서 상기 생성 혼합물을 0 ℃ 내지 70 ℃의 온도에서 반응시켜 화학식 c의 화합물을 생성시키고;
상기 화학식 c의 화합물을
상기 화학식 d-2의 화합물을 -78 ℃ 내지 30 ℃의 온도에서 반응시켜 화학식 e의 화합물을 생성시키고;
상기 화학식 e의 화합물을 정제시켜 화학식 II에 의해 나타낸 화합물을 생성시킨다
상기에서,
X는 플루오로, 클로로, 브로모 또는 요오도를 나타내고,
G는 트라이메틸실릴, 트라이에틸실릴, 벤질, 파라-메톡시벤질, 파라-나이트로벤질, 피발로일, 알릴, 메톡시메틸, 벤질옥시메틸 및 트라이메틸실릴에틸 중에서 선택된 하이드록시 보호 그룹을 나타낸다.A process for the preparation of a compound represented by formula (II), comprising the steps of:
(The above compound is obtained by reacting (2S, 3R, 4R, 5S, 6R) -2- (3- (4- ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)
Dissolving the compound of formula b in an organic solvent; Adding the compound of formula a to the resulting mixture; The resulting mixture is then reacted at a temperature of from 0 캜 to 70 캜 to yield a compound of formula c;
The compound of formula (c)
Reacting the compound of formula d-2 at a temperature between -78 [deg.] C and 30 [deg.] C to yield a compound of formula e;
The compound of formula e is purified to give the compound represented by formula II
In the above,
X represents fluoro, chloro, bromo or iodo,
G represents a hydroxy protecting group selected from trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl and trimethylsilylethyl .
유기 용매가 N-메틸피롤리돈, N,N-다이메틸폼아미드, 테트라하이드로퓨란, 다이옥산 및 아세토나이트릴 중에서 선택되는, 화학식 II에 의해 나타낸 화합물의 제조 방법.3. The method of claim 2,
Wherein the organic solvent is selected from N-methylpyrrolidone, N, N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile.
화학식 e의 화합물을 하기의 단계들에 의해 정제하여 화학식 II에 의해 나타낸 화합물을 생성시키는 화학식 II에 의해 나타낸 화합물의 제조 방법:
상기 화학식 e의 화합물에 하이드록시 보호 반응을 가하여 화학식 f의 화합물을 생성시키고;
상기 화학식 f의 화합물에 탈보호 반응을 가하여 화학식 II에 의해 나타낸 화합물을 생성시킨다:
화학식 f
상기 식에서,
G'는 아세틸, 트라이메틸실릴, 트라이에틸실릴, 벤질, 파라-메톡시벤질, 파라-나이트로벤질, 피발로일, 알릴, 메톡시메틸, 벤질옥시메틸, 트라이메틸실릴에틸, 프로피오닐, 아이소부티릴 및 벤조일 중에서 선택된 하이드록시 보호 그룹을 나타낸다.3. The method of claim 2,
Process for the preparation of compounds represented by formula (II) wherein the compound of formula (e) is purified by the following steps to produce the compound represented by formula
Subjecting the compound of formula e to a hydroxy protecting reaction to produce a compound of formula f;
The compound of formula (f) is deprotected to give the compound represented by formula (II): < EMI ID =
Formula f
In this formula,
G 'is selected from the group consisting of acetyl, trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, Butyryl, and benzoyl.
(상기 화합물은 (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-바이사이클로[3.1.0]헥산-3-일)옥시)벤질)-4-클로로페닐)-6-(하이드록시메틸)테트라하이드로-2H-피란-3,4,5-트라이올이다)
화학식 a의 화합물을 유기 용매에 용해시키고; 상기 생성 혼합물에 화학식 b의 화합물을 가하고; 이어서 상기 생성 혼합물을 0 ℃ 내지 70 ℃의 온도에서 반응시켜 화학식 c'의 화합물을 생성시키고;
상기 화학식 c'의 화합물을
상기 화학식 d'-2의 화합물을 -78 ℃ 내지 30 ℃의 온도에서 반응시켜 화학식 e'의 화합물을 생성시키고;
상기 화학식 e'의 화합물을 정제시켜 화학식 III에 의해 나타낸 화합물을 생성시킨다
상기에서,
X는 플루오로, 클로로, 브로모 또는 요오도를 나타내고,
G는 트라이메틸실릴, 트라이에틸실릴, 벤질, 파라-메톡시벤질, 파라-나이트로벤질, 피발로일, 알릴, 메톡시메틸, 벤질옥시메틸 및 트라이메틸실릴에틸 중에서 선택된 하이드록시 보호 그룹을 나타낸다.A process for the preparation of compounds represented by formula (III), comprising the steps of:
(This compound was synthesized in the same manner as (1S, 3R, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)
Dissolving the compound of formula (a) in an organic solvent; Adding the compound of formula b to the product mixture; The resulting mixture is then reacted at a temperature of 0 ° C to 70 ° C to yield a compound of formula c ';
The compound of formula c '
Reacting said compound of formula (D-2) at a temperature of from -78 [deg.] C to 30 [deg.] C to give a compound of formula e ';
The compound of formula e ' is purified to produce the compound represented by formula III
In the above,
X represents fluoro, chloro, bromo or iodo,
G represents a hydroxy protecting group selected from trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl and trimethylsilylethyl .
유기 용매가 톨루엔, N,N-다이메틸폼아미드, 테트라하이드로퓨란, 다이옥산 및 아세토나이트릴 중에서 선택되는, 화학식 III에 의해 나타낸 화합물의 제조 방법.6. The method of claim 5,
Wherein the organic solvent is selected from toluene, N, N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile.
화학식 e'의 화합물을 하기의 단계들에 의해 정제하여 화학식 III에 의해 나타낸 화합물을 생성시키는 화학식 III에 의해 나타낸 화합물의 제조 방법:
상기 화학식 e'의 화합물에 하이드록시 보호 반응을 가하여 화학식 f'의 화합물을 생성시키고;
상기 화학식 f'의 화합물에 탈보호 반응을 가하여 화학식 III에 의해 나타낸 화합물을 생성시킨다:
화학식 f'
상기 식에서,
G'는 아세틸, 트라이메틸실릴, 트라이에틸실릴, 벤질, 파라-메톡시벤질, 파라-나이트로벤질, 피발로일, 알릴, 메톡시메틸, 벤질옥시메틸, 트라이메틸실릴에틸, 프로피오닐, 아이소부티릴 및 벤조일 중에서 선택된 하이드록시 보호 그룹을 나타낸다.6. The method of claim 5,
A process for the preparation of compounds represented by formula (III) wherein the compound of formula (e ') is purified by the following steps to yield the compound represented by formula (III)
Subjecting the compound of formula e 'to a hydroxy protecting reaction to produce a compound of formula f';
The compound of formula f 'is deprotected to give the compound represented by formula III:
The formula f '
In this formula,
G 'is selected from the group consisting of acetyl, trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, Butyryl, and benzoyl.
상기 G는 트라이메틸실릴인, 화학식 II에 의해 나타낸 화합물의 제조 방법.3. The method of claim 2,
Wherein G is trimethylsilyl. ≪ RTI ID = 0.0 > 11. < / RTI >
상기 유기 용매는 N-메틸피롤리돈인 화학식 II에 의해 나타낸 화합물의 제조 방법.The method of claim 3,
Wherein the organic solvent is N-methyl pyrrolidone.
상기 G'는 아세틸, 피발로일, 프로피오닐, 아이소부티릴 및 벤조일 중에서 선택된 하이드록시 보호 그룹을 나타내는, 화학식 II에 의해 나타낸 화합물의 제조 방법.5. The method of claim 4,
Wherein G 'represents a hydroxy protecting group selected from acetyl, pivaloyl, propionyl, isobutyryl and benzoyl.
상기 G는 트라이메틸실릴인, 화학식 III에 의해 나타낸 화합물의 제조 방법.6. The method of claim 5,
Wherein G is trimethylsilyl. ≪ RTI ID = 0.0 > 11. < / RTI >
상기 유기 용매는 톨루엔인 화학식 III에 의해 나타낸 화합물의 제조 방법.The method according to claim 6,
RTI ID = 0.0 > (III) < / RTI > wherein said organic solvent is toluene.
상기 G'는 아세틸, 피발로일, 프로피오닐, 아이소부티릴 및 벤조일 중에서 선택된 하이드록시 보호 그룹을 나타내는, 화학식 III에 의해 나타낸 화합물의 제조 방법.8. The method of claim 7,
Wherein G 'represents a hydroxy protecting group selected from acetyl, pivaloyl, propionyl, isobutyryl and benzoyl.
As intermediates for the compounds represented by formula II,
상기 약학 조성물은 하나 이상의 혈당강하제를 또한 함유하고, 상기 혈당강하제가 시타글립틴 포스페이트, 빌다글립틴, 삭사글립틴, 알로글립틴 벤조에이트, 리나글립틴, 테넬리글립틴, 제미글립틴, 메트포르민, 펜포르민, 엑세나타이드 및 리라글루티드 중에서 선택되는, 당뇨병 또는 당뇨병 관련된 질병의 치료 또는 예방을 위한 약학 조성물.17. The method of claim 16,
Wherein the pharmaceutical composition further comprises at least one hypoglycemic agent and wherein the hypoglycemic agent is selected from the group consisting of citagliptin phosphate, valdagliptin, saxagliptin, allogliptin benzoate, linagliptin, teneligliptin, gemigliptin, metformin , ≪ / RTI > phenorphin, exenatide, and liraglutide, for the treatment or prevention of diabetes or diabetes related diseases.
상기 당뇨병은 인슐린 의존성 당뇨병 또는 비-인슐린 의존성 당뇨병인, 방법. 19. The method of claim 18,
Wherein said diabetes is insulin dependent diabetes or non-insulin dependent diabetes.
상기 당뇨병 관련된 질병은 인슐린 내성 질병 또는 비만증인, 방법. 19. The method of claim 18,
Wherein said diabetes-related disease is insulin-resistant disease or obesity.
상기 포유동물은 인간인, 방법.19. The method of claim 18,
Wherein said mammal is a human.
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| DK3404033T3 (en) * | 2016-01-04 | 2020-11-02 | Jeil Pharmaceutical Co Ltd | C-glucoside derivative with fused phenyl ring or pharmaceutically acceptable salt thereof, process for its preparation and pharmaceutical composition containing it |
| EP3466940B1 (en) * | 2016-05-28 | 2021-11-17 | Ji Lin Hui Sheng Bio-Pharmaceutical Co., Ltd. | Crystal form of sodium-glucose cotransporter 2 inhibitor |
| CN108285439B (en) * | 2017-01-09 | 2023-05-02 | 江苏天士力帝益药业有限公司 | Carbonoside sodium glucose transport protein body 2 inhibitor |
| CN111465598B (en) * | 2018-03-30 | 2023-04-21 | 山东丹红制药有限公司 | Glucoside derivative as SGLTs inhibitor and application thereof |
| CN110551088B (en) * | 2018-06-01 | 2022-10-21 | 北京惠之衡生物科技有限公司 | Deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives |
| CN112047915B (en) * | 2019-06-05 | 2023-02-17 | 北京惠之衡生物科技有限公司 | Novel preparation process of C-glycoside derivatives |
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| CN113045525B (en) * | 2021-05-31 | 2021-09-17 | 北京惠之衡生物科技有限公司 | Preparation method of C-glucoside derivative and preparation thereof |
| CN113336733B (en) * | 2021-05-31 | 2022-02-18 | 北京惠之衡生物科技有限公司 | Preparation method of L-proline co-crystal of SGLT-2 inhibitor |
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