dimethyl 3-[(3-methoxymethyl)phenyl]-2-oxopropanephosphonate | 256382-39-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: dimethyl 3-[(3-methoxymethyl)phenyl]-2-oxopropanephosphonate
• 英文别名: {2-[(3-methoxymethyl-phenyl)methyl]-2-oxo-ethyl}phosphonic acid dimethyl ester；dimethy 3-[(3-methoxymethyl)phenyl]-2-oxopropanephosphonate；dimethyl 3-(3-methoxymethylphenyl)-2-oxopropylphosphonate；3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl ester；1-dimethoxyphosphoryl-3-[3-(methoxymethyl)phenyl]propan-2-one
• CAS: 256382-39-5
• 化学式: C₁₃H₁₉O₅P
• 分子量: 286.265
• InChiKey: YWYSQALFNCOQHA-UHFFFAOYSA-N

物化性质

• 沸点：
  383.5±32.0 °C(Predicted)
• 密度：
  1.168±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  dimethyl 3-[(3-methoxymethyl)phenyl]-2-oxopropanephosphonate 以 7-{(R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-trifluoromethyl-furan-2-yl)-propenyl]-pyrrolidin-1-yl}-heptanoic acid ethyl ester 为溶剂， 生成 7-{(R)-5-[(E)-3-Hydroxy-4-(3-methoxymethyl-phenyl)-but-1-enyl]-3,3-dimethyl-2-oxo-pyrrolidin-1-yl}-heptanoic acid
  参考文献：
  名称：

  8-Aza-11-deoxy prostaglandin analogues

  摘要：

  本发明涉及一般为EP4受体激动剂的化合物，其表示为式I：其中A为—CH2—CH2—，或—CH═CH—；B为不存在、芳基或杂芳基；R1为烷基、烯烃基、炔烃基、环烷基烷基、杂环烷基烷基、芳基、芳基烷基或杂芳基，当B为芳基或杂芳基且R3、R4、R5和R6不同时为氢时，或者R1为杂环烷基烷基、芳基或杂芳基，当B为不存在且R3、R4、R5和R6同时为氢时；其他取代基如规范中所定义；或其单体异构体、消旋或非消旋异构体混合物，或其药学上可接受的盐或溶剂。该发明还涉及含有此类化合物的药物组合物、用作治疗剂的方法以及其制备方法。

  公开号：

  US20030120079A1
• 作为产物：
  描述：

  N-methoxy-N-methyl-(3-methoxymethylphenyl)acetic acid amide 、 甲基膦酸二甲酯 在 正丁基锂 作用下， 以 正己烷 、 甲苯 为溶剂， 以76.2%的产率得到dimethyl 3-[(3-methoxymethyl)phenyl]-2-oxopropanephosphonate
  参考文献：
  名称：

  选择性EP4受体激动剂ONO-4819的改进合成

  摘要：

  高度选择性的EP4-受体激动剂ONO-4819的改进合成已经被开发出来。先前的合成方法具有几个缺点，其中一个关键的问题是难以除去副产物，导致活性药物成分（API）的质量不能令人满意。此外，在通过联萘酚改性的氢化铝锂立体选择性还原烯酮中间体时，低浓度的反应条件和繁琐的纯化步骤以除去过量的联萘酚是API生产过程中的关键问题。在改进的过程中，我们开发了使用γ-硫代丁内酯代替硫代乙酸钾作为硫源的改进条件，以引入含硫的C4侧链而不会形成副产物。对于手性醇的立体选择性合成，发现（-）-DIP-氯化物还原是最好的方法，这不仅可以提高对映选择性，而且可以提高纯化过程中去除手性改性剂的工作量。此外，苯甲酰基和叔丁基二甲基甲硅烷基作为羟基官能团的保护基用于所有中间体的精确工艺控制。通过改变这些保护基团，可以通过结晶中间体严格控制ONO-4819的纯度。因此，开发了具有高化学纯度的用于ONO-4819的改进的稳健方法。

  DOI：

  10.1021/jo901497u

文献信息

• Discovery of an 8-Aza-5-thiaProstaglandin E1 Analog as a Highly Selective EP4 Receptor Agonist
  作者：Tohru Kambe、Toru Maruyama、Atsushi Naganawa、Masaki Asada、Akiteru Seki、Takayuki Maruyama、Hisao Nakai、Masaaki Toda

  DOI：10.1248/cpb.59.1494

  日期：——

  For the purpose of discovering an orally available EP4 subtype-selective agonist, a series of 8-aza prostaglandin E1 (PGE1) analogs were synthesized and evaluated for their affinity for PGE2 receptor subtypes. Additionally, the structure–activity relationships of these compounds were studied. Among the tested compounds, the 8-aza PGE1 analog 6 and 8-aza-5-thiaPGE1 analog 12 had highly potent EP4 receptor affinity, good functional activity, and excellent subtype-selectivity. Furthermore, these analogs demonstrated good stability in human liver microsomes. As a result, we concluded that these two series of 8-aza PGE1 analogs could be promising chemical leads for an orally available EP4 subtype-selective agonist.

  为了发现一种口服可用的EP4亚型选择性激动剂，合成并评估了一系列8-氮原子前列腺素E1（PGE1）类似物对PGE2受体亚型的亲和力。此外，还研究了这些化合物的结构-活性关系。在测试的化合物中，8-氮PGE1类似物6和8-氮-5-硫PGE1类似物12对EP4受体具有高效的亲和力、良好的功能活性和优异的亚型选择性。此外，这些类似物在人体肝微粒体中表现出良好的稳定性。因此，我们得出结论，这两系列的8-氮PGE1类似物可能是口服可用的EP4亚型选择性激动剂的有前景的化学先导物。
• 5-thia-&ohgr;-substituted phenyl-prostaglandin E derivatives, process for producing the same and drugs containing the same as the active ingredient
  申请人：Ono Pharmaceutical Co., Ltd.

  公开号：US06462081B1

  公开（公告）日：2002-10-08

  The present invention relates to 5-thia-&ohgr;-substituted phenylprostaglandin E derivatives of the formula (I) (wherein, all the symbols are as defined in the specification), process for producing them and pharmaceutical compositions comprising them as active ingredient. The compounds of the formula (I) can bind to PGE2 receptors (especially, subtype EP4) strongly, so they are expected to be useful for prevention and/or treatment of immunological diseases (autoimmune diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemic lupus erythematosus etc., and rejection after organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death, lung failure, liver damage, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardiac ischemia, systemic inflammatory response syndrome, ambustion pain, sepsis, hemophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, and shock etc. Further, it is thought that EP4 subtype receptor relates to sleeping disorder and blood platelet aggregation, so the compounds of the present invention are expected to be useful for the prevention and/or treatment of such diseases.

  本发明涉及公式(I)的5-硫代-ω-取代苯基前列腺素E衍生物（其中，所有符号如规范中所定义），生产它们的方法以及包含它们作为活性成分的药物组合物。公式(I)的化合物可以强烈结合到PGE2受体（尤其是EP4亚型），因此预计它们对预防和/或治疗免疫性疾病（自身免疫疾病，如肌萎缩性侧索硬化（ALS），多发性硬化症，Sjögren综合症，慢性风湿性关节炎和系统性红斑狼疮等，器官移植后的排斥等），哮喘，异常骨形成，神经细胞死亡，肺功能衰竭，肝损伤，急性肝炎，肾炎，肾功能不全，高血压，心肌缺血，全身性炎症反应综合征，烧伤疼痛，败血症，血吞噬综合征，巨噬细胞活化综合征，Still氏病，川崎病，烧伤，全身性肉芽肿，溃疡性结肠炎，克罗恩病，透析时的高细胞因子血症，多器官功能衰竭和休克等方面有用。此外，据认为EP4亚型受体与睡眠障碍和血小板聚集有关，因此本发明的化合物预计对预防和/或治疗此类疾病有用。
• Remedies for diseases with bone mass loss having ep4 agonist as the active ingredient
  申请人：Maruyama Toru

  公开号：US20050020686A1

  公开（公告）日：2005-01-27

  A pharmaceutical composition for topical administration for prevention and/or treatment of diseases associated with decrease in bone mass comprising an EP 4 agonist as an active ingredient. An EP 4 agonist, in which includes a compound possessing prostaglandin skeleton as a representative, possesses promoting action on bone formation, so it is useful for prevention and/or treatment of diseases associated with decrease in bone mass (bone diseases such as primary osteoporosis, secondary osteoporosis, bone metastasis of cancer, hypercalcemia, Paget's disease, bone loss and bone necrosis, postoperative osteogenesis, alternative therapy for bone grafting).

  一种用于局部给药以预防和/或治疗与骨质减少相关的疾病的药物组合物，其包括EP4激动剂作为活性成分。EP4激动剂包括具有前列腺素骨架的化合物，具有促进骨形成的作用，因此对于预防和/或治疗与骨质减少相关的疾病（如原发性骨质疏松症、继发性骨质疏松症、骨转移性癌症、高钙血症、Paget病、骨丢失和骨坏死、术后成骨、骨移植替代疗法）非常有用。
• PHARMACEUTICAL COMPOSITION FOR TREATMENT OF DISEASES ASSOCIATED WITH DECREASE IN BONE MASS COMPRISING EP4 AGONIST AS ACTIVE INGREDIENT
  申请人：MARUYAMA Toru

  公开号：US20100010222A1

  公开（公告）日：2010-01-14

  A pharmaceutical composition for topical administration for prevention and/or treatment of diseases associated with decrease in bone mass comprising an EP 4 agonist as an active ingredient. An EP 4 agonist, in which includes a compound possessing prostaglandin skeleton as a representative, possesses promoting action on bone formation, so it is useful for prevention and/or treatment of diseases associated with decrease in bone mass (bone diseases such as primary osteoporosis, secondary osteoporosis, bone metastasis of cancer, hypercalcemia, Paget's disease, bone loss and bone necrosis, postoperative osteogenesis, alternative therapy for bone grafting).

  一种用于局部治疗预防和/或治疗与骨量减少相关疾病的药物组合物，包括EP4激动剂作为活性成分。EP4激动剂，其中包括具有前列腺素骨架的化合物作为代表，具有促进骨形成的作用，因此对于预防和/或治疗与骨量减少相关的疾病（如原发性骨质疏松症、继发性骨质疏松症、骨癌转移、高钙血症、帕吉特病、骨丢失和骨坏死、术后骨生成、骨移植替代疗法）非常有用。
• 5-THIA-OMEGA-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES, PROCESS FOR PRODUCING THE SAME AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT
  申请人：ONO PHARMACEUTICAL CO., LTD.

  公开号：EP1097922A1

  公开（公告）日：2001-05-09

  5-Thia-ω-substituted phenyl-prostaglandin E derivatives represented by general formula (I) wherein each symbol is as defined in the specification. Because of being capable of bonding strongly to PEG2receptors (in particular, the subtype EP4), the compounds represented by general formula (I) are expected as useful in preventing and/or treating immunologic diseases, asthma, bone dysplasia, nerve cell death, lung failure, hepatopathy, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory syndrome, ambustion pain, sepsis, hemophagous syndrome, macrophage activation syndrome, Still disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, shock, etc. Moreover, these compounds participate in sleep disorders and platelet aggregation and, therefore, are expected as useful in preventing/treating these diseases.

  通式（I）代表的 5-噻-ω-取代苯基-前列腺素 E 衍生物，其中各符号如说明书中所定义。肾功能不全、高血压、心肌缺血、全身炎症综合征、灸痛、败血症、嗜血综合征、巨噬细胞活化综合征、斯蒂尔病、川崎病、烧伤、全身肉芽肿病、溃疡性结肠炎、克罗恩病、透析时的高细胞血症、多器官衰竭、休克等。此外，这些化合物还参与睡眠障碍和血小板聚集，因此有望用于预防/治疗这些疾病。