(S)-4-(3,4-difluorophenyl)-1,2,3,4-tetrahydro-6-(methoxymethyl)-2-oxo-5-pyrimidinecarboxylic acid methyl ester | 218430-63-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (S)-4-(3,4-difluorophenyl)-1,2,3,4-tetrahydro-6-(methoxymethyl)-2-oxo-5-pyrimidinecarboxylic acid methyl ester
• 英文别名: 4-(+)-(3,4-difluorophenyl)-2-oxo-6-methoxymethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester；(S)-methyl-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate；(S)-methyl 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate；(+)-(6S)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxopyrimidine；methyl (4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-3,4-dihydro-1H-pyrimidine-5-carboxylate
• CAS: 218430-63-8
• 化学式: C₁₄H₁₄F₂N₂O₄
• 分子量: 312.273
• InChiKey: XVOMKCVOLOSQTJ-LBPRGKRZSA-N

物化性质

• 熔点：
  137-140 °C
• 沸点：
  391.7±42.0 °C(Predicted)
• 密度：
  1.309±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  76.7
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  对硝基苯基氯甲酸酯 、 (S)-4-(3,4-difluorophenyl)-1,2,3,4-tetrahydro-6-(methoxymethyl)-2-oxo-5-pyrimidinecarboxylic acid methyl ester 在 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 0.5h， 以67%的产率得到(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-3-(4-nitrophenoxycarbonyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
  参考文献：
  名称：

  SNAP-7941 的对映选择性合成：MCH1-R 的手性二氢嘧啶酮抑制剂。

  摘要：

  通过使用两种有机催化方法实现了 SNAP-7941（一种有效的黑色素浓缩激素受体拮抗剂）的对映选择性合成。用于合成富含对映体的二氢嘧啶酮核的第一种方法是金鸡纳生物碱催化的 β-酮酯曼尼希反应生成酰基亚胺，第二种方法是手性磷酸催化的 Biginelli 反应。通过在具有 3-(4-苯基哌啶-1-基)丙胺侧链片段的二氢嘧啶酮的 N3 位置选择性形成尿素来完成合成。SNAP-7921 的合成突出了不对称有机催化方法在构建一类重要的手性杂环中的实用性。

  DOI：

  10.1021/jo801463j
• 作为产物：
  描述：

  3,4-二氟苯甲醛 在 copper diacetate 、 Purafect 4000L 、 三氟化硼乙醚 、 三羟甲基氨基甲烷盐酸盐 、 溶剂黄146 、 三羟甲基氨基甲烷 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 248.0h， 生成 (S)-4-(3,4-difluorophenyl)-1,2,3,4-tetrahydro-6-(methoxymethyl)-2-oxo-5-pyrimidinecarboxylic acid methyl ester
  参考文献：
  名称：

  Efficient synthesis of the optically active dihydropyrimidinone of a potent α_1A- selective adrenoceptor antagonist

  摘要：

  描述了一种有效的α_1A-选择性肾上腺素受体拮抗剂的汇聚合成。合成的显著特点包括对混合二氢嘧啶酮的酶分离和在2,4'-二吡啶基的合成中使用钯偶联反应。关键词：二氢嘧啶酮，酶分离，钯偶联。

  DOI：

  10.1139/v02-079

文献信息

• Highly Enantioselective Organocatalytic Biginelli and Biginelli-Like Condensations: Reversal of the Stereochemistry by Tuning the 3,3′-Disubstituents of Phosphoric Acids
  作者：Nan Li、Xiao-Hua Chen、Jin Song、Shi-Wei Luo、Wu Fan、Liu-Zhu Gong

  DOI：10.1021/ja905320q

  日期：2009.10.28

  and Biginelli-like reactions by chiral phosphoric acids derived from 3,3'-disubstituted binaphthols have been investigated. The size of 3,3'-substituents of the catalysts is able to control the stereochemistry of the Biginelli reaction. By tuning the 3,3'-disubstituents of the phosphoric acids, the stereochemistry of the Biginelli reaction can be reversed. This organocatalytic Biginelli reaction by

  已经研究了衍生自 3,3'-二取代联萘的手性磷酸的有机催化对映选择性 Biginelli 和 Biginelli 样反应。催化剂的 3,3'-取代基的大小能够控制 Biginelli 反应的立体化学。通过调整磷酸的 3,3'-二取代基，可以逆转 Biginelli 反应的立体化学。这种由 Brønsted 酸 12b 和 13 进行的有机催化 Biginelli 反应适用于广泛的醛和各种 β-酮酯，提供了一种高度对映选择性的方法来访问 DHPM。3,3'-二（三苯基甲硅烷基）联萘酚衍生的磷酸提供了广泛的醛类和可烯醇化的酮类与苄基硫脲的类 Biginelli 反应，提供具有优异光学纯度的结构多样的二氢嘧啶硫酮。使用 ONIOM 方法对立体中心形成步骤的过渡态进行理论计算表明，亚胺和烯醇通过形成氢键同时被双官能手性磷酸活化。磷酸中的 3,3'-取代基对 Biginelli 反应立体化学的影响也
• Combination therapy for the treatment of benign prostatic hyperplasia
  申请人：Merck & Co., Inc.

  公开号：US06410554B1

  公开（公告）日：2002-06-25

  This invention relates to combination therapy for the treatment of benign prostatic hyperplasia comprising an alpha-1a antagonist and an endothelin antagonist. More specifically, the use of a selective alpha-1a adrenergic receptor antagonist in combination with a subtype non-selective endothelin antagonist provides relief of lower urinary tract symptoms in patients with symptomatic prostatism or benign prostatic hyperplasia. This combination therapy improves lower urinary tract symptoms including increasing urine flow rate, decreasing residual urine volume and improving overall obstructive and irritative symptoms in patients with benign prostatic hyperplasia or symptomatic prostatism.

  本发明涉及一种治疗良性前列腺增生的联合疗法，包括α-1a拮抗剂和内皮素拮抗剂。更具体地说，选择性α-1a肾上腺素受体拮抗剂与亚型非选择性内皮素拮抗剂的联合使用可为有症状的前列腺增生或前列腺症患者提供下尿路症状的缓解。这种联合疗法可以改善良性前列腺增生或有症状的前列腺症患者的下尿路症状，包括增加尿流率，减少残余尿量和改善整体阻塞性和刺激性症状。
• Alpha 1a adrenergic receptor antagonists
  申请人：Merck & Co., Inc.

  公开号：US06320049B1

  公开（公告）日：2001-11-20

  This invention relates to crystalline pharmaceutically acceptable salts of an alpha 1a adrenergic receptor antagonist, Compound A, which are useful in the treatment of benign prostatic hyperplasia. Pharmaceutical compositions employing the crystalline salts, and processes for making and using the crystalline salts and pharmaceutical compositions of Compound A are also disclosed. This invention further relates to a process for obtaining enantiomerically pure intermediate useful for the synthesis of end product alpha 1a adrenergic receptor antagonists. The end product compounds are useful for the treatment of benign prostatic hyperplasia and for relaxing lower urinary tract tissue. The invention also relates to a process for preparing a class of dihydropyrimidinone compounds of which Compound A is a member, wherein the process involves deprotonating a dihydropyrimidinone compound and then coupling the deprotonated derivative with a primary amine.

  本发明涉及一种α1a肾上腺素能受体拮抗剂化合物A的结晶药物可接受盐，该盐在良性前列腺增生的治疗中有用。还公开了采用这些结晶盐的制药组合物，以及制备和使用化合物A的结晶盐和制药组合物的过程。本发明还涉及一种用于合成最终产物α1a肾上腺素能受体拮抗剂的对映纯中间体的过程。最终产物化合物对于治疗良性前列腺增生和放松下尿道组织有用。本发明还涉及一种制备一类二氢嘧啶酮化合物的过程，其中化合物A是该类化合物的成员，该过程涉及去质子化二氢嘧啶酮化合物，然后将去质子化衍生物与一级胺偶联。
• Enzymatic process of making alpha 1a adrenergic receptor antagonists using protease
  申请人：Merck & Co., Inc.

  公开号：US06207444B1

  公开（公告）日：2001-03-27

  This invention relates to crystalline pharmaceutically acceptable salts of an alpha 1a adrenergic receptor antagonist, Compound A, which are useful in the treatment of benign prostatic hyperplasia. Pharmaceutical compositions employing the crystalline salts, and processes for making and using the crystalline salts and pharmaceutical compositions of Compound A are also disclosed. This invention further relates to a process for obtaining enantiomerically pure intermediate useful for the synthesis of end product alpha 1a adrenergic receptor antagonists. The end product compounds are useful for the treatment of benign prostatic hyperplasia and for relaxing lower urinary tract tissue. The invention also relates to a process for preparing a class of dihydropyrimidinone compounds of which Compound A is a member, wherein the process involves deprotonating a dihydropyrimidinone compound and then coupling the deprotonated derivative with a primary amine.

  本发明涉及一种α1a肾上腺素能受体拮抗剂化合物A的结晶药物可接受盐，其在良性前列腺增生的治疗中有用。还公开了使用这些结晶盐的制药组合物，以及制备和使用化合物A的结晶盐和制药组合物的过程。本发明还涉及一种用于合成最终产物α1a肾上腺素能受体拮抗剂的对映纯中间体的制备过程。最终产物化合物对于治疗良性前列腺增生和放松下尿路组织有用。本发明还涉及一种制备二氢嘧啶酮化合物的类的过程，其中该过程涉及去质子化二氢嘧啶酮化合物，然后与一级胺偶联。
• In Vitro and in Vivo Evaluation of Dihydropyrimidinone C-5 Amides as Potent and Selective α_1A Receptor Antagonists for the Treatment of Benign Prostatic Hyperplasia
  作者：James C. Barrow、Philippe G. Nantermet、Harold G. Selnick、Kristen L. Glass、Kenneth E. Rittle、Kevin F. Gilbert、Thomas G. Steele、Carl F. Homnick、Roger M. Freidinger、Rick W. Ransom、Paul Kling、Duane Reiss、Theodore P. Broten、Terry W. Schorn、Raymond S. L. Chang、Stacey S. O'Malley、Timothy V. Olah、Joan D. Ellis、Andrea Barrish、Kelem Kassahun、Paula Leppert、Dhanapalan Nagarathnam、Carlos Forray

  DOI：10.1021/jm990612y

  日期：2000.7.1

  alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K-i values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1d) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.