ethyl (2S)-2-<4-<<(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl>oxy>phenyl>-3-(7-cyano-2-naphthyl)propanoate | 150610-65-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: ethyl (2S)-2-<4-<<(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl>oxy>phenyl>-3-(7-cyano-2-naphthyl)propanoate
• 英文别名: tert-butyl (S)-3-(4-((S)-3-(7-cyanonaphthalen-2-yl)-1-ethoxy-1-oxopropan-2-yl)phenoxy)pyrrolidine-1-carboxylate；(2S)-2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester；ethyl (2S)-2-[4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionate；ethyl (2S)-2-[4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphtyl) propionate；Ethyl (2S)-(4-(((3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl)oxy)phenyl)-3-(7-cyano-2-naphthyl)propanoate；tert-butyl (3S)-3-[4-[(2S)-3-(7-cyanonaphthalen-2-yl)-1-ethoxy-1-oxopropan-2-yl]phenoxy]pyrrolidine-1-carboxylate
• CAS: 150610-65-4
• 化学式: C₃₁H₃₄N₂O₅
• 分子量: 514.621
• InChiKey: NMJRXFTUIGIPII-NSOVKSMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  38
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  88.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl (2S)-2-<4-<<(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl>oxy>phenyl>-3-(7-cyano-2-naphthyl)propanoate 在 盐酸 、 氨 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 146.5h， 生成 ethyl (2S)-2-<4-<<(3S)-1-acetimidoyl-3-pyrrolidinyl>oxy>phenyl>3-(7-amidino-2-naphthyl)propanoate dihydrochloride
  参考文献：
  名称：

  Dibasic (Amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors

  摘要：

  Since activated factor X (FXa) is a coagulant enzyme that generates thrombin and participates in both intrinsic and extrinsic coagulation pathways, inhibition of FXa may be more effective than inactivation of thrombin for interrupting blood coagulation. To assess the possible effectiveness of FXa inhibition as an anticoagulant, we designed and synthesized 3-(amidinoaryl)-2-[4-[(3S)-3-pyrrolidinyloxyl phenyl]propanoic acid derivatives as low molecular weight, nonpeptidic, orally active FXa inhibitors. These derivatives exhibited potent and highly selective anti-FXa activity in vitro and anticoagulant activity on oral administration. The most promising compound, (2S)-2-[4-[(3S)-1- acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (4, DX-9065a), inhibited 50% of FXa activity (IC50) at 0.07 mu M, doubled plasma recalcification time (PRCT) at 0.5 mu M, and significantly prolonged activated partial thromboplastin time (APTT) at a dose of 100 mg/kg on oral administration. In contrast with FXa inhibition, 4 showed no activity against thrombin (IC50 > 2000 mu M).

  DOI：

  10.1021/jm00034a018
• 作为产物：
  描述：

  2-(4-羟苯基)-2-氧代乙酸乙酯 在 palladium(II) oxide 、 barium sulfate 、 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 7.75h， 生成 ethyl (2S)-2-<4-<<(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl>oxy>phenyl>-3-(7-cyano-2-naphthyl)propanoate
  参考文献：
  名称：

  Dibasic (Amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors

  摘要：

  Since activated factor X (FXa) is a coagulant enzyme that generates thrombin and participates in both intrinsic and extrinsic coagulation pathways, inhibition of FXa may be more effective than inactivation of thrombin for interrupting blood coagulation. To assess the possible effectiveness of FXa inhibition as an anticoagulant, we designed and synthesized 3-(amidinoaryl)-2-[4-[(3S)-3-pyrrolidinyloxyl phenyl]propanoic acid derivatives as low molecular weight, nonpeptidic, orally active FXa inhibitors. These derivatives exhibited potent and highly selective anti-FXa activity in vitro and anticoagulant activity on oral administration. The most promising compound, (2S)-2-[4-[(3S)-1- acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (4, DX-9065a), inhibited 50% of FXa activity (IC50) at 0.07 mu M, doubled plasma recalcification time (PRCT) at 0.5 mu M, and significantly prolonged activated partial thromboplastin time (APTT) at a dose of 100 mg/kg on oral administration. In contrast with FXa inhibition, 4 showed no activity against thrombin (IC50 > 2000 mu M).

  DOI：

  10.1021/jm00034a018

文献信息

• Enantioselective α-Benzylation of Acyclic Esters Using π-Extended Electrophiles
  作者：Kevin J. Schwarz、Chao Yang、James W. B. Fyfe、Thomas N. Snaddon

  DOI：10.1002/anie.201806742

  日期：2018.9.10

  esters is reported. This reaction proceeds via stereodefined C1‐ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX‐9065a.

  报道了无环酯的第一次不对称协作路易斯碱/钯催化的苄基烷基化。该反应通过立体定义的C1-烯醇铵盐亲核试剂进行。成功的关键是鉴定具有独特反应性的磷酸苄基亲电试剂。获得的烷基化产物具有很高的对映选择性，该方法已应用于凝血酶抑制剂DX‐9065a的合成。
• Process for preparing 2-phenyl-3-naphthylpropionic acid derivatives
  申请人：Daiichi Pharmaceutical Co., Ltd.

  公开号：US06337405B1

  公开（公告）日：2002-01-08

  A process for preparing a compound represented by general formulae (5) and (6) in the following reaction scheme or salts thereof, wherein R1 represents a protective group for a nitrogen atom; R2 represents a methanesulfonyl group or p-toluenesulfonyl group; R3 represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms; and X represents a halogen atom. Reaction Scheme: The above process is useful as an industrial process for preparing intermediates of anticoagulant aromatic amidine derivatives described in Japanese Patent Application Laid-Open (kokai) No. 208946/1993.

  一种制备以下反应方案中的通用式（5）和（6）所代表的化合物或其盐的方法，其中R1代表氮原子的保护基团；R2代表甲磺酰基团或对甲苯磺酰基团；R3代表氢原子、芳基烷基团或具有1至6个碳原子的烷基团；X代表卤素原子。反应方案：上述方法可用作制备日本专利申请公开（公开号208946/1993）中描述的抗凝血芳香胺衍生物中间体的工业方法。
• Process for preparing 3-(7-amidino-2-naphthyl)-2-phenylpropionic acid derivatives
  申请人：Daiichi Pharmaceutical Co., Ltd.

  公开号：US06342609B2

  公开（公告）日：2002-01-29

  A process for industrially preparing intermediates of aromatic amidine derivatives having anticoagulant activity, i.e., compounds represented by formula (3) or salts thereof, by the following reaction scheme including (1), (2), and (3), wherein R1 represents H or an alkyl group; and R3 represents H, an alkyl group, or an alkanoyl group

  一种用于工业制备具有抗凝血活性的芳香族酰胺衍生物中间体的过程，即通过以下反应方案（包括（1）、（2）和（3））制备化合物（3）或其盐，其中R1代表氢或烷基；而R3代表氢，烷基或脂肪酰基。
• PROCESS FOR PREPARING 2-PHENYL-3-NAPHTHYLPROPIONIC ACID DERIVATIVES
  申请人：DAIICHI PHARMACEUTICAL CO., LTD.

  公开号：EP0936215A1

  公开（公告）日：1999-08-18

  A process for preparing a compound represented by general formulae (5) and (6) in the following reaction scheme or salts thereof, wherein R1 represents a protective groupfor a nitrogen atom; R2 represents a methanesulfonyl group or p-toluenesulfonyl group; R3 represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms; and X represents a halogen atom. The above process is useful as an industrial process for preparing intermediates of anticoagulant aromatic amidine derivatives described in Japanese Patent Application Laid-Open (kokai) No. 208946/1993.

  一种制备下述反应方案中通式(5)和(6)所代表的化合物或其盐的工艺，其中 R1 代表氮原子的保护基团；R2 代表甲磺酰基或对甲苯磺酰基；R3 代表氢原子、芳烷基或具有 1 至 6 个碳原子的烷基；以及 X 代表卤素原子。 上述工艺可作为制备日本专利申请公开（kokai）第 208946/1993 号所述抗凝剂芳香族脒衍生物中间体的工业工艺。
• US6252088B1
  申请人：——

  公开号：US6252088B1

  公开（公告）日：2001-06-26