ethyl (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate | 149709-59-1

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 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: ethyl (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate
• 英文别名: (R,E)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpent-2-enoate；ethyl (E,4R)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pent-2-enoate
• CAS: 149709-59-1
• 化学式: C₂₅H₃₁NO₄
• 分子量: 409.525
• InChiKey: QOCQMJHAWNNWAV-BKELBIJQSA-N

物化性质

• 沸点：
  562.7±50.0 °C(Predicted)
• 密度：
  1.081±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  30
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  储存温度：2-8°C，需存放在干燥密封的环境中。

反应信息

• 作为反应物：
  描述：

  ethyl (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate 在 palladium on activated charcoal 吡啶 、 盐酸 、 氢气 作用下， 以 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 25.0~80.0 ℃ 、344.73 kPa 条件下， 反应 44.0h， 生成 沙库巴曲
  参考文献：
  名称：

  Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors

  摘要：

  The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.

  DOI：

  10.1021/jm00010a014
• 作为产物：
  描述：

  methyl N-(tert-butoxycarbonyl)-O-[(trifluoromethyl)sulfonyl]-D-tyrosinate 在 四(三苯基膦)钯 sodium hydroxide 、 lithium aluminium tetrahydride 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 二氯甲烷 、 甲苯 为溶剂， 反应 34.33h， 生成 ethyl (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate
  参考文献：
  名称：

  Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors

  摘要：

  The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.

  DOI：

  10.1021/jm00010a014

文献信息

• NEW PROCESS
  申请人：ZHEJIANG JIUZHOU PHARMACEUTICAL CO., LTD

  公开号：US20150210632A1

  公开（公告）日：2015-07-30

  The invention relates to a new enantioselective process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone.

  本发明涉及一种新的手性选择性工艺，用于生产制造NEP抑制剂或其前药的有用中间体，特别是包含γ-氨基-δ-联苯-α-甲基链烷酸或酸酯骨架的NEP抑制剂。
• [EN] NEW PROCESS<br/>[FR] NOUVEAU PROCÉDÉ
  申请人：ZHEJIANG JIUZHOU PHARM CO LTD

  公开号：WO2014032627A1

  公开（公告）日：2014-03-06

  Provided is a new enantioselective process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ -amino- δ -biphenyl- a -methylalkanoic acid, or acid ester, backbone.

  提供了一种新的对映选择性工艺，用于生产制造NEP抑制剂或其前药的有用中间体，特别是包含γ-氨基-δ-联苯-α-甲基链烷酸或酸酯骨架的NEP抑制剂。
• [EN] NOVEL PRODRUGS AND COMBINATIONS FOR TREATMENT OF HYPERTENSION AND CARDIOVASCULAR DISEASES<br/>[FR] NOUVEAUX PRO-MÉDICAMENTS ET COMBINAISONS POUR LE TRAITEMENT DE L'HYPERTENSION ET DE MALADIES CARDIOVASCULAIRES
  申请人：WANG ZHAOYIN

  公开号：WO2015154673A1

  公开（公告）日：2015-10-15

  The invention relates a pharmaceutical composition comprising (i) prodrugs of NEP inhibitors, (ii) mutual prodrugs of angiotensin receptor antagonist and a NEP inhibitor, (iii) a combination of an angiotensin receptor antagonist prodrug and a NEP inhibitor and (iv) a combination of angiotensin receptor antagonist including prodrug, a NEP inhibitor prodrug and a diuretic drug (v) a combination of angiotensin receptor antagonist, a NEP inhibitor prodrug and a calcium channel blocker. The angiotensin receptor antagonist is selected from the group selected from the group consisting of allisartan, elisartan, candesartan, eprosartan, irbesartan, losartan, saprisartan, tasosartan, telmisartan and valsartan. The invention also includes a method for treating hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke.

  该发明涉及一种药物组合物，包括（i）NEP抑制剂的前药，（ii）AT1受体拮抗剂和NEP抑制剂的相互前药，（iii）AT1受体拮抗剂前药和NEP抑制剂的组合，以及（iv）包括AT1受体拮抗剂前药、NEP抑制剂前药和利尿药的组合，（v）包括AT1受体拮抗剂、NEP抑制剂前药和钙通道阻滞剂的组合。AT1受体拮抗剂选自阿利沙坦、依利沙坦、坎地沙坦、依普沙坦、厄贝沙坦、洛卡特普、沙普利沙坦、他索坦、替米沙坦和缬沙坦等组中选择的组。该发明还包括一种治疗高血压、心力衰竭（急性和慢性）充血性心力衰竭、左心室功能障碍和肥厚型心肌病、糖尿病性心肌病、心房和心室心律失常、心房颤动、心房扑动、有害的血管重塑、心肌梗死及其后遗症、动脉粥样硬化、心绞痛（无论不稳定还是稳定）、肾功能不全（糖尿病和非糖尿病）、心力衰竭、心绞痛、糖尿病、继发性醛固酮分泌亢进、原发性和继发性肺动脉高压、肾功能衰竭病情，如糖尿病性肾病、肾小球肾炎、硬皮病、肾小球硬化、原发性肾脏疾病的蛋白尿，以及肾脏血管性高血压、糖尿病视网膜病变、其他血管疾病的管理，如偏头痛、周围血管疾病、雷诺病、管腔内增生、认知功能障碍（如阿尔茨海默病）、青光眼和中风的方法。
• 一种LCZ-696关键中间体的制备方法
  申请人：重庆市碚圣医药科技股份有限公司

  公开号：CN106431993B

  公开（公告）日：2018-10-30

  本发明涉及一种LCZ‑696关键中间体的制备方法；目的是提供一种收率高、纯度高、对生产设备要求低、便于工业化生产的LCZ‑696关键中间体的新制备方法。将NaHCO3加入水中搅拌溶清，将NaHCO3水溶液降温最终恒温至10‑20℃，向其中滴加入NaClO溶液；将醋酸异丙酯、化合物I、NaBr依次加入到反应釜中，20‑35℃搅拌20‑40min充分溶解后，加入TEMPO；将NaHCO3‑NaClO水溶液快速滴加到化合物Ⅰ‑NaBr‑TEMPO醋酸异丙酯溶液中反应，提纯化合物II然后制备化合物IV。本发明的有益效果是：使得化合物Ⅳ的收率由现有技术的50％左右提高至80％以上，并且降低了杂质的含量，制备的产品纯度达到99.0％以上，可直接用于下步反应无需提纯。此外，反应温度可控制在10‑35℃范围内，降低了对工业设备及操作时间的要求，大大利于工业化生产。
• 一种三苯基氧磷含量低的沙库必曲中间体的制备方法
  申请人：常州沃腾化工科技有限公司

  公开号：CN106946742A

  公开（公告）日：2017-07-14

  本发明涉及一种三苯基氧磷含量低的沙库必曲中间体的制备方法，其步骤为在(R)‑叔丁基(1‑([1,1'‑联苯]‑4‑基)‑3‑羟基丙烷‑2‑基)氨基甲酸酯中加入水、乙酸异丙酯、溴化钠、碳酸氢钠和四甲基哌啶氧化物，滴加次氯酸钠溶液反应，反应结束后分层，取有机层，加入乙氧甲酰基亚乙基三苯基磷反应，反应结束后浓缩去除乙酸异丙酯，再加入乙醇、水和氢氧化锂后加热至回流，然后浓缩至干再加入水和活性白土后在室温搅拌，过滤，滤液中加入乙醇和乙酸后加热至回流，冷却、搅拌，析出固体即为成品沙库必曲中间体。本发明具有能减少沙库必曲中间体沙库必曲中间体(R,E)‑5‑([1,1'‑联苯]‑4‑基)‑4‑((叔丁氧羰基)氨基)‑2‑甲基‑2‑戊烯酸中三苯基氧磷的含量的优点。