ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate | 149193-78-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate
• 英文别名: ethyl-3-amino-5-trimethylsilyl-4-pentynoate；(+/-) Ethyl 3-amino-5-(trimethylsilyl)-4-Pentynoate；(+/-)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate；ethyl 3-amino-5-trimethylsilylpent-4-ynoate
• CAS: 149193-78-2
• 化学式: C₁₀H₁₉NO₂Si
• 分子量: 213.352
• InChiKey: OUWAIQPQYZYLGM-UHFFFAOYSA-N

物化性质

• 沸点：
  260.1±35.0 °C(Predicted)
• 密度：
  0.968±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.15
• 重原子数：
  14
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  52.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate 在 4-二甲氨基吡啶 、 硫酸氢铵 、 phosphate buffer 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 3-<<4-<<4-(aminoiminomethyl)phenyl>amino>-1,4-dioxobutyl>amino>-5-(trimethylsilyl)-4-pentynoic acid
  参考文献：
  名称：

  Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. (Aminobenzamidino)succinyl (ABAS) Series of Orally Active Fibrinogen Receptor Antagonists

  摘要：

  Our initial orally active fibrinogen receptor antagonist benzamidinopentanoyl (BAP) series which was discovered through truncation of our iv antiplatelet agent (SC-52012) demonstrated modest oral activity in canine studies (ethyl [5-(4-amidinophenyl)pentanoyl]3-3-amino-3 pyridyl)propionate, 1e). Introduction of an amide bond adjacent to the benzamidine led to a novel series with an (aminobenzamidino)succinyl (ABAS) Arg-Gly surrogate that had improved in vitro potency (5-17 times) relative to the BAP series. Four ester prodrug/acid active metabolite pairs (2a/2e, 60a/60e, 62a/62e, 63a/63e) from the ABAS series which varied in their 3-substituent on the beta-amino ester ''aspartate mimetic'' were prepared in enantiomerically enriched form (>95:5), and they were evaluated in canine studies for their ability to block collagen-induced aggregation in platelet-rich plasma, the elimination profile (t(1/2) beta-phase), repeated oral dosing studies, and oral systemic availability. Of the four ester prodrug/acid active metabolite pairs, 2e/2a (SC-54684A/SC-54701A) had the most favorable properties in the above studies with an IC50 = 67 +/- 5 nM (dog platelet-rich plasma, collagen), t(1/2) beta = 1.6 h tester) and 6.5 h (acid), no adverse effects upon repeated dosing, and a drug oral systemic availability of 62% (area under curve (AUG) of acid 2a (drug) following ig administration of ester 2e (prodrug, 2.5 mg/kg) divided by AUC of acid 2a (drug) following iv administration of ester 2e (prodrug, 2.5 mg/kg) as determined by HPLRC). In further pharmacokinetic studies using nonlabeled 2e/2a, the oral systemic availability tester 2e ig/ester 2e iv) of 2e was measured to be in the range of 44.7-53.0%. The more biologically relevant oral systemic availability tester 2e ig/acid 2a iv) of 2e was found to be in the range of 22.0-26.4%. A pharmacophore model. based on inhibitors from several different benzamidine classes including 2a (ABAS class) was developed using a combination of molecular modeling (MM2) and pharmacophore identification (APOLLO) methods.

  DOI：

  10.1021/jm00013a014
• 作为产物：
  描述：

  三甲基乙炔基硅 在 盐酸 、 正丁基锂 作用下， 反应 3.42h， 生成 ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate
  参考文献：
  名称：

  Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. (Aminobenzamidino)succinyl (ABAS) Series of Orally Active Fibrinogen Receptor Antagonists

  摘要：

  Our initial orally active fibrinogen receptor antagonist benzamidinopentanoyl (BAP) series which was discovered through truncation of our iv antiplatelet agent (SC-52012) demonstrated modest oral activity in canine studies (ethyl [5-(4-amidinophenyl)pentanoyl]3-3-amino-3 pyridyl)propionate, 1e). Introduction of an amide bond adjacent to the benzamidine led to a novel series with an (aminobenzamidino)succinyl (ABAS) Arg-Gly surrogate that had improved in vitro potency (5-17 times) relative to the BAP series. Four ester prodrug/acid active metabolite pairs (2a/2e, 60a/60e, 62a/62e, 63a/63e) from the ABAS series which varied in their 3-substituent on the beta-amino ester ''aspartate mimetic'' were prepared in enantiomerically enriched form (>95:5), and they were evaluated in canine studies for their ability to block collagen-induced aggregation in platelet-rich plasma, the elimination profile (t(1/2) beta-phase), repeated oral dosing studies, and oral systemic availability. Of the four ester prodrug/acid active metabolite pairs, 2e/2a (SC-54684A/SC-54701A) had the most favorable properties in the above studies with an IC50 = 67 +/- 5 nM (dog platelet-rich plasma, collagen), t(1/2) beta = 1.6 h tester) and 6.5 h (acid), no adverse effects upon repeated dosing, and a drug oral systemic availability of 62% (area under curve (AUG) of acid 2a (drug) following ig administration of ester 2e (prodrug, 2.5 mg/kg) divided by AUC of acid 2a (drug) following iv administration of ester 2e (prodrug, 2.5 mg/kg) as determined by HPLRC). In further pharmacokinetic studies using nonlabeled 2e/2a, the oral systemic availability tester 2e ig/ester 2e iv) of 2e was measured to be in the range of 44.7-53.0%. The more biologically relevant oral systemic availability tester 2e ig/acid 2a iv) of 2e was found to be in the range of 22.0-26.4%. A pharmacophore model. based on inhibitors from several different benzamidine classes including 2a (ABAS class) was developed using a combination of molecular modeling (MM2) and pharmacophore identification (APOLLO) methods.

  DOI：

  10.1021/jm00013a014

文献信息

• Platelet aggregation inhibitors
  申请人：G. D. Searle & Co

  公开号：US05721366A1

  公开（公告）日：1998-02-24

  This invention relates to compounds having the following formula ##STR1## or a pharmaceutically acceptable salt thereof which are useful in the inhibition of platelet aggregation, to pharmaceutical compositions of such phenylamidines derivatives, and to a method of inhibiting platelet aggregation in mammals by administering such compounds and compositions.

  这项发明涉及具有以下结构式的化合物##STR1##或其药用可接受盐，这些化合物对抑制血小板聚集具有用处，以及这些苯基酰胺衍生物的药物组合物，以及通过给予这些化合物和组合物来抑制哺乳动物的血小板聚集的方法。
• Use of enzyme penicillin acylase in selective amidation/amide hydrolysis to resolve ethyl 3-amino-4-pentynoate isomers
  作者：Ravindra S. Topgi、John S. Ng、Bryan Landis、Ping Wang、James R. Behling

  DOI：10.1016/s0968-0896(99)00155-8

  日期：1999.10

  and (S)-enantiomers of ethyl 3-amino-4-pentynoate in enantiomerically pure form employing the enzyme Penicillin acylase. In the acylation, phenylacetic acid was used as an acylating agent. We have shown that both the acylation and deacylation can be employed and that the activity of the enzyme Penicillin acylase can be controlled by maintaining an appropriate pH of the reaction medium.

  β-氨基酸，（S）-3-氨基-4-戊酸乙基酯，是一种手性合成子，用于合成抗血小板药盐酸西米洛非。开发了一种生物催化方法，以使用青霉素酰基转移酶分解对映体纯形式的3-氨基-4-戊酸乙酯的（R）-和（S）-对映体。在酰化中，使用苯基乙酸作为酰化剂。我们已经表明可以同时使用酰化和脱酰作用，并且可以通过维持反应介质的适当pH来控制青霉素酰基转移酶的活性。
• Substituted .beta.-amino acid derivatives useful as platelet aggregation
  申请人：Monsanto Company

  公开号：US05239113A1

  公开（公告）日：1993-08-24

  Novel substituted .beta. amino acid derivatives are provided which inhibit platelet aggregation and intermediates thereof. This invention also pertains to pharmaceutical compositions and methods of using such derivatives.

  本发明提供了一种替代的新型.beta.氨基酸衍生物，能够抑制血小板聚集，以及其中间体。本发明还涉及制备这些衍生物的药物组合物和使用这些衍生物的方法。
• Process for the preparation of ethyl
  申请人：G. D. Searle & Co.

  公开号：US05536869A1

  公开（公告）日：1996-07-16

  The present invention relates to a novel process for the preparation of ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyno ate and pharmaceutically acceptable acid addition salt thereof which comprises treating (trimethylsilyl)acetylene sequentially with n-butyllithium and 4-formylmorpholine followed by acid hydrolysis to give 3-(trimethylsilyl)-2-propynal; treating 3-(trimethylsilyl)-2-propynal with lithium bis(trimethylsilyl)amide to give in situ N,3-bis(trimethylsilyl)-2-propyn-1-imine; condensation of N,3-bis(trimethylsilyl)-2-propyn-1-imine with lithium t-butyl acetate to give (.+-.)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; treating (.+-.)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate- with p-toluenesulfonic acid to give (.+-.)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate, mono p-toluenesulfonic acid salt, treatment of resulting salt with ethanol in the presence of p-toluenesulfonic acid to give (.+-.)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; desilylation of (.+-.)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate to give in situ (.+-.)ethyl 3-amino-4-pentynoate; resolution of (.+-.)ethyl 3-amino-4-pentynoate using (R)-(-)-mandelic acid and treatment of the resolved product with gaseous hydrochloric acid to give ethyl 3S-amino-4-pentynoate, monohydrochloride; coupling the ethyl 3S-amino-4-pentynoate, monohydrochloride to 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid, monohydrochloride in the presence of isobutyl chloroformate and N-methylmorpholine to give ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyno ate, monohydrochloride.

  本发明涉及一种新型制备乙基3S-[[4-[[4-(氨基亚甲基)苯基]氨基]-1,4-二氧戊基]氨基]-4-戊炔酸乙酯及其药学上可接受的酸加成盐的方法，该方法包括以下步骤：将（三甲基硅基）乙炔依次与正丁基锂和4-甲酰吗啉处理，然后进行酸水解以得到3-(三甲基硅基)-2-丙炔醛；将3-(三甲基硅基)-2-丙炔醛与双(三甲基硅基)胺锂处理以在位生成N,3-双(三甲基硅基)-2-丙炔-1-亚胺；将N,3-双(三甲基硅基)-2-丙炔-1-亚胺与叔丁基乙酸锂缩合以得到(.+-.)1,1-二甲基乙基3-氨基-5-(三甲基硅基)-4-戊炔酸乙酯；将(.+-.)1,1-二甲基乙基3-氨基-5-(三甲基硅基)-4-戊炔酸乙酯与对甲苯磺酸处理以得到(.+-.)1,1-二甲基乙基3-氨基-5-(三甲基硅基)-4-戊炔酸乙酯单对甲苯磺酸盐，将所得盐在对甲苯磺酸存在下与乙醇处理以得到(.+-.)乙基3-氨基-5-(三甲基硅基)-4-戊炔酸乙酯；去硅化(.+-.)乙基3-氨基-5-(三甲基硅基)-4-戊炔酸乙酯以在位生成(.+-.)乙基3-氨基-4-戊炔酸乙酯；使用(R)-(-)-苯基乙酸对(.+-.)乙基3-氨基-4-戊炔酸乙酯进行拆分，然后在气态盐酸存在下处理拆分产物以得到乙基3S-氨基-4-戊炔酸乙酯单盐酸盐；将乙基3S-氨基-4-戊炔酸乙酯单盐酸盐与4-[[4-(氨基亚甲基)苯基]氨基]-4-氧代丁酸单盐酸盐在异丙基氯甲酸酯和N-甲基吗啡存在下偶联以得到乙基3S-[[4-[[4-(氨基亚甲基)苯基]氨基]-1,4-二氧戊基]氨基]-4-戊炔酸乙酯单盐酸盐。
• Method and apparatus for preparation of chiral beta amino acids using penicilln G acylase
  申请人：Monsanto Company

  公开号：US06214609B1

  公开（公告）日：2001-04-10

  A method for preparing a chiral beta amino acid or its corresponding esters which comprises contacting a racemic beta amino acid, an acyl donor and Penicillin G acylase enzyme under conditions appropriate to stereoselectively acylate one enantiomer of the racemic beta amino acid to its corresponding N-acylated derivative whereby the opposite enantiomer of the beta amino acid is retained in enantiomerically enriched form.

  一种制备手性β-氨基酸或其对应酯的方法，包括在适当的条件下，将外消旋的β-氨基酸、酰基供体和青霉素G酰化酶酶接触，以立体选择性地酰化外消旋β-氨基酸的一个对映体，制备其对应的N-酰化衍生物，从而使β-氨基酸的相反对映体以对映体富集的形式保留。