3-氨基戊腈 | 170277-77-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 中文名称: 3-氨基戊腈
• 英文名称: (S)-3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methanesulfonate
• 英文别名: (S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol bismethanesulfonate；(S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(triphenylmethoxy)-1-butanol methanesulfonate；(S)-3-[(2-methylsulfonyloxy)ethoxy]-4-trityloxybutyl methanesulfonate；(3S)-3-{2-[(Methanesulfonyl)oxy]ethoxy}-4-(triphenylmethoxy)butyl methanesulfonate；[(3S)-3-(2-methylsulfonyloxyethoxy)-4-trityloxybutyl] methanesulfonate
• CAS: 170277-77-7
• 化学式: C₂₇H₃₂O₈S₂
• 分子量: 548.678
• InChiKey: BEIIPJGHIJEDMT-SANMLTNESA-N

物化性质

• 沸点：
  721.7±60.0 °C(Predicted)
• 密度：
  1.267±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  37
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  122
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-氨基戊腈 在 四丁基氯化铵 作用下， 以 甲苯 为溶剂， 反应 0.5h， 以100%的产率得到(S)-4-(triphenylmethoxy)-2-(2-chloroethoxy)-1-chlorobutane
  参考文献：
  名称：

  Macrocyclic Bisindolylmaleimides:  Synthesis by Inter- and Intramolecular Alkylation

  摘要：

  Macrocyclic bisindolylmaleimides 1-4 have been identified as competitive reversible inhibitors of PKC beta(1) and beta(2) and are being advanced to the clinic for evaluation as a treatment of retinopathy associated with diabetic complications. Highly convergent and stereoselective syntheses of 1-4 have been developed. The key synthetic step involves intermolecular alkylation of symmetrical bisindolylmaleimide 9 with chiral bisalkylating agent 8c and is amenable to the preparation of multikilogram quantities of these compounds. The synthetic sequence to 1, the most active compound, proceeds in 11 steps and 26% overall yield (>98% ee) from (R)-1-chloro-2,3-propanediol. No chromatographic purifications are required throughout the process and the final product is isolated in >97% purity after crystallization from DMF/MeOH. Synthesis of 1-4 by intramolecular alkylation proved less efficient, requiring 1? steps and affording 1-4 in lower overall yields of 6.0-8.5%.

  DOI：

  10.1021/jo971980h
• 作为产物：
  描述：

  (R)-3-chloro-1-O-trityl-1,2-propanediol 在 氢氧化钾 、 sodium hydroxide 、 sodium tetrahydroborate 、 sudan red 、 乙烯基溴化镁 、 potassium tert-butylate 、 臭氧 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 14.75h， 生成 3-氨基戊腈
  参考文献：
  名称：

  Macrocyclic Bisindolylmaleimides:  Synthesis by Inter- and Intramolecular Alkylation

  摘要：

  Macrocyclic bisindolylmaleimides 1-4 have been identified as competitive reversible inhibitors of PKC beta(1) and beta(2) and are being advanced to the clinic for evaluation as a treatment of retinopathy associated with diabetic complications. Highly convergent and stereoselective syntheses of 1-4 have been developed. The key synthetic step involves intermolecular alkylation of symmetrical bisindolylmaleimide 9 with chiral bisalkylating agent 8c and is amenable to the preparation of multikilogram quantities of these compounds. The synthetic sequence to 1, the most active compound, proceeds in 11 steps and 26% overall yield (>98% ee) from (R)-1-chloro-2,3-propanediol. No chromatographic purifications are required throughout the process and the final product is isolated in >97% purity after crystallization from DMF/MeOH. Synthesis of 1-4 by intramolecular alkylation proved less efficient, requiring 1? steps and affording 1-4 in lower overall yields of 6.0-8.5%.

  DOI：

  10.1021/jo971980h

文献信息

• Method of manufacturing ruboxistarin
  申请人：Zentiva, k.s.

  公开号：EP2181999A1

  公开（公告）日：2010-05-05

  Method of manufacturing ruboxistaurin, comprising the steps of preparation of L-2-deoxyribose 1-cyano-3,4-dibenzoate, followed by deprotection to 1-cyano L-2-deoxyribose, oxidative cleaving to (S)-4-hydroxy-2-(2-hydroxy-ethoxy)-butyronitrile and transformation to the methanesulfonic acid (S)-3-cyano-3-(2-methanesulfonyloxyethoxy)-propyl ester, then coupling with 1-substituted-3,4-bis(3-indolyl)maleimide leading to 9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13] oxadiazacyclohexadecine-18,20(19H)-dione, 6,7,10,11-tetrahydro-19-substituted-9(S)-cyano, followed by methylation of the amino group and deprotection forming 5,21:12,17-dimetheno-9H-dibenzo[e,k]furo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20-dione, 6,7,10,11-tetrahydro-9-[(dimethylamino)methyl]-, (S)- (9CI), and the final step consisting of imido preparation to form ruboxistaurin.

  生产鲁博西他林的方法，包括以下步骤：制备L-2-去氧核糖-1-氰-3,4-二苯甲酸酯，然后去保护成为1-氰基L-2-去氧核糖，氧化断裂成(S)-4-羟基-2-(2-羟基乙氧基)-丁腈，并转化为甲磺酸(S)-3-氰基-3-(2-甲磺酰氧乙氧基)-丙基酯，然后与1-取代-3,4-双(3-吲哚基)马来酰亚胺偶联，得到9H,18H-5,21:12,17-二甲烯二苯并[e,k]吡咯并[3,4-h][1,4,13]噁二氮杂环十六烷-18,20(19H)-二酮，6,7,10,11-四氢-19-取代-9(S)-氰基，然后甲基化氨基团并去保护，形成5,21:12,17-二甲烯-9H-二苯并[e,k]呋喃[3,4-h][1,4,13]噁二氮杂环十六烷-18,20-二酮，6,7,10,11-四氢-9-[(二甲氨基)甲基]-，(S)- (9CI)，最后一步是制备亚砜以形成鲁博西他林。
• Synthesis and Characterization of the Selective, Reversible PKC_β Inhibitor (9<i>S</i>)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9<i>H</i>,18<i>H</i>-5,21:12,17-dimethenodibenzo[<i>e,k</i>]pyrrolo[3,4-<i>h</i>][1,4,13]oxadiazacyclohexadecine-18,20(19<i>H</i>)-dione, Ruboxistaurin (LY333531)
  作者：Anita H. Lewin、Larry Brieaddy、Jeffrey R. Deschamps、Gregory H. Imler、S. Wayne Mascarella、P. Anantha Reddy、F. Ivy Carroll

  DOI：10.1021/acschemneuro.8b00196

  日期：2019.1.16

  17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, ruboxistaurin. Despite the interest in development of ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization

  PKCβ在介导安非他明刺激的多巴胺流出中的调节作用，调节苯丙胺诱导的多巴胺转运蛋白的运输和活性，已证明促进了选择性可逆PKCβ抑制剂（9 S）-9-[（（二甲基氨基）甲基]- 6,7,10,11-四氢-9 H，18 H-5,21：12,17-二甲二苯并[e，k]吡咯并[3,4-h] [1,4,13]草二氮杂环十六烷-18,20 （19 H）-二酮，ruboxistaurin。尽管有兴趣开发鲁贝司他林作为甲磺酸盐一水合物（Arxxant）用于治疗糖尿病性视网膜病，黄斑水肿和肾病，但理化特性中的一些关键细节是错误的或缺失的。这份报告描述了Ruboxistaurin游离碱（作为一水合物）的合成和完整表征，包括X射线晶体学以确认其绝对构型，
• Process for producing butanetriol derivative
  申请人：Daiso Co., Ltd.

  公开号：US06620977B1

  公开（公告）日：2003-09-16

  A process for preparing a butanetriol derivative of the formula (1) useful as intermediates of medicines wherein R1 is the same defined below, which comprises reacting a compound of the formula (3) wherein R1 and R2 are the different protecting groups, and an ethylene glycol derivative in a basic condition to prepare a compound of the formula (4) or (4a) wherein R1 and R2 are the same defined above, and then subjecting the compound (4) or (4a) to selective deprotection reaction.

  一种制备丁二醇衍生物的方法，其化学式为（1），可用作药物中间体，其中R1如下所定义，包括将化合物的反应（3）其中R1和R2是不同的保护基团，和乙二醇衍生物在碱性条件下反应以制备化合物的方法（4）或（4a），其中R1和R2如上所定义相同，然后将化合物（4）或（4a）进行选择性去保护反应。
• Hetero Diels−Alder-Biocatalysis Approach for the Synthesis of (<i>S</i>)-3-[2-{(Methylsulfonyl) oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol Methanesulfonate, a Key Intermediate for the Synthesis of the PKC Inhibitor LY333531¹
  作者：Jean-Claude Caille、C. K. Govindan、Heiko Junga、Jim Lalonde、Yiming Yao

  DOI：10.1021/op020202a

  日期：2002.7.1

  and easily scaled-up process has been developed for the synthesis of (S)-3-[2-(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methanesulfonate, a key intermediate used in the synthesis of a protein kinase C inhibitor drug through a combination of hetero Diels−Alder and biocatalytic reactions. The Diels−Alder reaction between ethyl glyoxylate and butadiene was used to make racemic 2-ethoxycarbonyl-3

  已开发出一种具有成本效益且易于放大的工艺，用于合成 (S)-3-[2-(甲基磺酰基)氧基}乙氧基]-4-(三苯基甲氧基)-1-丁醇甲磺酸盐，这是一种使用的关键中间体通过异源 Diels-Alder 和生物催化反应的组合合成蛋白激酶 C 抑制剂药物。乙醛酸乙酯和丁二烯之间的 Diels-Alder 反应用于制备外消旋的 2-乙氧基羰基-3,6-二氢-2H-吡喃。用迟缓芽孢杆菌蛋白酶处理外消旋酯导致 R-对映异构体的选择性水解并产生具有优异光学纯度的 S-2-乙氧基羰基-3,6-二氢-2H-吡喃，其被还原为 S-3,6 -二氢-2H-吡喃-2-基甲醇。这种醇的三苯甲基化，然后是还原性臭氧分解和甲磺酰化，以 10-15% 的总产率和 > 99% ee 和化学纯度。给出了在每个步骤中完成的过程开发工作的详细信息。
• [EN] PROTEIN KINASE C INHIBITOR<br/>[FR] INHIBITEUR DE LA PROTEINE KINASE C
  申请人：ELI LILLY AND COMPANY

  公开号：WO1997018809A1

  公开（公告）日：1997-05-29

  (EN) This invention provides novel bis-indolylmaleimide macrocycle derivatives of formula (Ia), and solvates thereof. The invention further provides the preparation, pharmaceutical formulations and the methods of use for inhibiting Protein Kinase C in mammals.(FR) L'invention concerne des nouveaux dérivés de macrocycles de bis-indolylmaléimide de la formule (Ia) et des solvates de ces derniers. L'invention traite aussi de la préparation, de formulations pharmaceutiques et de procédés d'utilisation pour inhiber la protéine Kinase C chez des mammifères.

  这项发明提供了式(Ia)的新型双吲哚基马来酰亚胺大环衍生物及其溶剂化物。该发明还提供了在哺乳动物中抑制蛋白激酶C的制备、制药配方和使用方法。