(2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-naphtho<1,2-b><1,4>thiazepin-4(5H)one | 125276-26-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• 英文名称: (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-naphtho<1,2-b><1,4>thiazepin-4(5H)one
• 英文别名: (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b][1,4]thiazepin-4(5H)-one；cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one；[2S-(2β,3β)]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b][1,4]thiazepin-4(5H)-one；(+/-)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one；(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-3,5-dihydro-2H-benzo[i][1,5]benzothiazepin-4-one
• CAS: 125276-26-8
• 化学式: C₂₀H₁₇NO₃S
• 分子量: 351.426
• InChiKey: DHIBOKJJFVRTBX-MSOLQXFVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  83.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-naphtho<1,2-b><1,4>thiazepin-4(5H)one 在 4-二甲氨基吡啶 、 potassium carbonate 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 反应 16.0h， 生成 (2S,3S)-5-[2-(二甲氨基)乙基]-2-(4-甲氧苯基)-4-羰基-2,3,4,5-四氢萘并[1,2-b][1,4]硫氮杂卓-3-基乙酸酯盐酸(1:1)
  参考文献：
  名称：

  Enantioselective synthesis of calcium channel blockers of the diltiazem group

  摘要：

  A lipase-catalyzed kinetic resolution of racemic trans-2-phenylcyclohexanol readily provides the (-)-1R,2S enantiomer. This alcohol is employed as its chloroacetate 10a in a chiral auxiliary-induced asymmetric Darzens glycidic ester condensation with p-anisaldehyde (9). Crystallization of the Darzens product affords enantiomerically pure (1R,2S)-2-phenylcyclohexyl (1R,2S)-2-(p-methoxyphenyl)glycidate (11), the structure of which was established by X-ray crystallography. The use of this glycidic ester in syntheses of diltiazem (1) and naltiazem (8), members of the diltiazem group of calcium channel blockers, provides these drug substances directly in enantiomerically pure form.

  DOI：

  10.1021/jo00029a013
• 作为产物：
  描述：

  (2R,3S)-3-<(2-amino-1-naphthalenyl)thio>-2-hydroxy-3-(4-methoxyphenyl)propanoic acid (1R,2S)-2-phenylcyclohexyl ester 在 对甲苯磺酸 作用下， 以 xylene 为溶剂， 反应 16.0h， 以89%的产率得到(2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-naphtho<1,2-b><1,4>thiazepin-4(5H)one
  参考文献：
  名称：

  Enantioselective synthesis of calcium channel blockers of the diltiazem group

  摘要：

  A lipase-catalyzed kinetic resolution of racemic trans-2-phenylcyclohexanol readily provides the (-)-1R,2S enantiomer. This alcohol is employed as its chloroacetate 10a in a chiral auxiliary-induced asymmetric Darzens glycidic ester condensation with p-anisaldehyde (9). Crystallization of the Darzens product affords enantiomerically pure (1R,2S)-2-phenylcyclohexyl (1R,2S)-2-(p-methoxyphenyl)glycidate (11), the structure of which was established by X-ray crystallography. The use of this glycidic ester in syntheses of diltiazem (1) and naltiazem (8), members of the diltiazem group of calcium channel blockers, provides these drug substances directly in enantiomerically pure form.

  DOI：

  10.1021/jo00029a013

文献信息

• Naphtho[1,2-b]-1,4-thiazepinones
  申请人：Hoffmann-La Roche Inc.

  公开号：US04652561A1

  公开（公告）日：1987-03-24

  Compounds of the formula ##STR1## wherein R.sub.1 is phenyl substituted with 1 to 3 lower alkoxy groups or 1 to 3 halogens; R.sub.2 is hydroxy, lower alkoxy, lower alkanoyloxy, lower cycloalkylcarbonyloxy; ##STR2## R.sub.3 and R.sub.4 are independently lower alkyl, phenyl lower alkyl or together form a piperidine or pyrrolidine ring; n is 2 to 4; m is 1 to 2; or pharmaceutically acceptable acid addition salts thereof are described. The compounds of formula I have activity as calcium channel blockers and accordingly, are useful as agents for lowering blood pressure, and as agents for treating ischemia.

  式为##STR1##的化合物，其中R.sub.1是苯基，其上取代有1至3个较低的烷氧基或1至3个卤素；R.sub.2是羟基、较低的烷氧基、较低的烷酰氧基、较低的环烷基羰基氧基；##STR2## R.sub.3和R.sub.4独立地是较低的烷基、苯基较低的烷基，或者一起形成哌啶或吡咯烷环；n为2至4；m为1至2；或其药学上可接受的酸盐。式I的化合物具有作为钙通道阻滞剂的活性，因此可用作降低血压的药物，并用作治疗缺血的药物。
• Process for preparing 1,5-benzothiazepin derivatives
  申请人：DSM N.V.

  公开号：EP0450705A1

  公开（公告）日：1991-10-09

  The invention relates to a process for preparing a preferably stereoisomerically pure 1,5-benzothiazepin derivative with the general formula (I) by the cyclization of an ester of the corresponding 2-hydroxy-3-(4-R₃-phenyl)--3-(2-aminoarylthio)propanoic acid with the general formula (II) in the presence of a base and in an aprotic, polar solvent where R₁ and R₂, each independently, represent hydrogen, halogen, or an alkyl group with 1-6 carbon atoms or together with the phenyl group to which they are attached from a naphtalene group, R₄ represents a residual group with 1-20 carbon atoms and R₃ a hydrogen atom, a hydroxy group or an alkoxy group with 1-6 carbon atoms, at which a 2-hydroxy-3-(4-R₃-phenyl)-3-(2-aminoarylthio)propanoic acid ester with the general formula (II) is cyclized in the presence of an alkali metal alkanolate as base. The invention also relates to a process for the preparation of alkylated and/or acylated 1,5-benzothiazepin derivatives and to the new compounds of (2X,3Y)-2-phenyl-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, (2X,3Y)-2-phenyl-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-di hydro-1,5-benzothiazepin-4(5H)-one and (2X,3Y)-2-phenyl--3-acetyloxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benz othiazepin-4(5H)-one, where X and Y each independently represent the R or S configuration. Application of 1,5-benzothiazepin derivatives, obtained according to the process of the present invention, in the preparation of pharmaceuticals and particularly in the preparation of diltiazem.

  该发明涉及一种制备偏好立体异构纯的1,5-苯并噻吩基衍生物的过程，其具有通式（I），通过在无水极性溶剂中，在碱的存在下，将相应的2-羟基-3-(4-R₃-苯基)-3-(2-氨基芳硫基)丙酸酯与通式（II）进行环化，其中R₁和R₂，各自独立地代表氢、卤素或具有1-6个碳原子的烷基基团，或与它们连接的苯基一起形成萘基，R₄代表具有1-20个碳原子的残基，R₃代表氢原子、羟基或具有1-6个碳原子的烷氧基，在碱金属烷醇盐存在下，通过环化2-羟基-3-(4-R₃-苯基)-3-(2-氨基芳硫基)丙酸酯与通式（II）。 该发明还涉及一种制备烷基化和/或酰化1,5-苯并噻吩基衍生物的过程以及新化合物(2X,3Y)-2-苯基-3-羟基-2,3-二氢-1,5-苯并噻吩-4(5H)-酮，(2X,3Y)-2-苯基-3-羟基-5-[2-(二甲氨基)乙基]-2,3-二氢-1,5-苯并噻吩-4(5H)-酮和(2X,3Y)-2-苯基-3-乙酰氧基-5-[2-(二甲氨基)乙基]-2,3-二氢-1,5-苯并噻吩-4(5H)-酮，其中X和Y各自独立地代表R或S构型。 根据本发明的过程获得的1,5-苯并噻吩基衍生物的应用，特别是在制备药物，尤其是地尔硫卓的制备中。
• Process for making optically active
  申请人：Hoffmann-La Roche Inc.

  公开号：US04864058A1

  公开（公告）日：1989-09-05

  A process for preparing optically active naphtho[1,2-b][1,4]thiazepin-4(5H)-ones comprising resolution of rac-.beta.-[(2-amino-1-naphthalenyl)thio]-.alpha.-hydroxy-4-methoxybenzene propanoic acid and converting the optically active acids so obtained into final products is described. The end product naphtho[1,2-b][1,4]thiazepin-4(5H)-ones have activity as calcium channel blockers and accordingly are useful as agents for lowering blood pressure, and as agents for treating ischemia.

  本发明涉及一种制备光学活性的萘并[1,2-b][1,4]噻唑-4(5H)-酮的方法，包括将混合物中的rac-β-[(2-氨基-1-萘基)硫基]-α-羟基-4-甲氧基苯丙氨酸分离，并将得到的光学活性酸转化为最终产物。最终产物萘并[1,2-b][1,4]噻唑-4(5H)-酮具有作为钙通道阻滞剂的活性，因此可用作降低血压的药物和治疗缺血的药物。
• Glycidic acid ester and process of preparation
  申请人：Hoffmann-La Roche Inc.

  公开号：US05008411A1

  公开（公告）日：1991-04-16

  A process for the preparing a compound of the formula ##STR1## wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, trifluoromethyl or nitro; or R.sub.1 and R.sub.2 taken together with the benzene ring to which they are attached are naphthalene, and Ar is p-lower alkoxy phenyl. which comprises reacting ##STR2## wherein R.sub.1 and R.sub.2 are as described above with the compound of the formula ##STR3## wherein Ar is as described above, in an aromatic organic compound. The intermediates formed by the process of the invention are useful in the production of thiazepin-4(5H)-ones which have activity as calcium channel blockers and accordingly are useful as agents for lowering blood pressure and agents for treating ischemia.

  一种制备式为 ##STR1## 的化合物的方法，其中R.sub.1和R.sub.2各自独立地为氢，1至4个碳原子的烷基，1至4个碳原子的烷氧基，卤素，三氟甲基或亚硝基；或R.sub.1和R.sub.2与它们连接的苯环一起为萘基，而Ar为p-低烷氧基苯基。该方法包括在芳香有机化合物中反应式为 ##STR2## 的化合物（其中R.sub.1和R.sub.2如上所述）和式为 ##STR3## 的化合物（其中Ar如上所述）以制备中间体。该发明所制备的中间体在制备噻唑啉-4（5H）-酮方面有用，其具有作为钙通道阻滞剂的活性，因此可用作降低血压和治疗缺血的药物。
• 2,3-Dihydro-2-phenyl-5-aminoalkyl-naphtho [1,2-b]-1,4-thiazepin-4(5H)-one derivatives
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0234561A2

  公开（公告）日：1987-09-02

  It has been found that the novel compounds of the formula wherein R, is phenyl substituted with 1 to 3 lower alkoxy groups or 1 to 3 halogens, R2 is hydroxy, lower alkoxv. lower alkanovloxv. lower cvcloalkvlcarbonvloxv. R3 and R, are, independently, lower alkyl, phenyl lower alkyl or, taken together, form a piperidine or pyrrolidine ring, n is 2 to 4 and m is 1 to 2, and pharmaceutically acceptable acid addition salts thereof have activity as calcium channel blockers and, accordingly, are useful as agents for treating ischemia and as agents for lowering blood pressure. They can be prepared by reacting a compound of the formula with a compound of the formula and optionally converting the compound thus obtained to a compound wherein R2 is other than hydroxy.

  发现式中的新型化合物 其中 R 是被 1 至 3 个低级烷氧基或 1 至 3 个卤素取代的苯基，R2 是羟基、低级烷氧基、低级烷烃氧基、低级环烷烃氧基、低级环羰基氧基。 R3和R, 独立地是低级烷基、苯基低级烷基，或共同形成哌啶或吡咯烷环，n为2至4，m为1至2、 及其药学上可接受的酸加成盐具有钙通道阻滞剂的活性，因此可用作治疗缺血和降低血压的药物。它们可以通过将式 与式 并选择性地将由此得到的化合物转化为 R2 为羟基以外的化合物。