(R)-6-fluoro-2,3-dihydrospiro<4H-1-benzopyran-4,4'-imidazolidine>-2',5'-dione | 69881-27-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: (R)-6-fluoro-2,3-dihydrospiro<4H-1-benzopyran-4,4'-imidazolidine>-2',5'-dione
• 英文别名: (R)-sorbinil；(4R)-(-)-6-fluoro-2,3-dihydro-spiro-[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione；(R)-6-fluoro-2,3-dihydrospiro(4H-1-benzopyran-4,4'-imidazolidine)-2',5'-dione；(4R)-6-fluorospiro[2,3-dihydrochromene-4,5'-imidazolidine]-2',4'-dione
• CAS: 69881-27-2
• 化学式: C₁₁H₉FN₂O₃
• 分子量: 236.202
• InChiKey: LXANPKRCLVQAOG-LLVKDONJSA-N

物化性质

• 熔点：
  233-235 °C
• 密度：
  1.52±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  17
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  67.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-6-fluoro-2,3-dihydrospiro<4H-1-benzopyran-4,4'-imidazolidine>-2',5'-dione 、 对溴溴苄 在 sodium hydride 作用下， 生成 (R)-N₁',N₃'-Bis(4-bromobenzyl)-2,3-dihydro-6-fluorospiro<4H-1-benzopyran-4,4'-imidazolidine>-2',5'-dione
  参考文献：
  名称：

  醛糖还原酶抑制剂山梨醇的合成，绝对构型和构象。

  摘要：

  醛糖还原酶抑制剂2,3-二氢-6-氟螺[4H-1-苯并吡喃-4,4'-咪唑烷] -2'，5'-二酮被拆分为其对映体。Sorbinil，S异构体，在体内外比相应的R异构体是更好的酶抑制剂。介绍了用于确定其绝对构型的山梨醇X射线数据。溶液中山梨醇的NMR研究表明，存在两个构象异构体，它们具有较低的能量转换障碍。

  DOI：

  10.1021/jm00149a030
• 作为产物：
  描述：

  3-(4-氟苯氧基)丙酸 在 PPA 、 碳酸氢铵 作用下， 以 乙醇 、 水 为溶剂， 反应 63.33h， 生成 (R)-6-fluoro-2,3-dihydrospiro<4H-1-benzopyran-4,4'-imidazolidine>-2',5'-dione
  参考文献：
  名称：

  醛糖还原酶抑制剂山梨醇的合成，绝对构型和构象。

  摘要：

  醛糖还原酶抑制剂2,3-二氢-6-氟螺[4H-1-苯并吡喃-4,4'-咪唑烷] -2'，5'-二酮被拆分为其对映体。Sorbinil，S异构体，在体内外比相应的R异构体是更好的酶抑制剂。介绍了用于确定其绝对构型的山梨醇X射线数据。溶液中山梨醇的NMR研究表明，存在两个构象异构体，它们具有较低的能量转换障碍。

  DOI：

  10.1021/jm00149a030

文献信息

• Novel resolution process for racemic spiro-hydantoins
  申请人：Pfizer Inc.

  公开号：US04952694A1

  公开（公告）日：1990-08-28

  A novel three-step process for resolving a racemic spiro-hydantoin compound into its optical antipodes is disclosed, which involves (1) reacting said racemic compound with an optically-active asymmetric isocyanate of the formula RNCO, wherein R is (S)- or (R)-1-phenylethyl or (S) or (R)-1-(1-naphthyl)ethyl, to form the corresponding diastereomeric uredio compound; (2) separating the resulting diastereomeric mixture into its component parts, and (3) thereafter converting the separated ureido diastereomers obtained in step (b) to the corresponding asymmetric hydantoin compounds by treatment with an alkali metal lower alkoxide (C.sub.1 -C.sub.4), followed by acidification, whereupon the desired optical isomer is obtained. The final products so obtained, such as (4S)-(+)-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2' , 5'-dione (sorbinil) and (5'S)-3'-chloro-5', 6', 7', 8'-tetra-hydro-spiro[imidazolidine-4,5'-quinoline]-2,5-dione, are known to be useful in preventing or alleviating certain chronic diabetic complications. The aforementioned diastereomeric uredio intermediates are novel compounds.

  揭示了一种用于将一个混合氨基酸螺环脲化合物分离成其光学对映体的新颖三步过程，包括(1)将该混合氨基酸与一种光学活性不对称异氰酸酯（化学式为RNCO，其中R为(S)-或(R)-1-苯乙基或(S)或(R)-1-(1-萘基)乙基）反应，形成相应的二对映异构脲化合物；(2)将得到的二对映混合物分离成其组分；(3)然后通过用碱金属低碱度物（C.sub.1 -C.sub.4）处理，随后酸化，将在步骤(2)中获得的分离的脲二对映异构体转化为相应的不对称螺环脲化合物，从而得到所需的光学异构体。因此获得的最终产品，如(4S)-(+)-6-氟-2,3-二氢-螺[4H-1-苯并吡喃-4,4'-咪唑烷]-2'，5'-二酮（索必林）和(5'S)-3'-氯-5',6',7',8'-四氢-螺[咪唑烷-4,5'-喹啉]-2,5-二酮，已知在预防或缓解某些慢性糖尿病并发症方面具有用途。上述二对映异构脲中间体是新颖的化合物。
• Intermediates in a resolution process for racemic spiro hydantoins
  申请人：Pfizer Inc.

  公开号：US05006657A1

  公开（公告）日：1991-04-09

  A novel three-step process for resolving a racemic spiro-hydantoin compound into its optical antipodes is disclosed, which involves (1) reacting said racemic compound with an optically-active asymmetric isocyanate of the formula RNCO, wherein R is (S)- or (R)-1-phenylethyl or (S)-or (R)-1-(1-naphthyl)ethyl, to form the corresponding diastereomeric ureido compound; (2) separating the resulting diastereomeric mixture into its component parts, and (3) thereafter converting the separated ureido diasteromers obtained in step (b) to the corresponding asymmetric hydantoin compounds by treatment with an alkali metal lower alkoxide (C.sub.1 -C.sub.4), followed by acidification, whereupon the desired optical isomer is obtained. The final products so obtained, such as (4S)-(+)-6-fluoro-2,3-dihydro-spiro-[4H-1-benzopyran-4,4'-imidazolidine]-2 ',5'-dione(sorbinil) and (5'S)-3'-chloro-5', 6',7',8'-tetrahydro-spiro[imidazolidine-4,5'-quinoline]-2,5-dione, are known to be useful in preventing or alleviating certain chronic diabetic complications. The aforementioned diastereomeric ureido intermediates are novel compounds.

  公开了一种新型的三步法过程，用于将一种拉丁的螺环嘧啶化合物分离为其光学对映体，包括以下步骤：(1)将该拉丁化合物与具有光学活性的不对称异氰酸酯反应，所述不对称异氰酸酯的化学式为RNCO，其中R为(S)-或(R)-1-苯乙基或(S)-或(R)-1-(1-萘基)乙基，形成相应的二对映异构脲化合物；(2)将所得的二对映异构混合物分离成其组分部分；(3)然后通过用碱金属低级烷氧化物(C.sub.1-C.sub.4)处理所分离的脲二对映异构体，随后酸化，从而获得所需的光学异构体。所获得的最终产物，例如(4S)-(+)-6-氟-2,3-二氢螺-[4H-1-苯并吡喃-4,4'-咪唑啉]-2',5'-二酮(索比林)和(5'S)-3'-氯-5',6',7',8'-四氢螺[咪唑啉-4,5'-喹啉]-2,5-二酮，已知可用于预防或缓解某些慢性糖尿病并发症。上述二对映异构脲中间体是新型化合物。
• Regeneration of 6-fluoro-4-chromanone from by-products in the synthesis of sorbinil
  申请人：PFIZER INC.

  公开号：EP0111387A1

  公开（公告）日：1984-06-20

  6-Fluoro-4-chromanone, a sorbinil intermediate, is regenerated from enantiomeric and mixtures of enantiomeric and racemic compounds obtained as major by-products in the synthesis of sorbinil. The regenerated intermediate is useful in the synthesis of additional sorbinil.

  6-Fluoro-4-chromanone 是一种山梨醇中间体，可从合成山梨醇的主要副产品对映体和对映体混合物以及外消旋化合物中再生。 再生的中间体可用于合成更多的山梨醇。
• Process for preparing optically active hydantoins
  申请人：KANEGAFUCHI KAGAKU KOGYO KABUSHIKI KAISHA

  公开号：EP0175312A2

  公开（公告）日：1986-03-26

  A process for preparing optically active hydantoins having the general formula (II): wherein R' and R2, which are different from each other, are independently alkyl group aralkyl, group, aryl group, substituted alkyl group, substituted aralkyl group, or substituted aryl group, or R' and R2 form an asymmetric cyclic compound, characterized in that one configuration of racemic N-carbamoyl-a-amino acid having the general formula (I): wherein R' and R2 are as above, is enzymatically converted into the corresponding hydantoins. The present invention provides a process for an optical resolution with a high efficiency which can be used for the synthesis of (S)-6-fluoro-spiro- [chroman-4,4' -imidazolidine] -2',5'-dione (USAN; Sorbinil), which is an optically active hydantoins attracting public attention as a preventive or a remedy for the particular chronic symptoms of diabetes such as cataract and neuropathy, and (S)-a-methyl- 3,4-di- hydroxyphenylalanine (L-methyldopa), which is an optically active amino acid widely used as antihypertensives. Further, the present invention provides a novel finding that N-carbamoyl-a-amino acid having no hydrogen atom on its a-carbon atom can be biochemically converted into hydantoins by an enzymatic cyclization reaction.

  一种具有通式(II)的光学活性海因的制备方法： 其中R'和R2互不相同，独立地为烷基、芳基、取代的烷基、取代的芳基或取代的芳基，或R'和R2形成不对称环状化合物，其特征在于具有通式(I)的外消旋N-氨基甲酰基-a-氨基酸的一种构型： 其中 R' 和 R2 如上，通过酶法转化为相应的海因。 本发明提供了一种高效光学分解工艺，可用于合成(S)-6-氟-螺-[色满-4,4' -咪唑烷] -2',5'-二酮（USAN；(S)-a-甲基-3,4-二羟基苯丙氨酸(L-甲基多巴)，它是一种光学活性海因，作为白内障和神经病变等糖尿病特殊慢性症状的预防或治疗药物而备受公众关注；(S)-a-甲基-3,4-二羟基苯丙氨酸(L-甲基多巴)，它是一种光学活性氨基酸，被广泛用作抗高血压药物。此外，本发明还提供了一项新发现，即碳原子上没有氢原子的 N-氨基甲酰基-a-氨基酸可通过酶环化反应生化转化为 hydantoins。
• Synthesis of optically active spirohydantoins by asymmetric induction. Hydantoin formation from amino nitriles and chlorosulfonyl isocyanates
  作者：Reinhard Sarges、Harry R. Howard、Paul R. Kelbaugh

  DOI：10.1021/jo00142a016

  日期：1982.10