(2R,4S)-6-氟-2-甲基螺[色满-4,5'-咪唑烷]-2',4'-二酮 | 102916-95-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 中文名称: (2R,4S)-6-氟-2-甲基螺[色满-4,5'-咪唑烷]-2',4'-二酮
• 英文名称: (2R,4S)-6-fluoro-2-methylspiro[chroman-4,4’-imidazolidine]-2’,5’-dione
• 英文别名: 2R,4S,6-fluoro-2-methyl-spiro-2',5'-dione；2R,4S,6-fluoro-2-methyl-spiro-2',5-dione；(4S)-2,3-dihydro-6-fluoro-2(R)-methylspiro[chroman-4,4'-imidazole]-2',5'-dione；2-methylsorbinil；methylsorbinil；2R,4S-6-fluoro-2-methyl-spiro[chroman-4,4'-imidazolidine]-2',5'-dione；(2R,4S)-6-fluoro-2-methylspiro[2,3-dihydrochromene-4,5'-imidazolidine]-2',4'-dione
• CAS: 102916-95-0
• 化学式: C₁₂H₁₁FN₂O₃
• 分子量: 250.229
• InChiKey: SEAQTHCVAGBRFY-INWYIAFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  18
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  67.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-氟苯酚 在 lithium aluminium tetrahydride 、 氯化亚砜 、 甲烷磺酸 、 溴 、 乙酸酐 、 potassium carbonate 、 三苯基膦 、 α-chymotrypsin 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 盐酸 、 甲醇 、 水 、 溶剂黄146 、 N,N-二甲基甲酰胺 、 丙酮 、 sodium chloride 为溶剂， 反应 125.0h， 生成 (2R,4S)-6-氟-2-甲基螺[色满-4,5'-咪唑烷]-2',4'-二酮
  参考文献：
  名称：

  Novel synthesis of the aldose reductase inhibitor sorbinil via amidoalkylation, intramolecular oxazolidin-5-one alkylation and chymotrypsin resolution

  摘要：

  DOI：

  10.1021/jo00392a017

文献信息

• [EN] TOPICAL TREATMENT OF CATARACTS IN DOGS<br/>[FR] TRAITEMENT TOPIQUE DE LA CATARACTE CHEZ LES CHIENS
  申请人：KADOR PETER F

  公开号：WO2010065024A1

  公开（公告）日：2010-06-10

  The topical treatment of cataracts in dogs is a composition having an aldose reductase inhibitor (ARI) in a topical carrier. The ARI is preferably 2R,4S-6-fluoro-2-methyl-spiro[chroman-4,4'-imidazolidine]-2',5'-dione, referred to as 2R-methyl sorbinil. The topical carrier is formed from EDTA and deionized water containing about 2.5% carbomer, 1.5% glycerin, 0.02% EDTA and 0.1% benzalkonium chloride mixed to form a uniform emulsion. The concentration of the ARI in the topical carrier is preferably about 5-6%. The treatment includes administering to a dog an effective amount of the composition for preventing the formation of cataracts, reversing the formation of cataracts, and for treating diabetic retinopathy and pathological conditions resulting from diabetes affecting the cornea, iris, ciliary bodies, etc. The composition is preferably administered in the form of about two to four eye drops daily.

  翻译结果如下： 犬白内障的局部治疗是一种具有醛糖还原酶抑制剂（ARI）的局部载体的组合物。 ARI 最好是 2R，4S-6-氟-2-甲基-螺[色酮-4,4'-咪唑啉]-2'，5'-二酮，称为 2R-甲基索比林。局部载体由 EDTA 和去离子水形成，含约 2.5％ 的卡波姆，1.5％ 的甘油，0.02％ 的 EDTA 和 0.1％ 的苯扎氯铵混合形成均匀乳液。 ARI 在局部载体中的浓度最好约为5-6％。治疗包括向犬中投与有效量的该组合物，以预防白内障的形成，逆转白内障的形成，并治疗糖尿病视网膜病变和糖尿病影响角膜，虹膜，睫状体等的病理情况。该组合物最好以每日约两到四滴眼药水的形式投与。
• Spectral assignments for the aldose reductase inhibitor 4(S)-2,3-dihydro-6-fluoro-2(R)-methylspiro[chroman-4,4′-imidazoline]-2′,5′-dione and its synthetic intermediates
  作者：Mingan Wang、Manoj K. Mishra、Wenjun Zhu、Peter F. Kador

  DOI：10.1002/mrc.1697

  日期：2005.12

  The 1H and 13C NMR chemical shifts of the aldose reductase inhibitor 4(S)‐2,3‐dihydro‐6‐fluoro‐2(R)‐methylspiro[chroman‐4,4′‐imidazoline]‐2′,5′‐dione, methylsorbinil, and its seven synthetic intermediates, have been completely assigned on the basis of DEPT, COSY, g‐HSQC and g‐HMBC. All CF coupling constants from one‐bond to four‐bond in the 13C NMR spectra and HF and HH coupling constants from three‐bond

  醛糖还原酶抑制剂 4(S)-2,3-dihydro-6-fluoro-2(R)-methylspiro[chroman-4,4'-imidazoline]-2',5'-的 1H 和 13C NMR 化学位移二酮、甲基山梨醇及其七种合成中间体已完全基于 DEPT、COSY、g-HSQC 和 g-HMBC 进行分配。获得了13C NMR光谱中从单键到四键的所有CF耦合常数以及1H光谱中从三键到四键的HF和HH耦合常数。版权所有 © 2005 John Wiley & Sons, Ltd.
• Topical treatment of cataracts in dogs
  申请人：Kador Peter F.

  公开号：US20090082415A1

  公开（公告）日：2009-03-26

  The topical treatment of cataracts in dogs is a composition having an aldose reductase inhibitor (ARI) in a topical carrier. The ARI is preferably 2R,4S-6-fluoro-2-methyl-spiro[chroman-4,4′-imidazolidine]-2′,5′-dione, referred to as 2R-methyl sorbinil, having the structure: The topical carrier is formed from EDTA and deionized water containing about 2.5% carbomer, 1.5% glycerin, 0.02% EDTA and 0.1% benzalkonium chloride mixed to form a uniform emulsion. The concentration of the ARI in the topical carrier is preferably about 5-6%. The treatment includes administering to a dog an effective amount of the composition for preventing the formation of cataracts, reversing the formation of cataracts, and for treating diabetic retinopathy and pathological conditions resulting from diabetes affecting the cornea, iris, ciliary bodies, etc. The composition is preferably administered in the form of about two to four eye drops daily.

  犬类白内障的局部治疗是一种具有醛糖还原酶抑制剂（ARI）的局部载体组成的药物。 ARI 最好是 2R,4S-6-氟-2-甲基-螺[色酮-4,4'-咪唑啉]-2',5'-二酮，称为 2R-甲基索比林，其结构式为：局部载体由 EDTA 和去离子水组成，含有约2.5％的卡波姆，1.5％的甘油，0.02％的 EDTA 和 0.1％苯扎氯铵混合形成均匀乳液。在局部载体中的 ARI 浓度最好约为5-6％。治疗包括向犬类施用有效量的该组成物，以预防白内障的形成，逆转白内障的形成，并治疗糖尿病视网膜病变和由糖尿病影响角膜，虹膜，睫状体等的病理情况。该组成物最好以每天约两到四滴眼药水的形式施用。
• Process for the production as asymmetric hydantoins
  申请人：PFIZER INC.

  公开号：EP0172719A1

  公开（公告）日：1986-02-26

  An improved process for preparing (4S)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',S'-dione (sorbinil) or its (2R)-methyl derivative (2-methylsorbinil) is disclosed herein, starting from p-fluorophenol in each instance. The final products obtained have known pharmaceutical value as agents for the control of certain chronic diabetic complications. Key steps concerned with the process involve converting p-fluorophenol into the appropriate β-(4-fluorophenoxy)-alkane halide, followed by amidoalkylation with N-benzoyl or N-(lower alkanoyl)- a-hydroxyglycine to form an intermediate 2-amidoalkylated derivative thereof, and then dehydration and spiroalkylation of said intermediate by treatment with a dehydrating agent and a base to yield a spiroalkylated azlactone compound. The latter compound is then subsequently converted to the known 4-amino-6-fluorochroman-4-carboxylic acid or the novel (2R-methyl derivative thereof, both in the form of their hydrohalide acid addition salts, by employing acid hydrolysis and the intermediate spiro-amino acid hydrohalide salt is thereafter converted to the corresponding methyl or ethyl ester and resolved with a-chymotrypsin to afford the desired (S)-methyl or (S)-ethyl ester. Treatment of either of these latter two esters with an alkali metal cyanate in an acid medium then effects conversion of same to the desired spiro-hydantoin ring compound. Alternatively, the spiro-amino acid hydrohalide salt can also be converted to the desired spiro-hydantoin ring compound in a known manner, involving a sequence of three reaction steps. The spiroalkylated azlactone compound of the instant invention, as well as the methyl and ethyl esters mentioned above, are themselves novel compounds and are valuable as synthetic intermediates in the process of this invention.

  本文公开了一种制备(4S)-6-氟-螺-[色满-4,4'-咪唑烷]-2',S'-二酮（sorbinil）或其(2R)-甲基衍生物（2-甲基sorbinil）的改进工艺，每种工艺均从对氟苯酚开始。所获得的最终产品作为控制某些慢性糖尿病并发症的药物具有已知的药用价值。该工艺的关键步骤包括将对氟苯酚转化为适当的 β-（4-氟苯氧基）-卤代烷烃，然后用 N-苯甲酰基或 N-（低级烷酰基）-a-羟基甘氨酸进行氨基烷基化，形成其 2-氨基烷基化衍生物中间体，然后用脱水剂和碱对上述中间体进行脱水和螺烷基化处理，得到螺烷基化氮内酯化合物。然后通过酸水解将后一种化合物转化为已知的 4-氨基-6-氟二氢苯并吡喃-4-羧酸或其新型（2R-甲基）衍生物，二者均为氢卤酸加成盐形式，随后将中间体螺烷基氨基酸氢卤酸盐转化为相应的甲酯或乙酯，并用 a-胸腺胰蛋白酶溶解，得到所需的（S）-甲酯或（S）-乙酯。用碱金属氰酸酯在酸性介质中处理后两种酯中的任何一种，都会将其转化为所需的螺环海因环化合物。另外，螺烷基氨基酸氢卤化物盐也可以按照已知的方式转化为所需的螺海因环化合物，其中涉及三个反应步骤。本发明的螺烷基化氮内酯化合物以及上述的甲酯和乙酯本身就是新颖的化合物，在本发明的工艺中作为合成中间体是很有价值的。
• 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。