2,3-dihydro-6-fluoro-4H-ureido-1-benzopyran-4-carboxylic acid | 90477-47-7

• 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: 2,3-dihydro-6-fluoro-4H-ureido-1-benzopyran-4-carboxylic acid
• 英文别名: 6-fluoro-4-ureidochroman-4-carboxylic acid；4-(carbamoylamino)-6-fluoro-2,3-dihydrochromene-4-carboxylic acid
• CAS: 90477-47-7
• 化学式: C₁₁H₁₁FN₂O₄
• 分子量: 254.218
• InChiKey: PLFOGGJHQOVQAF-UHFFFAOYSA-N

物化性质

• 熔点：
  189-191 °C (decomp)
• 沸点：
  477.6±45.0 °C(Predicted)
• 密度：
  1.51±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  102
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,3-dihydro-6-fluoro-4H-ureido-1-benzopyran-4-carboxylic acid 在 盐酸 、 potassium permanganate 作用下， 以 水 、 溶剂黄146 为溶剂， 以87%的产率得到6-氟-4-二氢色原酮
  参考文献：
  名称：

  Regeneration of 6-fluoro-4-chromanone from

  摘要：

  6-氟-4-香豆酮可以通过过氧化钾（尤其是高锰酸钾）氧化(R)-6-氟-4-尿素基香豆酸和(R)-6-氟-4-尿素基香豆酸的混合物再生。6-氟-4-香豆酮是一种化学中间体，用于制备索比尼尔（一种醛糖还原酶抑制剂），可用于临床医学中控制糖尿病的慢性并发症。 (R)-6-氟-4-尿素基香豆酸及其外消旋体是从6-氟-4-香豆酮制备索比尼尔的副产物。

  公开号：

  US04551542A1
• 作为产物：
  描述：

  4-acetamido-2,3-dihydro-6-fluoro-4H-1-benzopyran-4-carboxylic acid 在 盐酸 、 sodium hydroxide 、 甲酸 作用下， 以 水 为溶剂， 反应 6.0h， 生成 2,3-dihydro-6-fluoro-4H-ureido-1-benzopyran-4-carboxylic acid
  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

• Sorbinil by optical resolution of precursor
  申请人：Pfizer Inc.

  公开号：US04435578A1

  公开（公告）日：1984-03-06

  Sorbinil is obtained by cyclization of S-6-fluoro-4-ureidochromane-4-carboxylic acid, which is in turn obtained by resolution of racemic 6-fluoro-4-ureidochroman-4-carboxylic acid via diasteromeric salts with either D-(+)-(1-phenethyl)amine or L-(-)-ephedrine.

  Sorbinil是通过S-6-氟-4-脲基色甘醇-4-羧酸的环化反应获得的，而S-6-氟-4-脲基色甘醇-4-羧酸则是通过与D-(+)-(1-苯乙基)胺或L-(-)-麻黄碱的对映体盐分离得到的，而该对映体盐是由外消旋的6-氟-4-脲基色甘醇-4-羧酸分离而来的。
• Process for the production of an (S)-methyl or (S)-ethyl
  申请人：Pfizer Inc.

  公开号：US04716113A1

  公开（公告）日：1987-12-29

  An improved process for preparing (4S)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-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 .beta.-(4-fluorophenoxy)alkane halide, followed by amidoalkylation with N-benzoyl or N-(lower alkanoyl)-.alpha.-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 .alpha.-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.

  本发明公开了一种改进的制备（4S）-6-氟-螺-[色满-4,4'-咪唑啉]-2'，5'-二酮（索比尼尔）或其（2R）-甲基衍生物（2-甲基索比尼尔）的方法，两者均以对氟苯酚为起始物。所得的最终产物作为控制某些慢性糖尿病并发症的药物具有已知的药理学价值。该方法涉及的关键步骤包括将对氟苯酚转化为适当的β-(4-氟苯氧)烷基卤化物，随后与N-苯甲酰或N-(较低的脂肪酰)-α-羟基甘氨酸进行酰胺烷基化反应，形成其中间体2-酰胺烷基化衍生物，然后通过使用脱水剂和碱处理其中间体，进行螺烷基化反应，得到螺烷基化的氮内酯化合物。然后，利用酸水解，将该化合物进一步转化为已知的4-氨基-6-氟色满-4-羧酸或新颖的（2R）-甲基衍生物，均以其水合卤酸盐的形式存在，中间的螺烷基化氨基酸卤酸盐随后转化为相应的甲基或乙基酯，并通过α-凝乳酶分离得到所需的（S）-甲基或（S）-乙基酯。然后，在酸性介质中，将这两种酯之一与碱金属氰酸盐反应，即可将其转化为所需的螺噻嗪环化合物。或者，也可以使用已知的方法，通过三个反应步骤的序列，将螺烷基化氨基酸卤酸盐转化为所需的螺噻嗪环化合物。本发明中的螺烷基化氮内酯化合物以及上述提到的甲基和乙基酯本身均为新颖化合物，并且在本发明中的合成中作为合成中间体具有重要价值。
• Process for the production of asymmetric hydantoins
  申请人：Pfizer, Inc.

  公开号：US04841079A1

  公开（公告）日：1989-06-20

  An improved process for preparing (4S)-6-fluorospiro-[chroman-4,4'-imidazolidine]-2',5'-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 .beta.-(4-fluorophenoxy)alkane halide, followed by amidoalkylation with N-benzoyl or N-(lower alkanoyl)-.alpha.-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 .alpha.-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.

  本文揭示了一种改进的方法，从对氟苯酚开始，制备（4S）-6-氟螺[色酮-4,4'-咪唑啉]-2'，5'-二酮（索比尼尔）或其（2R）-甲基衍生物（2-甲基索比尼尔）。所得的最终产物在控制某些慢性糖尿病并发症的药物价值方面已知。与该过程有关的关键步骤包括将对氟苯酚转化为适当的β-（4-氟苯氧）烷基卤化物，随后与N-苯甲酰或N-（较低的烷酰基）-α-羟基甘氨酸进行酰胺烷基化，形成其中间体2-酰胺基烷基化衍生物，然后通过使用脱水剂和碱处理该中间体进行脱水和螺环烷基化，以产生螺环烷基化的氮内酯化合物。然后，通过使用酸水解，该化合物随后转化为已知的4-氨基-6-氟色酮-4-羧酸或其新型（2R）-甲基衍生物，均以其氢卤酸加成盐的形式存在，其中间体螺环氨基酸氢卤酸盐随后转化为相应的甲基或乙酯，并与α-胰蛋白酶分离，以得到所需的（S）-甲基或（S）-乙酯。然后，在酸性介质中，将这两种酯之一与碱金属氰酸盐处理，然后将其转化为所需的螺环咪唑环化合物。或者，该螺环氨基酸氢卤酸盐也可以通过已知方法转化为所需的螺环咪唑环化合物，其中涉及三个反应步骤的序列。本发明的螺环烷基化的氮内酯化合物，以及上述提到的甲基和乙酯本身就是新型化合物，并且在本发明的过程中作为合成中间体是有价值的。
• Sorbinal by optical resolution of precursor 6-fluro-4-ureidochroman-4-carboxylic acid
  申请人：PFIZER INC.

  公开号：EP0109232A1

  公开（公告）日：1984-05-23

  Sorbinil is obtained by cyclization of S-6-fluoro-4-ureidoch- romane-4-carboxylic acid, wich is in turn obtained by resolution of racemic 6-fluoro-4-ureidochroman-4-carboxylic acid via dias- teromeric salts with either D-(+)-(1-phenethyl) amine or L-(-)-ephedrine.

  索比尼尔是由 S-6-氟-4-脲基-4-罗曼-4-羧酸环化而成，而 S-6-氟-4-脲基-4-罗曼-4-羧酸又是由外消旋 6-氟-4-脲基-4-罗曼-4-羧酸通过与 D-(+)-(1-苯乙基)胺或 L-(-)-麻黄碱的二异构盐解析而成。
• 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。