(S)-methyl 4-amino-6-fluorochroman-4-carboxylate | 103197-13-3

• 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: (S)-methyl 4-amino-6-fluorochroman-4-carboxylate
• 英文别名: methyl (4R,S)-amino-2,3-dihydro-6-fluoro-4H-1-benzopyran-4-carboxylate；methyl RS-4-amino-6-fluorochroman-4-carboxylate；methyl 4-amino-6-fluorochroman-4-carboxylate；methyl 4-amino-6-fluorochroman4-carboxylate；methyl 4-amino-6-fluoro-2,3-dihydrochromene-4-carboxylate
• CAS: 103197-13-3
• 化学式: C₁₁H₁₂FNO₃
• 分子量: 225.22
• InChiKey: ICRFTBHKBZHNBZ-UHFFFAOYSA-N

物化性质

• 熔点：
  64-65.5 °C
• 沸点：
  320.6±42.0 °C(Predicted)
• 密度：
  1.286±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  61.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-methyl 4-amino-6-fluorochroman-4-carboxylate 以 水 、 溶剂黄146 为溶剂， 生成 索比尼尔
  参考文献：
  名称：

  Process for the production of asymmetric hydantoins

  摘要：

  本文揭示了一种改进的制备(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）的方法，两者均以对氟苯酚为起始物。得到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价值。该过程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，随后通过N-苯甲酰或N-(低级脂肪酰)-α-羟基甘氨酸进行酰胺烷基化，形成中间体2-酰胺烷基化衍生物，然后通过脱水和螺环烷基化处理该中间体，使用脱水剂和碱处理，得到螺环烷基化的氮内酯化合物。然后，使用酸水解将后者转化为已知的4-氨基-6-氟色酮-4-羧酸或其新型（2R）-甲基衍生物，均以其氢卤酸盐的形式存在，中间螺环氨基酸氢卤酸盐随后转化为相应的甲基或乙基酯，并通过α-凝乳蛋白酶分离得到所需的（S）-甲基或（S）-乙基酯。然后，在酸性介质中，使用碱金属氰酸盐处理这两种酯之一，将其转化为所需的螺环咪唑环化合物。或者，螺环氨基酸氢卤酸盐也可以通过一系列三步反应以已知方式转化为所需的螺环咪唑环化合物。本发明的螺环烷基化的氮内酯化合物以及上述的甲基和乙基酯本身都是新型化合物，并且在本发明的过程中作为合成中间体具有价值。

  公开号：

  US04841079A1
• 作为产物：
  描述：

  4-acetamido-2,3-dihydro-6-fluoro-4H-1-benzopyran-4-carboxylic acid 在 盐酸 、 甲酸 、 氯化亚砜 作用下， 以 甲醇 、 水 为溶剂， 反应 6.0h， 生成 (S)-methyl 4-amino-6-fluorochroman-4-carboxylate
  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

• 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 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 and intermediates for sorbinil
  申请人：PFIZER INC.

  公开号：EP0173522A2

  公开（公告）日：1986-03-05

  Chiral sorbinil intermediates of the formula wherein R is hydrogen or benzyloxycarbonyl and Y is hydroxy or amino, processes therefor, and processes forthe conversion thereof to sorbinil.

  式中 R 为氢或苄氧羰基，Y 为羟基或氨基的手性山梨醇中间体，以及将其转化为山梨醇的工艺。 式中 R 为氢或苄氧羰基，Y 为羟基或氨基的手性山梨醇中间体、其工艺以及将其转化为山梨醇的工艺。
• Resolution process for racemic spiro-hydantoins
  申请人：PFIZER INC.

  公开号：EP0352959A1

  公开（公告）日：1990-01-31

  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 diastereomers obtained in step (b) to the corresponding asymmetric hydantoin compounds by treatment with an alkali metal lower alkoxide (C₁-C₄), 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.

  本发明公开了一种将外消旋螺海因化合物分解为其光学对映体的三步法新工艺，包括 (1) 将所述外消旋化合物与式 RNCO 的光学活性不对称异氰酸酯反应，其中 R 为(S)-或(R)-1-苯基乙基或(S)-或(R)-1-(1-萘基)乙基，形成相应的非对映脲基化合物；(2) 将得到的非对映异构体混合物分离成各组分，以及 (3) 随后通过碱金属低级烷氧化物（C₁-C₄）处理，将步骤(b)中分离得到的脲基非对映异构体转化为相应的不对称海因化合物，然后进行酸化，从而得到所需的光学异构体。这样得到的最终产物，如(4S)-(+)-6-氟-2,3-二氢-螺[4H-1-苯并吡喃-4,4′-咪唑烷]-2′,5′-二酮（sorbinil）和(5′S)-3′-氯-5′、6′，7′，8′-四氢-螺[咪唑烷-4，5′-喹啉]-2，5-二酮，可用于预防或减轻某些慢性糖尿病并发症。上述非对映脲中间体是新型化合物。
• J. Org. Chem. 1987, 52, 3587-3591
  作者：

  DOI：——

  日期：——