5-{2-[2-(2,2-Dimethyl-propionylamino)-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-d]pyrimidin-6-yl]-ethyl}-4-methyl-thiophene-2-carboxylic acid ethyl ester | 815579-28-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 5-{2-[2-(2,2-Dimethyl-propionylamino)-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-d]pyrimidin-6-yl]-ethyl}-4-methyl-thiophene-2-carboxylic acid ethyl ester
• 英文别名: ethyl 5-[2-[2-(2,2-dimethylpropanoylamino)-4-oxo-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-6-yl]ethyl]-4-methylthiophene-2-carboxylate
• CAS: 815579-28-3
• 化学式: C₂₂H₃₀N₄O₄S
• 分子量: 446.571
• InChiKey: JKZLZTVORPUQOE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  137
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-{2-[2-(2,2-Dimethyl-propionylamino)-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-d]pyrimidin-6-yl]-ethyl}-4-methyl-thiophene-2-carboxylic acid ethyl ester 在 Chirazyme L-2 、 citric buffer 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 (S)-2-[(5-{2-[(S)-2-(2,2-Dimethyl-propionylamino)-8-ethoxyoxalyl-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-d]pyrimidin-6-yl]-ethyl}-4-methyl-thiophene-2-carbonyl)-amino]-pentanedioic acid diethyl ester
  参考文献：
  名称：

  Efficient Chemoenzymatic Synthesis of Pelitrexol via Enzymic Differentiation of a Remote Stereocenter

  摘要：

  An efficient chemoenzymatic process is described for the synthesis of pelitrexol, a novel GARFT inhibitor. The remoteness of this molecule's stereocenter in the tetrahydropterin moiety from the terminal carbonyl group provided a significant challenge in synthesis. The introduction of an oxalamic ester adjacent to the stereocenter dramatically enhanced an enzyme's enantioselectivity for hydrolysis at the terminal ester, producing the desired S-acid with high optical purity and yield. The recycling of the "wrong" enantiomer is achieved via a dehydrogenation/hydrogenation strategy.

  DOI：

  10.1021/ol0602755
• 作为产物：
  描述：

  5-{2-[2-(2,2-dimethyl-propionylamino)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-ethyl}-4-methyl-thiophene-2-carboxylic acid ethyl ester 在 palladium on activated charcoal 氢气 、 溶剂黄146 作用下， 75.0 ℃ 、344.74 kPa 条件下， 反应 16.0h， 以95%的产率得到5-{2-[2-(2,2-Dimethyl-propionylamino)-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-d]pyrimidin-6-yl]-ethyl}-4-methyl-thiophene-2-carboxylic acid ethyl ester
  参考文献：
  名称：

  Efficient Chemoenzymatic Synthesis of Pelitrexol via Enzymic Differentiation of a Remote Stereocenter

  摘要：

  An efficient chemoenzymatic process is described for the synthesis of pelitrexol, a novel GARFT inhibitor. The remoteness of this molecule's stereocenter in the tetrahydropterin moiety from the terminal carbonyl group provided a significant challenge in synthesis. The introduction of an oxalamic ester adjacent to the stereocenter dramatically enhanced an enzyme's enantioselectivity for hydrolysis at the terminal ester, producing the desired S-acid with high optical purity and yield. The recycling of the "wrong" enantiomer is achieved via a dehydrogenation/hydrogenation strategy.

  DOI：

  10.1021/ol0602755

文献信息

• Stereoselective process for the synthesis of chiral garft compounds and intermediates
  申请人：Rahman Leera

  公开号：US20050085492A1

  公开（公告）日：2005-04-21

  The present invention describes a stereoselective preparation of derivatives and precursors of molecules having formula 1: Method of preparing the compounds, intermediates and derivatives are described. The methods described herein allow the preparation of diastereomeric forms of compound having formula 1. The compounds of the invention are GARFT inhibitors.

  本发明描述了具有化学式1的分子的立体选择性衍生物和前体的制备方法。描述了化合物、中间体和衍生物的制备方法。本文描述的方法允许制备具有化学式1的化合物的对映异构体形式。本发明的化合物是GARFT抑制剂。
• Convergent processes for the synthesis of a GARFT inhibitor containing a methyl substituted thiophene core and intermediates therefor
  申请人：AGOURON PHARMACEUTICALS, INC.

  公开号：US20040266796A1

  公开（公告）日：2004-12-30

  The invention relates to processes for the preparation of a GARFT inhibitor containing a methyl substituted thiophene core having the following structure: 1 wherein each of R 1 and R 2 are independently a hydrogen atom or a moiety that together with the attached CO 2 forms a readily hydrolyzable ester group; from an intermediate of the formula 2 wherein R 3 is a moiety that together with the attached CO 2 forms a readily hydrolyzable ester group; Pg 1 is an amino protecting group; R 4 is H; or Pg 1 can optionally be taken together with R 4 and the nitrogen to which Pg 1 and R 4 are attached to form (i) an imine; or (ii) a fused or bridged bicyclic ring or a spirocyclic ring, wherein said ring is saturated and contains from 5 to 12 carbon atoms in which up to 2 carbon atoms are optionally replaced with a hetero moiety selected from O, S(O) j wherein j is an integer from 0 to 2, and —NR 8 —, provided that two O atoms, two S(O) j moieties, or an O atom and a S(O) j moiety are not attached directly to each other; R 5 is selected from the group consisting of —C≡C— and —CH═CH—; and R 8 is independently H or C 1 -C 6 alkyl; to form the compound of the formula (I) that is optically pure; and to processes for preparing intermediates thereof.

  本发明涉及一种制备含有甲基取代噻吩核心的GARFT抑制剂的过程，其具有以下结构： 其中R1和R2中的每一个独立地是氢原子或者与连接的CO2形成易水解酯基团的基团；从具有以下结构的中间体开始： 其中R3是一个基团，与连接的CO2一起形成易水解酯基团；Pg1是氨基保护基团；R4是H；或者Pg1可以选择与R4及Pg1和R4连接的氮一起形成(i)亚胺；或者(ii)融合的或者桥接的双环或者螺环，其中所述环是饱和的，含有5至12个碳原子，其中最多有2个碳原子可以选择性地被来自O、S(O)j（其中j是0到2的整数）和—NR8—的杂原子基团替代，前提是两个O原子、两个S(O)j基团，或者一个O原子和一个S(O)j基团不能直接连接在一起；R5选自由—C≡C—和—CH2CH—的基团；R8独立地是H或者C1-C6烷基；形成具有光学纯度的化合物的公式(I)；以及制备其中间体的过程。
• Efficient Chemoenzymatic Synthesis of Pelitrexol via Enzymic Differentiation of a Remote Stereocenter
  作者：Shanghui Hu、Sean Kelly、Steve Lee、Junhua Tao、Erik Flahive

  DOI：10.1021/ol0602755

  日期：2006.4.1

  An efficient chemoenzymatic process is described for the synthesis of pelitrexol, a novel GARFT inhibitor. The remoteness of this molecule's stereocenter in the tetrahydropterin moiety from the terminal carbonyl group provided a significant challenge in synthesis. The introduction of an oxalamic ester adjacent to the stereocenter dramatically enhanced an enzyme's enantioselectivity for hydrolysis at the terminal ester, producing the desired S-acid with high optical purity and yield. The recycling of the "wrong" enantiomer is achieved via a dehydrogenation/hydrogenation strategy.