3(R)-hydroxypyrrolidine-1-carboxylic acid allyl ester | 135920-53-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 3(R)-hydroxypyrrolidine-1-carboxylic acid allyl ester
• 英文别名: Prop-2-enyl (3R)-3-hydroxypyrrolidine-1-carboxylate
• CAS: 135920-53-5
• 化学式: C₈H₁₃NO₃
• 分子量: 171.196
• InChiKey: ARYQJCFLKYAKHY-SSDOTTSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3(R)-hydroxypyrrolidine-1-carboxylic acid allyl ester 在 盐酸 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 77.0h， 生成 3(S)-<4-<(ethoxycarbonyl)(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)methyl>phenoxy>pyrrolidine-1-carboxylic acid allyl ester hydrochloride
  参考文献：
  名称：

  Tetrahydro-isoquinoline-Based Factor Xa Inhibitors

  摘要：

  Derivatives of (2-amidino-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)phenylacetic acid (TIPAC) were developed as inhibitors of factor Xa (fXa). The compounds are prepared using 15 synthetic steps on average. The most potent compounds (14, 17, 22-26) display inhibition constants of K-i = 21-55 nM but do not inhibit thrombin (K-i = 5->100 mu M) and only weakly inhibit trypsin (K-i = 0.08-5 mu M). They bear a second basic moiety, e.g., substituted 1-(iminomethyl)piperidines, which is linked to C-4 of the phenyl group of TIPAC via an oxygen atom. The inhibition constants of these compounds are almost independent of the size of the (iminomethyl)piperidine substituent. Due to the fact that fXa displays two cation binding sites, namely, the S1 and S4 sites, in principle two binding modes are conceivable for the novel dibasic fXa inhibitors. Molecular modeling experiments based on the X-ray structures of uninhibited fXa and the DX-9065a/fXa complex were carried out. The results taken together with the inhibition constants clearly favor one binding mode: the tetrahydro-isoquinoline fills the S1 pocket even better than the naphthalene moiety of DX-9065a, and the (iminomethyl)piperidine residues occupy the S4 site.

  DOI：

  10.1021/jm9800402
• 作为产物：
  描述：

  (R)-3-吡咯烷醇 、 氯甲酸烯丙酯 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 二氯甲烷 为溶剂， 以88%的产率得到3(R)-hydroxypyrrolidine-1-carboxylic acid allyl ester
  参考文献：
  名称：

  Tetrahydro-isoquinoline-Based Factor Xa Inhibitors

  摘要：

  Derivatives of (2-amidino-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)phenylacetic acid (TIPAC) were developed as inhibitors of factor Xa (fXa). The compounds are prepared using 15 synthetic steps on average. The most potent compounds (14, 17, 22-26) display inhibition constants of K-i = 21-55 nM but do not inhibit thrombin (K-i = 5->100 mu M) and only weakly inhibit trypsin (K-i = 0.08-5 mu M). They bear a second basic moiety, e.g., substituted 1-(iminomethyl)piperidines, which is linked to C-4 of the phenyl group of TIPAC via an oxygen atom. The inhibition constants of these compounds are almost independent of the size of the (iminomethyl)piperidine substituent. Due to the fact that fXa displays two cation binding sites, namely, the S1 and S4 sites, in principle two binding modes are conceivable for the novel dibasic fXa inhibitors. Molecular modeling experiments based on the X-ray structures of uninhibited fXa and the DX-9065a/fXa complex were carried out. The results taken together with the inhibition constants clearly favor one binding mode: the tetrahydro-isoquinoline fills the S1 pocket even better than the naphthalene moiety of DX-9065a, and the (iminomethyl)piperidine residues occupy the S4 site.

  DOI：

  10.1021/jm9800402

文献信息

• 4-Substituted alkyl carbapenem antibiotics
  申请人：Bristol-Myers Squibb Company

  公开号：EP0433759A1

  公开（公告）日：1991-06-26

  Compounds of the formula wherein R1 is hydrogen, C1-2 alkyl, -CH20H, -CH2NH2, A is an unsubstituted or hydroxy-substituted straight or branched C, -, 10 alkylene group or a straight or branched C1-10 alkylene group having an intervening heteroatom selected from oxygen, sulfur and nitrogen; R2 is hydroxy, halogen, C1-4 alkoxy, nitrile, azido, a quaternary ammonio group, -NRSR6, azetidinyl, or a 5- or 6-membered heterocyclic group selected from heteroaromatic and heteroalicyclic joined through a carbon atom thereof; B is a straight or branched C, -6 alkylene group or a direct bond when R3 is joined to the sulfur atom through a carbon atom thereof; R3 is a residue of an organic group; R4 is hydrogen, a removable carboxy-protecting group or a physiologically hydrolyzable ester group; R5 and R6 each are independently hydrogen, C1-6 alkyl, C1-4 alkoxy, hydroxyethyl, azidoethyl, aminoethyl, and when R5 is hydrogen or C, -a alkyl, R6 is hydroxy, C1-4 alkoxy, amino, C1-4 alkylamino, di(Ci-4.)alkylamino, substituted C1-4 alkyl wherein said alkyl substituent is selected from hydroxy, azido, amino, guanidino, nitrile, carboxy, formimidoyl and phenyl, or an acyl residue of an amino acid or peptide; or R5 and R6, taken together with the nitrogen atom to which they are attached, is an unsubstituted or substituted heterocyclic ring having 1 to 2 ring members and having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, wherein said substituent is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, hydroxy, halogen, amino, nitrile, carboxy, carbamido, carbamoyl, C, -4 alkylamino and amino (C1-4) alkyl; W is a direct bond, oxygen, sulfur or NR'°; Y is oxygen or NR10; Z is hydrogen, hydroxy, C1-4 alkyl, C1-4 alkoxy, -NR7R8, amino(C1-4)alkyl, azido(C1-4)alkyl or hydroxy (C1-4)alkyl; R7 and R8 each are independently hydrogen, C1-4 alkyl or alkanoyl; and R10 is hydrogen, C1-4 alkyl, C1-4 alkylamino or di(C1-4)alkylamino; or a non-toxic pharmaceutically acceptable salt thereof, are novel antimicrobial agents which are useful in the treatment of infectious disease in humans and other animals. Novel intermediates and processes for their preparation are also disclosed.

  式中的化合物 其中 R1 为氢、C1-2 烷基、-CH20H、-CH2NH2、 A 是未取代的或羟基取代的直链或支链 C,-,10-亚烷基，或具有选自氧、硫和氮的杂原子的直链或支链 C1-10 亚烷基； R2 是羟基、卤素、C1-4 烷氧基、腈、叠氮、季铵基、-NRSR6、 氮杂环丁基，或通过一个碳原子连接的 5 或 6 元杂环基团，这些杂环基团选自杂芳族和杂脂环； B 是直链或支链 C, -6 亚烷基，或当 R3 通过其碳原子与硫原子相连时的直接键； R3 是有机基团的残基； R4 是氢、可去除的羧基保护基团或生理上可水解的酯基； R5和R6各自独立地是氢、C1-6烷基、C1-4烷氧基、羟乙基、叠氮乙基、氨基乙基，当R5是氢或C, -a烷基时，R6是羟基、C1-4烷氧基、氨基、C1-4烷基氨基、二(Ci-4.当 R5 为氢或 C-a烷基时，R6 为羟基、C1-4烷氧基、氨基、C1-4烷基氨基、二(Ci-4. )烷基氨基、取代的 C1-4 烷基，其中所述烷基取代基选自羟基、叠氮基、氨基、胍基、腈基、羧基、甲酰亚胺基和苯基，或氨基酸或肽的酰基残基；或 R5 和 R6，连同它们所连接的氮原子，是一个未取代或取代的杂环，具有 1 至 2 个环成员，且每个环中具有最多 4 个独立选自氧、氮和硫的杂原子，其中所述取代基选自由 C1-4 烷基、C1-4 烷氧基、三氟甲基、羟基、卤素、氨基、腈、羧基、氨基甲酰基、氨基甲酰基、C, -4 烷基氨基和氨基（C1-4）烷基组成的组；W 是直接键、氧、硫或 NR'°； Y 是氧或 NR10 Z 是氢、羟基、C1-4 烷基、C1-4 烷氧基、-NR7R8、氨基（C1-4）烷基、叠氮（C1-4）烷基或羟基（C1-4）烷基； R7 和 R8 各自独立地为氢、C1-4 烷基或烷酰基；以及 R10 是氢、C1-4 烷基、C1-4 烷基氨基或二(C1-4)烷基氨基； 或其无毒药学上可接受的盐，是新型抗菌剂，可用于治疗人类和其他动物的传染性疾病。此外，还公开了新型中间体及其制备工艺。
• US5672701A
  申请人：——

  公开号：US5672701A

  公开（公告）日：1997-09-30
• Tetrahydro-isoquinoline-Based Factor Xa Inhibitors
  作者：Ralf Kucznierz、Frank Grams、Herbert Leinert、Klaus Marzenell、Richard A. Engh、Wolfgang von der Saal

  DOI：10.1021/jm9800402

  日期：1998.12.1

  Derivatives of (2-amidino-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)phenylacetic acid (TIPAC) were developed as inhibitors of factor Xa (fXa). The compounds are prepared using 15 synthetic steps on average. The most potent compounds (14, 17, 22-26) display inhibition constants of K-i = 21-55 nM but do not inhibit thrombin (K-i = 5->100 mu M) and only weakly inhibit trypsin (K-i = 0.08-5 mu M). They bear a second basic moiety, e.g., substituted 1-(iminomethyl)piperidines, which is linked to C-4 of the phenyl group of TIPAC via an oxygen atom. The inhibition constants of these compounds are almost independent of the size of the (iminomethyl)piperidine substituent. Due to the fact that fXa displays two cation binding sites, namely, the S1 and S4 sites, in principle two binding modes are conceivable for the novel dibasic fXa inhibitors. Molecular modeling experiments based on the X-ray structures of uninhibited fXa and the DX-9065a/fXa complex were carried out. The results taken together with the inhibition constants clearly favor one binding mode: the tetrahydro-isoquinoline fills the S1 pocket even better than the naphthalene moiety of DX-9065a, and the (iminomethyl)piperidine residues occupy the S4 site.