(2S,5S)-N-叔丁氧羰基-5-叔丁基吡咯烷-2-甲酸 | 185142-24-9

• 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
• 中文名称: (2S,5S)-N-叔丁氧羰基-5-叔丁基吡咯烷-2-甲酸
• 中文别名: (2S,5S)-N-Boc-5-叔丁基吡咯烷-2-甲酸
• 英文名称: (2S,5S)-N-Boc-5-tert-butylproline
• 英文别名: Boc-5(S)-tert-butyl-L-proline；(2S,5S)-5-tert-butyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid
• CAS: 185142-24-9
• 化学式: C₁₄H₂₅NO₄
• 分子量: 271.357
• InChiKey: WODLVEFJKWRNHB-UWVGGRQHSA-N

物化性质

• 沸点：
  373.8±35.0 °C(Predicted)
• 密度：
  1.105

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S,5S)-N-叔丁氧羰基-5-叔丁基吡咯烷-2-甲酸 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 26.0h， 生成 (2S,5S)-5-tert-Butyl-pyrrolidine-2-carboxylic acid ((S)-1-phenyl-ethyl)-amide; compound with trifluoro-acetic acid
  参考文献：
  名称：

  5-tert-Butylproline

  摘要：

  Steric effects on the isomer equilibrium of amides N-terminal to proline can be explored with 5-alkylprolines having bulky 5-position substituents. Enantiopure 5-tert-butylprolines were thus synthesized from glutamic acid via an acylation/diastereoselective reductive amination sequence. Double deprotonation of gamma-methyl N-(PhF)glutamate (2) with LiN(SiMe(3))(2) and C-acylation with pivaloyl chloride provided beta-keto ester 3, which upon gamma-ester hydrolysis and decarboxylation gave delta-oxo-alpha-[N-(PhF)amino]heptanoic acid (4). Syntheses of (2S,5R)- and (2R, 5S)-N-(BOC)-5-tert-butylprolines ((2S,5R)-1 and (2R,5S)-1) were accomplished by catalytic hydrogenation of their respective (2S)- and (2R)-methyl delta-ore-alpha-[N-(PhF)amino]heptanoates ((2S)-5a and (2R)-5a) in methanol with di-tert-butyl dicarbonate followed by chromatography and ester hydrolysis with potassium trimethylsilanolate. The 5-tert-butylproline cis-diastereomers were proven to be of >99% enantiomeric purity after their conversion to diastereomeric alpha-methylbenzylamides 10. Good diastereoselectivity in favor of the trans-diastereomer was observed when (2S,5S)-5-tert-butylproline was synthesized from (2S)-delta-oxo-alpha-[N-(PkF)amino]heptanoate ((2S)-4) by solvolysis of the PhF group in trifluoroacetic acid and subsequent reduction of 5-tert-butyl-Delta 5-dehydroproline (11) with tetramethylammonium triacetoxyborohydride; however, imino acid 11 was shown to be configurationally labile and racemized under acidic conditions. 5-tert-Butyl-Delta 5-dehydroproline N'-methylamide 15 was configurationally stable in acid, yet preliminary attempts to reduce 15 favored cis-diastereomer 16. Alternatively, enantiopure trans-diastereomer, (2R,5R)-methyl N-(BOC)-5-tert-butylprolinate (9) was prepared by epimerization of(2S,5R)-9. In summary, this synthetic methodology now provides access to all four enantiopure 5-tert-butylproline isomers from inexpensive L- and D-glutamate as chiral educts.

  DOI：

  10.1021/jo9618738
• 作为产物：
  描述：

  (2S,5S)-N-Boc-5-tert-butylprolinol 在 sodium chlorite 、 sodium dihydrogenphosphate 、 四丙基高钌酸铵 、 4 A molecular sieve 、 N-甲基吗啉氧化物 作用下， 以 二氯甲烷 、 水 、 乙腈 、 叔丁醇 为溶剂， 反应 6.0h， 生成 (2S,5S)-N-叔丁氧羰基-5-叔丁基吡咯烷-2-甲酸
  参考文献：
  名称：

  （2 S，5 S）-5-叔丁基脯氨酸的改进合成

  摘要：

  （2 S，5 S）-N -Boc-5-叔丁基脯氨酸（1）通过一种改进的方法合成，该方法的特征是将（2 S）-1-叔丁基二甲基甲硅烷氧基-2- N-（PhF）氨基-将5-氧代-6,6-二甲基庚烷（16）转化为其相应的亚氨基醇，然后进行定向氢化物传递，以95：5的非对映选择性降低亚胺官能度。酮16是从2- N-（PhF）氨基-5-氧代6,6-二甲基庚酸甲酯（13）获得的，后者是先前报道的合成（2 S，5 R）-5-的前体。叔丁基脯氨酸，通过还原成其相应的二醇，对伯醇进行选择性保护，并对仲醇进行氧化。该路线提供了适用于肽化学的对映体纯度> 96％的（2 S，5 S）-N - Boc -5-叔丁基脯氨酸（1），来自酮13的总收率为39％。

  DOI：

  10.1016/s0040-4020(01)00535-x

文献信息

• Compounds having prolyl oligopeptidase inhibitory activity
  申请人：Gynther Jukka

  公开号：US20060229254A1

  公开（公告）日：2006-10-12

  A compound of formula (I), wherein X, R 1 , R 2 and R 3 are as defined in the disclosure, or a pharmaceutically acceptable salt or ester thereof, useful as a prolyl oligopeptidase inhibitor. The compounds can be used for the treatment of diseases or conditions where prolyl oligopeptidase inhibitors are indicated to be effective, for example for the treatment of neurodegenerative diseases, such as Alzheimer's disease and senile dementia.

  式(I)的化合物，其中X、R1、R2和R3如所披露的定义，或其药学上可接受的盐或酯，可用作脯氨酰寡肽酶抑制剂。这些化合物可用于治疗需要脯氨酰寡肽酶抑制剂具有疗效的疾病或情况，例如用于治疗神经退行性疾病，如阿尔茨海默病和老年性痴呆症。
• COMPOUNDS HAVING PROLYL OLIGOPEPTIDASE INHIBITORY ACTIVITY
  申请人：Orion Corporation

  公开号：EP1581489A2

  公开（公告）日：2005-10-05
• [EN] COMPOUNDS HAVING PROLYL OLIGOPEPTIDASE INHIBITORY ACTIVITY<br/>[FR] COMPOSES PRESENTANT UN EFFET INHIBITEUR SUR LA PROLYL-OLIGOPEPTIDASE
  申请人：ORION CORP

  公开号：WO2004060862A2

  公开（公告）日：2004-07-22

  The invention provides a compound of formula (I), wherein in the formula X, R1, R2 and R3 are as defined in claim 1, or a pharmaceutically acceptable salt or ester thereof, useful as a prolyl oligopeptidase inhibitor. The compounds of formula (I) can be used for the treatment of diseases or conditions where prolyl oligopeptidase inhibitors are indicated to be effective, for example for the treatment of neurodegenerative diseases, such as Alzheimer's disease and senile dementia
• Improved synthesis of (2S,5S)-5-tert-butylproline
  作者：Liliane Halab、Laurent Bélec、William D Lubell

  DOI：10.1016/s0040-4020(01)00535-x

  日期：2001.7

  oline (1) was synthesized by an improved procedure featuring the conversion of (2S)-1-tert-butyldimethylsiloxy-2-N-(PhF)amino-5-oxo-6,6-dimethylheptane (16) into its corresponding imino alcohol followed by directed hydride delivery to reduce the imine functionality with a 95:5 diastereoselectivity. Ketone 16 was obtained from methyl 2-N-(PhF)amino-5-oxo-6,6-dimethylheptanoate (13), a previously reported

  （2 S，5 S）-N -Boc-5-叔丁基脯氨酸（1）通过一种改进的方法合成，该方法的特征是将（2 S）-1-叔丁基二甲基甲硅烷氧基-2- N-（PhF）氨基-将5-氧代-6,6-二甲基庚烷（16）转化为其相应的亚氨基醇，然后进行定向氢化物传递，以95：5的非对映选择性降低亚胺官能度。酮16是从2- N-（PhF）氨基-5-氧代6,6-二甲基庚酸甲酯（13）获得的，后者是先前报道的合成（2 S，5 R）-5-的前体。叔丁基脯氨酸，通过还原成其相应的二醇，对伯醇进行选择性保护，并对仲醇进行氧化。该路线提供了适用于肽化学的对映体纯度> 96％的（2 S，5 S）-N - Boc -5-叔丁基脯氨酸（1），来自酮13的总收率为39％。
• 5-<i>tert</i>-Butylproline
  作者：Eric Beausoleil、Benoît L'Archevêque、Laurent Bélec、Mohamed Atfani、William D. Lubell

  DOI：10.1021/jo9618738

  日期：1996.1.1

  Steric effects on the isomer equilibrium of amides N-terminal to proline can be explored with 5-alkylprolines having bulky 5-position substituents. Enantiopure 5-tert-butylprolines were thus synthesized from glutamic acid via an acylation/diastereoselective reductive amination sequence. Double deprotonation of gamma-methyl N-(PhF)glutamate (2) with LiN(SiMe(3))(2) and C-acylation with pivaloyl chloride provided beta-keto ester 3, which upon gamma-ester hydrolysis and decarboxylation gave delta-oxo-alpha-[N-(PhF)amino]heptanoic acid (4). Syntheses of (2S,5R)- and (2R, 5S)-N-(BOC)-5-tert-butylprolines ((2S,5R)-1 and (2R,5S)-1) were accomplished by catalytic hydrogenation of their respective (2S)- and (2R)-methyl delta-ore-alpha-[N-(PhF)amino]heptanoates ((2S)-5a and (2R)-5a) in methanol with di-tert-butyl dicarbonate followed by chromatography and ester hydrolysis with potassium trimethylsilanolate. The 5-tert-butylproline cis-diastereomers were proven to be of >99% enantiomeric purity after their conversion to diastereomeric alpha-methylbenzylamides 10. Good diastereoselectivity in favor of the trans-diastereomer was observed when (2S,5S)-5-tert-butylproline was synthesized from (2S)-delta-oxo-alpha-[N-(PkF)amino]heptanoate ((2S)-4) by solvolysis of the PhF group in trifluoroacetic acid and subsequent reduction of 5-tert-butyl-Delta 5-dehydroproline (11) with tetramethylammonium triacetoxyborohydride; however, imino acid 11 was shown to be configurationally labile and racemized under acidic conditions. 5-tert-Butyl-Delta 5-dehydroproline N'-methylamide 15 was configurationally stable in acid, yet preliminary attempts to reduce 15 favored cis-diastereomer 16. Alternatively, enantiopure trans-diastereomer, (2R,5R)-methyl N-(BOC)-5-tert-butylprolinate (9) was prepared by epimerization of(2S,5R)-9. In summary, this synthetic methodology now provides access to all four enantiopure 5-tert-butylproline isomers from inexpensive L- and D-glutamate as chiral educts.