(2S)-2({(1Z)-3-oxo-1-(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-]pyrazin-7(8H)-yl]prop-1-enyl}amino-2-phenylethanamide) | 769195-19-9

• 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
• 英文名称: (2S)-2({(1Z)-3-oxo-1-(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-]pyrazin-7(8H)-yl]prop-1-enyl}amino-2-phenylethanamide)
• 英文别名: (S,Z)-2-((4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-en-2-yl)amino)-2-phenylacetamide；(2S)-2-[[(Z)-4-oxo-4-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-yl]amino]-2-phenylacetamide
• CAS: 769195-19-9
• 化学式: C₂₄H₂₀F₆N₆O₂
• 分子量: 538.452
• InChiKey: PKFNIQXTCJPYGT-SDQNTSPESA-N

物化性质

• 沸点：
  737.0±70.0 °C(Predicted)
• 密度：
  1.52±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  (2S)-2({(1Z)-3-oxo-1-(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-]pyrazin-7(8H)-yl]prop-1-enyl}amino-2-phenylethanamide) 在 sodium tetrahydroborate 、 zinc(II) chloride 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 以57.1%的产率得到(3R)-3-[[(1S)-1-carboxamidophenylmethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
  参考文献：
  名称：

  Synthesis of Sitagliptin Phosphate by a NaBH₄/ZnCl₂-catalyzed Diastereoselective Reduction

  摘要：

  本研究以 1-{3-(三氟甲基)-5,6-二氢-[1,2,4]三唑并-[4,3-a]吡嗪-7(8H)-基}-4-(2,4,5-三氟苯基)丁烷-1,3-二酮为原料，不对称合成了磷酸西他列汀，总收率为 65.3%。目标化合物是通过烯化、非对映选择性还原、胺脱保护和磷酸化合成的。关键的非对映选择性还原是用 NaBH4 和 ZnCl2 进行的，经过简单的加工和用 IPA/PE 重结晶后，产物的收率几乎达到定量，d.e.值为 68.5%；还可以获得高对映体纯度（d.e.% = 99.3%），收率为 57.1%。

  DOI：

  10.1246/cl.150390
• 作为产物：
  描述：

  L-苯甘氨酰胺 、 (2Z)-4-氧代-4-[3-(三氟甲基)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7-(8H)-基]-1-(2,4,5-三氟苯基)丁-2-酮 在 溶剂黄146 作用下， 以 异丙醇 为溶剂， 反应 10.0h， 以91.3%的产率得到(2S)-2({(1Z)-3-oxo-1-(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-]pyrazin-7(8H)-yl]prop-1-enyl}amino-2-phenylethanamide)
  参考文献：
  名称：

  Synthesis of Sitagliptin Phosphate by a NaBH₄/ZnCl₂-catalyzed Diastereoselective Reduction

  摘要：

  本研究以 1-{3-(三氟甲基)-5,6-二氢-[1,2,4]三唑并-[4,3-a]吡嗪-7(8H)-基}-4-(2,4,5-三氟苯基)丁烷-1,3-二酮为原料，不对称合成了磷酸西他列汀，总收率为 65.3%。目标化合物是通过烯化、非对映选择性还原、胺脱保护和磷酸化合成的。关键的非对映选择性还原是用 NaBH4 和 ZnCl2 进行的，经过简单的加工和用 IPA/PE 重结晶后，产物的收率几乎达到定量，d.e.值为 68.5%；还可以获得高对映体纯度（d.e.% = 99.3%），收率为 57.1%。

  DOI：

  10.1246/cl.150390

文献信息

• INTERMEDIATES OF SITAGLIPTIN AND PREPARATION PROCESS THEREOF
  申请人：Pan Xianhua

  公开号：US20130281695A1

  公开（公告）日：2013-10-24

  Disclosed are intermediates of Sitagliptin, a preparation process thereof, and a process for synthesizing Sitagliptin using these intermediates. Sitagliptin is synthesized by using chiral amino compounds as a raw material, without having to build a chiral center with a chiral asymmetric catalytic hydrogenation, and high-pressure hydrogenation is avoided.

  揭示了西他列汀的中间体、其制备过程以及利用这些中间体合成西他列汀的方法。西他列汀是通过使用手性氨基化合物作为原料合成的，无需通过手性不对称催化氢化建立手性中心，并且避免了高压氢化反应。
• [EN] A NOVEL PROCESS FOR THE PREPARATION OF SITAGLIPTIN<br/>[FR] NOUVEAU PROCÉDÉ DE PRÉPARATION DE SITAGLIPTINE
  申请人：SMILAX LAB LTD

  公开号：WO2013114173A1

  公开（公告）日：2013-08-08

  The present invention is directed to a process for the preparation of enantiomerically enriched β-amino acid derivatives which are important chiral building blocks and intermediates in pharmaceuticals. More specifically, the invention pertains to a novel process for practically convenient and economically producing enantiomerically enriched β-amino acid derivatives which are useful for the synthesis of amide inhibitors of dipeptidyl peptidase IV like Sitagliptin, which have been used to treat type 2 diabetes.

  本发明涉及一种制备对映富集的β-氨基酸衍生物的方法，这些衍生物是重要的手性构建块和药物中间体。更具体地，该发明涉及一种新颖的方法，用于方便实用和经济地生产对映富集的β-氨基酸衍生物，这些衍生物对于合成类似西他列汀的二肽基肽酶IV抑制剂的酰胺具有用处，这些抑制剂已被用于治疗2型糖尿病。
• PROCESS FOR PREPARATION OF (2R)-4-OXO-4-[3- (TRIFLUOROMETHYL)-5,6-DIHYDRO [1,2,4]-TRIAZOLO[4,3-A]PYRAZIN- 7(8H)-YL]-L-(2,4,5-TRIFLUOROPHENYL)BUTAN-2-AMINE & NEW IMPURITIES IN PREPARATION THEREOF
  申请人：Kothari Himanshu Madhusudan

  公开号：US20110213149A1

  公开（公告）日：2011-09-01

  The present invention relates to synthesis of β-amino acid derivatives of formula (I) and its salts of formula (Ia) by a novel process. The process comprises the reduction of a protected or unprotected prochiral β-amino acrylic acid or derivative there of, by using borane containing reducing agents at atmospheric pressure. The resulting racemic β-amino compound is resolved to a pure stereoisomer of formula (I), specifically to (2R)-4-oxo-4-[3-Ctrifluoromethyl)-5,6-dihydrol[1,2,4]triazolo[4,3-alpyrazin-7(8H)-yl]-1-(2,4,4-trifluorophenyl)butan-2-amine. In an embodiment the invention disclosed polymorphic forms of formula (I), phosphate salt of formula (I) and also a Dibenzoyl-L-tartaric acid salt of formula (I).

  本发明涉及通过一种新方法合成公式（I）的β-氨基酸衍生物及其公式（Ia）的盐。该方法包括使用含硼烷还原剂在大气压下还原受保护或未保护的β-氨基丙烯酸或其衍生物，生成外消旋β-氨基化合物，然后将其分离成公式（I）的纯立体异构体，具体为（2R）-4-氧代-4-[3-三氟甲基)-5,6-二氢-[1,2,4]三唑[4,3-a]吡嗪-7(8H)-基]-1-(2,4,4-三氟苯基)丁-2-胺。在一个实施例中，本发明揭示了公式（I）的多形式、公式（I）的磷酸盐以及公式（I）的苹果酸二苯甲酰盐。
• Process for the synthesis of beta-amino acids and derivatives thereof
  申请人：LEK Pharmaceuticals d.d.

  公开号：EP2397141A1

  公开（公告）日：2011-12-21

  The present invention relates to a process for the preparation of β-amino acids and derivatives thereof, which is especially suited for gliptins and particularly sitagliptin. A key step makes use of suitably derivatized epoxides or aziridines, which owing to a chirality provides a source of chirality for intermediates which are suitable for building up β-amino acids and similar compounds, in particular in the construction of the sitagliptin molecule.

  本发明涉及一种制备β-氨基酸及其衍生物的方法，该方法特别适用于格列酮类药物，尤其是西他列汀。关键步骤利用适当衍生的环氧化物或氮杂环丙烷，由于手性而为中间体提供手性来源，适用于构建β-氨基酸和类似化合物，特别是在构建西他列汀分子时。
• METHOD FOR PREPARING INTERMEDIATE COMPOUND OF SITAGLIPTIN
  申请人：ZHEJIANG MEDICINE CO., LTD. XIANCHANG PHARMAUCEUTICAL FACTORY

  公开号：US20160229859A1

  公开（公告）日：2016-08-11

  The present invention provides a method for preparing an intermediate compound of sitagliptin represented by formula I. The preparation method comprises: dissolving a compound represented by formula II into an organic solvent; and under the catalysis of fatty acid and effect of chlorosilane, performing a reduction reaction of carbon-carbon double bonds, so as to obtain the intermediate compound of sitagliptin represented by formula I, R being methyl or formoxyl. The preparation method of the present invention avoids precious metal as a catalyst, and accordingly, the cost is low, the post-treatment is simple, the product has a high yield, chemical purity and optical purity, and de % is greater than 99.6%, and the preparation method can be used in synthesis of sitagliptin and is suitable for industrial production.

  本发明提供了一种制备西他列汀中间体化合物的方法，其表示为式I。制备方法包括：将式II表示的化合物溶解于有机溶剂中；在脂肪酸的催化作用和氯硅烷的影响下，进行碳-碳双键的还原反应，从而获得西他列汀中间体化合物，其表示为式I，其中R为甲基或甲氧基。本发明的制备方法避免了贵金属作为催化剂，因此成本低廉，后处理简单，产品产率高，化学纯度和光学纯度高，de%大于99.6%，该制备方法可用于西他列汀的合成，并适用于工业生产。