- Vildagliptin diketopiperazine and preparation method thereof
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The preparation method comprises the following steps: (1) L - proline is dissolved, and chloroacetyl chloride is mixed, and the compound 1 is generated. (2) Compound 1 and 3 - amino -1 - adamantanol undergo a substitution reaction under basic conditions to give compound 2. (3) The compound 2 is cyclised under basic conditions, i.e. diketopiperazine. The preparation method of the vildagliptin diketopiperazine provided by the invention takes L - proline as a raw material, is synthesized through chloroacetylation, substitution and dehydration 3 steps, is simple in synthesis method, mild and easy to control in reaction conditions, cheap in raw material, and capable of 98.0% effectively reducing the synthesis cost.
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Paragraph 0013; 0028-0031; 0036-0039; 0044-0047; 0052; ...
(2021/10/27)
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- A facile method to synthesize vildagliptin
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An efficient and high-yielding synthetic method for the preparation of vildagliptin via four steps is reported. The process starts from L-proline and involves a successful reaction with chloroacetyl chloride in tetrahydrofuran to afford (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid, followed by a reaction with acetonitrile in the presence of sulfuric acid to give (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. This is then reacted with 3-aminoadamantanol to give vildagliptin. 3-Aminoadamantanol is prepared from 1-aminoadamantane hydrochloride via oxidation with sulfuric acid/nitric acid and boric acid as the catalyst followed by ethanol extraction. The overall yield is 95%.
- Zhang, Li,Jiang, Lan,Guan, Xiaoshu,Cai, Linhong,Wang, Jingyu,Xiang, Peng,Pan, Junyi,Hu, Xiangnan
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p. 305 - 309
(2020/12/01)
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- Preparation method of high chiral purity (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile
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The invention discloses a preparation method of high chiral purity (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile, the preparation method comprises: S1, in the presence of a solvent and an acid-binding agent, carrying out a coupling reaction on L-proline and chloracetyl chloride to obtain an intermediate I; s2, in the presence of a solvent and sodium iodide, carrying out cyclization reaction on the intermediate I in an alkaline environment to obtain an intermediate II; s3, in the presence of a solvent and an ammonolysis agent, carrying out ammonolysis ring-opening reaction on the intermediate II to obtain an intermediate III; and S4, in the presence of a solvent and phosphorus oxychloride, carrying out chlorination and dehydration reaction on the intermediate III to obtain (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile. The method has the advantages of high chiral purity, simple steps, easily available and cheap raw materials, convenient post-treatment and high yield, and is suitable for industrial production.
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Paragraph 0037-0039; 0049-0051; 0056-0058; 0063-0065; ...
(2021/08/19)
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- Preparation process of vildagliptin impurity
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The invention discloses a preparation process of a vildagliptin impurity, namely 2-(3-hydroxy adamantane-1-yl) hexahydropyrrole [1, 2-a] piperazine-1, 4-diketone. According to the process, L-proline is used as an initial raw material, and 2-(3-hydroxy adamantane- 1-yl) hexahydropyrrole [1, 2-a] piperazine-1, 4-diketone is prepared through secondary N-chloracetylation reaction, amino substitution and intramolecular cyclization. The method is mainly characterized in that reaction steps and time are shortened, and expensive catalysts and tedious operation means are not involved in the whole reaction process. The preparation process has the advantages of easily available raw materials, mild and easily controllable reaction conditions and high product purity, and the vildagliptin impurity can be used as a reference substance for vildagliptin bulk drug quality control.
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Paragraph 0023-0025
(2021/01/04)
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- 2 - substituted pyrrolidines compound, preparation method and its application in the preparation of the peculiar smell (by machine translation)
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The invention discloses a 2 - substituted pyrrolidines compound, preparation method and its application in the preparation of the peculiar smell, the tetrahydro-pyrrole derivatives of formula (I) has the structure as illustrated, using the intermediate synthesis when the peculiar smell, the preparation method of the original source of auxiliary materials are cheap and easily obtained, the process route is short, low cost, mild conditions in the reaction process of the security, without the special requirements of the device, can be suitable for industrial production. (by machine translation)
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Paragraph 0005; 0062-0064
(2017/08/25)
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- Direct Synthesis of Cyanopyrrolidinyl β-Amino Alcohols for the Development of Diabetes Therapeutics
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Cyanopyrrolidinyl β-amino alcohols are novel scaffolds with potential for a wide array of pharmacological properties. We have discovered that we can selectively access these scaffolds from simple and inexpensive commercially available chemicals in few synthetic steps with minimal purification. We have produced a 36-compound library of these scaffolds and tested them as dipeptidyl peptidase IV (DPP4) inhibitors. These novel inhibitors are useful in the treatment of diabetes and inflammatory disorders.
- Lizza, Joseph R.,Patel, Savan V.,Yang, Catherine F.,Moura-Letts, Gustavo
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supporting information
p. 5160 - 5168
(2016/10/26)
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- A facile and economical method to synthesize vildagliptin
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A mild and economical method to prepare vildagliptin had been reported with a good yield. In this paper, vildagliptin was synthesized from L-proline and 3-amino-1-adamantanol through chloride acetylation, amination, dehydration and substitution. The total yield of the target compound was 59%.
- Deng, Yu,Wang, Anmin,Tao, Zhu,Chen, Yingjie,Pan, Xinmei,Hu, Xiangnan
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p. 780 - 784
(2015/04/14)
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- An economical and facile method to synthesize vildagliptin
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A facile and economical synthefic method to prepare vildagliption with-reported.It was started from L proline via succsessful reaction with chloried in tetrahydrofuran to-afford 1(2-chloroacetyl) pyrrolidine-2-carboxylic-acid, followed by reacting with 2-chloro-46-dimethoxy-1,3,5-triazine,N-methylmorpholine and 2,4,6-triazine,N-methlmorpholine-2,4,6-trichloro-1,3,5-triazine-to-give 1-(2-chloroacetyl)-pynolidine 2-carbonitrile which was-reacfed-with 3-aminoadmantanol to get the-forget-compound-of-vildagliption.
- Deng, Yu,Wang, Anmin,Tao, Zhu,Chen, Yingjie,Pan, Xinmei,Hu, Xiangnan
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p. 6275 - 6278
(2015/02/19)
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- Synthesis of main impurity of vildagliptin
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A four-step synthesis of the main impurity of vildagliptin has been easily accomplished with high-yielding starting from L-proline. This compound can be used as a reference marker in an analytical method to determine the chemical purity of the vildagliptin.
- Tao, Zhu,Deng, Yu,Chen, Yingjie,Wang, Anmin,Hu, Xiangnan
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p. 3489 - 3492
(2014/08/05)
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- A cost-effective method to prepare pure vildagliptin
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A cost-effective synthetic approach to prepare vildagliptin under gentle experimental conditions has been reported with good yield and high purity. It was initiated with L-proline via successful reaction with chloroacetyl chloride in THF (Tetrahydrofuran) to give the 1-(2-chloroacetyl)-pyrrolidine-2-carboxylic acid, which was then treated by TCT (2, 4, 6-trichloro-1, 3, 5-triazine) in DCM (dichloromethane), and converted into 1-(2-chloroacetyl)-pyrrolidine-2- carboxamide, then further converted into 1-(2-chloroacetyl)-pyrrolidine-2- carbonitrile after dehydrated by TCT in DMF (N, N- dimethylformamide), the latter product was reacted with 3-Aminoadamantanol to get vildagliptin. The total yield of vildagliptin was about 48%, the purity was about 99%.
- Peng, Jun,Feng, Yue,Tao, Zhu,Chen, Yingjie,Hu, Xiangnan
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p. 159 - 163
(2013/07/26)
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- Novel synthesis of heterocycle-containing adamantane derivatives
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A novel approach to synthesize the of heterocycle-containing adamantane derivatives 1-{[(3-hydroxy-1-adamantyl)amino]acetyl}-2- cyano-(S)-pyrrolidine and N-{2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl}adamantane-1-carboxamide, which were effective in treatment of diabetes and depression respectively, have been described. The target compounds were synthesized by raw materials of inexpensive L-proline and available 1-(2-pyrimidinyl) piperazine respectively. Compared with traditional synthetic routes, the method provides several advantages such as inexpensive and readily available raw materials, convenient manipulation and high yield.
- Xu, Xiaojian,Guo, Jianwei,Su, Qiang,Zhong, Xing
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p. 7557 - 7560
(2013/08/23)
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- Investigation of peptoid chiral stationary phases terminated with N′-substituted phenyl-L-proline/leucine amide
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Eight peptoid chiral stationary phases (CSPs) terminated with N′-substituted phenyl-L-proline or L-leucine amide were prepared and evaluated under normal phase mode. With 59 racemic analytes, we compared the enantiomeric separations on CSPs terminated with p-methylphenyl, p-chlorophenyl and unsubstituted phenyl. For short peptoid selectors containing only one S-N-(1-phenylethyl) glycine (Nspe) unit, the terminal p-methyl substituent did not affect chiral recognition abilities significantly. In L-proline amide terminated CSPs, p-chloro substituent resulted in obviously inferior selectivity while in L-leucine amide terminated CSPs, it worked much better. Longer peptoid selectors containing two more Nspe units generally performed much better than the shorter ones, due to the great contributions of peptoid chain to chiral recognition. Meanwhile, the effects of the terminal substituent on selectivity were found changed on these CSPs. For CSPs terminated with L-leucine amide, the terminal p-chloro substituent in longer selector no longer produced the best recognition ability; the CSP with unsubstituted phenyl instead performed best. Comparison of these peptoid CSPs varied in terminal substituents and chain length was conducted to gain a better understanding of the chiral recognition mechanism of this type CSP and promote the development of more useful CSPs. Copyright
- Wu, Haibo,Song, Guangjun,Liang, Xinmiao,Ke, Yanxiong
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supporting information
p. 2791 - 2797
(2013/08/23)
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- PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
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The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D-amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
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Page/Page column 80; 89
(2011/02/26)
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- PROCESS FOR PREPARATION OF DPP-IV INHIBITORS
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Process for the preparation of DPP-IV inhibitors, such as 1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine are disclosed.
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Page/Page column 20-21
(2011/09/19)
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- PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
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The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D- amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
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Page/Page column 111
(2010/04/03)
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- Reactions of N-(2-chloroacetyl)-α-amino acids with 3-cyanopyridine-2(1H)-thiones. New promising route to 3,4- dihydropyrido[3′,2′:4,5]thieno[3,2-e][1,4]diazepine-2(1H),5-diones
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The reactions of N-(2-chloroacetyl)-α-amino acids with 3-cyanopyridine-2(1H)-thiones afforded N-(3-ammothieno[2,3-b]pyridin-2- ylcarbonyl)-α-amino acids. Heating of the latter smoothly produced 3,4-dihydropyrido[3′,2′:4,5]thieno[3,2-e][1,4]diazepine-2(1H), 5-diones in high yields.
- Fedorov,Shestopalov,Belyakov
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p. 2197 - 2202
(2007/10/03)
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- Synthesis of fused 1,2,5-triazepine-1,5-diones and some N2- and N3-substituted derivatives: Potential conformational mimetics for cis-peptidyl prolinamides
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The synthesis of a new fused 1,2,5-triazepine-1,5-dione heterocycle, which is expected to mimic structural features of cis-peptldyl prolinamides, is described. The required parent heterocycle, corresponding to cis-glycy-(2S)-prolinamide, has been prepared in good yield by the cyclisation of N-(2-bromoacetylprolyl)-hydrazine which is itself generated in situ from the bromoacetyl proline methyl ester. Analogues corresponding to cis-(2R)-alanyl- and cis-(2S)-alanyl-(2S)-prolinamide have been similarly prepared from the appropriate N-(2-bromopropionyl)proline methyl esters and hydrazine hydrate where the cyclisation step, involving the displacement of bromide, has been shown to occur with inversion of configuration at C-2 of the propionyl moiety. Acylation at the N-3 position of the triazepine is equivalent to N-terminal acylation of the residue preceding the proline residue in cis-aminoacyl prolinamides. This has been achieved without incident using standard peptide coupling procedures. Extension at the 'C-terminal' has been achieved by preparing elaborated hydrazine precursors which are reacted with suitably activated esters of N-α-halogenoacylprolines, prior to cyclisation, to give the required fused triazepine dione. Thus it is possible to prepare constrained cis-peptidyl prolyl peptide mimetics of defined stereochemistry based upon this new triazepine dione in which all of the non-proline residues can be varied.
- Lenman, Morag M.,Lewis, Arwel,Gani, David
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p. 2297 - 2311
(2007/10/03)
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