- Development of an Enzymatic Process for the Synthesis of the Key Intermediate of Telotristat Ethyl
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(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethan-1-ol [(R)-2] is a key chiral intermediate in the synthesis of telotristat ethyl, an anti-carcinoid syndrome drug. However, the synthetic methods for (R)-2 mainly include chemical reductions, rarely involving biocatalysis or bioreduction until now. Here, we report a method for obtaining (R)-2 by biocatalytic reduction of corresponding prochiral acetophenone (1) with bulky o-substitution using recombinant Lactobacillus fermentum short-chain dehydrogenase/reductase 1 (LfSDR1) as a biocatalyst. Further engineering of LfSDR1 variants could access asymmetric reduction of 1 and yield (R)-2 with a >99% ee and a >99% conversion. In addition, through the test of different co-solvents and a series of initial substrate concentrations, substrate 1 with the concentration of 60 g/L can be completely converted into (R)-2 on a preparative scale (1.13 g, 3.93 mmol, 75.6% isolated yield) in 24 hours. This study presents an efficient enzymatic process for the biocatalytic synthesis of key chiral intermediate (R)-2 in the synthesis of telotristat ethyl. (Figure presented.).
- Li, Hengyu,Zhang, Wenhe,Jiang, Xianyan,Wang, Huibin,Wang, Qi,Wang, Jiajun,Jia, Xian,Qin, Bin,You, Song
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- Discovery of spirocyclic proline tryptophan hydroxylase-1 inhibitors
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The central role of the biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter with important cognitive and behavioral functions is well known. However, 5-HT produced in the brain only accounts for approximately 5% of the total amount of 5-HT generated in the body. At the onset of our work, it appeared that substituted phenylalanine derivatives or related aryl amino acids were required to produce potent inhibitors of TPH1, as significant losses of inhibitory activity were noted in the absence of this structural element. We disclose herein the discovery of a new class of TPH1 inhibitors that significantly lower peripherally 5-HT.
- Aiello, Robert,Barucci, Nicole,Bourassa, Patricia,Goldberg, Daniel R.,Paralkar, Vishwas,Valentine, James,Zavadoski, William,Zhang, Qing,De Lombaert, Stéphane
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- Application of asymmetric 1,2-addition reaction in compounding of telotristat ethyl midbody
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The invention provides a compounding method for a compound telotristat ethyl midbody as shown in formula (1). The method comprises the following steps: by taking a compound as shown in formula (2) as an initial raw material, performing grignard and asymmetric 1,2-addition reaction and finally acquiring the compound as shown in formula (1), thereby acquiring the telotristat ethyl midbody as shown in the specification. Compared with the prior art, the compounding method has the advantages that the telotristat ethyl midbody compounding process is simple and the compounding cost is low, the compounding method has the advantages that the compounding method is simple and feasible, the cost is low, the yield is higher, the product quality is high and the method is suitable for industrial production.
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Paragraph 0020; 0021; 0022
(2018/03/01)
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- Based on 4 - phenyl -6 - (2, 2, 2 - trifluoro -1 - phenyl ethoxy) pyrimidine compound and its application method
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The present invention relates to compounds based on 4-phenyl-6-(2,2,2-trifluoro-1-phenyl ethoxy) pyrimidine and an application method thereof, particularly discloses compounds of formula I and compositions comprising the compounds, and the application method thereof in treatment, prevention and / or management of diseases or disorders.
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Paragraph 0230
(2017/08/25)
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- SPIROCYCLIC COMPOUNDS AS TRYPTOPHAN HYDROXYLASE INHIBITORS
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The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.
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Page/Page column 68; 69; 71; 72
(2015/03/28)
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- METHODS OF PREPARING 4-PHENYL-6-(2,2,2-TRIFLUORO-1-PHENYLETHOXY)PYRIMIDINE-BASED COMPOUNDS
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Methods useful for preparing compounds of formula I: and salts thereof are disclosed. Also disclosed are intermediates useful in the preparation of such compounds.
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Page/Page column 7-8
(2009/04/24)
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- SOLID FORMS OF (S)-ETHYL 2-AMINO-3-(4-(2-AMINO-6-((R)-1-(4-CHLORO-2-(3-METHYL-1H-PYRAZOL-1-YL)PHENYL)-2,2,2-TRIFLUOROETHOXY)-PYRIMIDIN-4-YL)PHENYL)PROPANOATE AND METHODS OF THEIR USE
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Solid forms of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate and salts thereof are disclosed.
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Page/Page column 5
(2009/04/24)
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- 4-PHENYL-6-(2,2,2-TRIFLUORO-1-PHENYLETHOXY)PYRIMIDINE-BASED COMPOUNDS AND METHODS OF THEIR USE
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Compounds of formula I are disclosed, as well as compositions comprising them and methods of their use to treat, prevent and/or manage diseases and disorders:
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Page/Page column 19
(2008/12/06)
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