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DOI: 10.1055/a-2587-7778
Synthesis of Sacubitril Isomers Governed by Differential Facial Selectivity during the Hydrogenation of Conjugated System
We thank the management of Dr. Reddy’s laboratories Limited for supporting this work.
Abstract
A stereoselective process for the synthesis of sacubitril isomers with high yield is reported. Previously reported preparation of these isomers is cumbersome, requiring isolation by repetitive fractional crystallization from the mother liquors remaining after the separation of the major diastereomers (sacubitril) and its enantiomer, respectively. The key feature in our approach is a reversal of stereoselectivity during the catalytic hydrogenation of β,γ-ene amino acid by altering the protecting group on nitrogen. This led to the formation of isomers as the major products providing rapid access to multigram quantities of sacubitril isomers.
Key words
sacubitril isomers - impurities synthesis - facial selectivity - transition state - spectral analysisSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2587-7778.
Single-crystal X-ray diffraction data and files for compound 1 (CCDC2453255)
- Supporting Information
Publication History
Received: 25 February 2025
Accepted after revision: 14 April 2025
Accepted Manuscript online:
14 April 2025
Article published online:
28 May 2025
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References and Notes
- 1 McMurray JJ. V, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR. N. Engl. J. Med. 2014; 371: 993
- 2 FDA approves new drug to treat heart failure. https://wayback.archive-it.org/7993/20180126023455/ https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453845.htm
- 3 https://www.novartis.com/sites/novartis_com/files/q2-2022-investor-presentation.pdf (accessed 5th May, 2025)
- 4 https://www.novartis.com/sites/novartis_com/files/q4-2022-investor-presentation.pdf (accessed 5th May, 2025)
- 5 International Council of Harmonization (ICH) guidelines (accessed 5th May, 2025). https://www.ich.org/page/quality-guidelines
- 6a Ksander GM, Ghai RD, de Jesus R, Diefenbacher CG, Yuan A, Berry C, Sakane Y, Trapani A. J. Med. Chem. 1995; 38: 1689
- 6b Hook D, Riss B, Kaufmann D, Napp M, Bappert E, Polleux P, Medlock J, Zangotti-Gerosa A. PCT Int. Appl WO 2009/090251, 2009 ; Chem. Abstr. 2009, 151, 198239
- 6c Lau SH, Bourne SL, Martin B, Schenkel B, Penn G, Ley SV. Org. Lett. 2015; 17: 5436
- 6d Xu X-N. CN Patent CN 104557600 A, 2015 ; Chem. Abstr. 2015, 162, 603569
- 6e Wang Y, Chen F.-E, Shi Y, Tian W.-S. Tetrahedron Lett. 2016; 57: 5928
- 6f Ksander G. US Patent 5(217):996, 1993
- 6g Hook D, Ruch T, Riss B, Wietfeld B, Sedelmaier G, Napp M, Bänzinger M, Hawker S, Ciszewski L, Waykole L. PCT Int. Appl WO 2008/083967 A2, 2008 ; Chem. Abstr. 2008, 149, 176170
- 6h Martin B, Mandrelli F, Venturoni S.-L. US Pat. Appl US 2018/0022690 A1, 2018 ; Chem. Abstr. 2018, 165, 298456
- 7 Halama A, Zapadlo M. Org. Process Res. Dev. 2019; 23: 102
- 8 Koskinen AM. P, Pihko PM. Tetrahedron Lett. 1994; 35: 7417
- 9 Koskinen AM. P, Pihko MP. J. Org. Chem. 1998; 63: 92
- 11 Gaussian 16, Revision C.01. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JA. Jr, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ. Gaussian, Inc; Wallingford CT: 2016
- 12 Schrödinger Release 2022-2. Schrödinger LLC; New York: 2021
- 13 Buchanan JG, Sable HZ. In Selective Organic Transformations, Vol. 2. Thyagarajan BS. Wiley-Interscience; New York: 1972: 1-95
- 14 Lyle FR. US Patent 5 973 257, 1985 ; Chem. Abstr. 1985, 65, 2870
For selected syntheses, see: