LGD-4033 synthesis

1synthesis methods

Product Name:LGD-4033
CAS Number:1165910-22-4
Molecular formula:C14H12F6N2O
Molecular Weight:338.25

LGD-4033 is a novel nonsteroidal oral selective androgen receptor modulator (SARM) for treatment of conditions such as muscle wasting and osteoporosis.It is synthesised by N-[(3,5-dichlorophenyl)methylene]-2,2-diethoxy- Ethanamine with (Trifluoromethyl)trimethylsilane,in THF was stirred over night at 60°C.

Ethanamine, N-[(3,5-dichlorophenyl)methylene]-2,2-diethoxy-

1000210-73-0
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81290-20-2 Synthesis

81290-20-2
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4-[(2R)-2-[(1S)-2,2,2-Trifluoro-1-hydroxyethyl]-1-pyrrolidinyl]-2-(trifluoromethyl)-benzonitrile

1165910-23-5
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1165910-22-4
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Yield:-

Steps:

1
A mixture of D-prolinol, 4-fluoro-2-trifluoromethylbenzonitrile, and triethylamine in THF was stirred over night at 60°C. Standard work-up of the reaction mixture provided R-4-(2-hydroxylmethylpyrrolidinyl)-2-trifluoromethyl- benzonitrile in moderate yield. The intermediate alcohol was oxidized by sulfur trioxide pyridine complex to give /?-4-(2-formyl-pyrrolidinyl)-2-trifluoromethyl- benzonitrile. The aldehyde intermediate was treated with trimethyl(trifluoromethyl)- silane to provide a mixture of two diastereomers. HPLC separation generated pure forms of Compounds 101 and 102. Compound 101: ¹H-NMR (500 MHz, CDCl₃) 7.59 (d, J= 8.8, IH), 7.07 (d, J= 2.9, IH), 6.92 (dd, J= 8.8 and 2.9, IH), 4.24 (t, J= 7.5, IH), 3.91 (t, J= 6.3, IH), 3.63 (dd, J= 7.8 and 9.3, IH), 3.29 (td, J= 6.9 and 9.7, IH), 2.55 (s, IH), and 2.05- 2.23 (m, 4H).Compound 102: ¹H-NMR (500 MHz, acetone-d₆) 7.78 (d, J= 8.8, IH), 7.01 (d, J= 2.9, IH), 6.94 (dd, J= 8.8 and 2.9, IH), 5.68 (bd, J= 3.3, IH), 4.44-4.50 (m, IH), 4.36 (d, J= 8.3, IH), 3.64-3.77 (m, IH), 3.44 (td, J= 9.8 and 7.8, IH), 2.30-2.47 (m, 2H), and 2.07-2.17 (m, 2H).

References:

LIGAND PHARMACEUTICALS INCORPORATED WO2009/82437, 2009, A2 Location in patent:Page/Page column 145