somatostatin receptor antagonist
C27 H23 F N8 O
1H-Pyrido[3,4-b]indole, 3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]-2,3,4,9-tetrahydro-1-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(1-methyl-1H-pyrazol-4-yl)-, (1R,3R)-
Merck & Co. (Originator)
Somatostatin srif1C (sst3) Antagonists
The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes
(ACS Medicinal Chemistry Letters) Thursday May 10th 2012
Author(s): Shuwen He, Zhixiong Ye, Quang Truong, Shrenik Shah, Wu Du, Liangqin Guo, Peter H. Dobbelaar, Zhong Lai, Jian Liu,Tianying Jian, Hongbo Qi, Raman K. Bakshi, Qingmei Hong, James Dellureficio, Alexander Pasternak, Zhe Feng, Reynalda deJesus, Lihu Yang, Mikhail Reibarkh, Scott A. Bradley, Mark A. Holmes, Richard G. Ball, Rebecca T. Ruck, Mark A. Huffman,Frederick Wong, Koppara Samuel, Vijay B. Reddy, Stan Mitelman, Sharon X. Tong, Gary G. Chicchi, Kwei-Lan Tsao, Dorina Trusca, Margaret Wu, Qing Shao, Maria E. Trujillo, George J. Eiermann, Cai Li, Bei B. Zhang, Andrew D. Howard, Yun-Ping Zhou,Ravi P. Nargund, William K. Hagmann,
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The fast eluting diastereomer(52 mg, 10%) was 3-((1R,3R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-5-methyl-1,2,4-oxadiazole(8, MK-4256).[α]D= +24.2, c=10 mg/mL in MeOH. LC-MS: m/z 495.3 (M+ H)+.
By:Ruck, RT (Ruck, Rebecca T.)[ 1 ] ; Huffman, MA (Huffman, Mark A.)[ 1 ] ; Stewart, GW (Stewart, Gavin W.)[ 2 ] ; Cleator, E (Cleator, Ed)[ 2 ] ; Kandur, WV (Kandur, Wynne V.)[ 1 ] ; Kim, MM (Kim, Mary M.)[ 1 ] ; Zhao, DL (Zhao, Dalian)[ 1 ]
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Reprint Address: Ruck, RT (reprint author)
|Merck & Co Inc, Dept Proc Chem, Merck Res Labs, Rahway, NJ 07065 USA.|
|[ 1 ] Merck & Co Inc, Dept Proc Chem, Merck Res Labs, Rahway, NJ 07065 USA|
|[ 2 ] Merck Sharp & Dohme Res Labs, Dept Proc Chem, Hoddesdon EN11 9BU, Herts, England|
Route development and demonstration on multikilogram scale for the first GMP delivery of MK-4256 are described. Key aspects of the convergent route include a regioselective green iodination, one-pot oxadiazole synthesis, and an efficient ketone Pictet–Spengler reaction with diastereomeric upgrade via crystallization to afford 6 kg of API. A recycle procedure augmented the yield of desired diastereomer in the Pictet–Spengler reaction from a mixture of diastereomers heavily enriched in the undesired diastereomer.
Residual metals were <10 ppm. Chiral method: Chiralcel OD-H, 250 mm × 4.6 mm, 40 °C, 1 mL/min, 260 nm, 30 min run time, 20% (1:1 IPA/MeOH) in heptane +0.1% TEA isocratic: rt (1): 7.61 min, rt (enantiomer-1): 14.45 min. By HPLC assay, final product was 99.60 LCAP 1, 0.17 LCAP 22, 0.24 LCAP enantiomer-22, enantiomer-1 was undetectable.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are either commercially available or made by known procedures in the literature or as illustrated. The present invention further provides processes for the preparation of compounds of structural formula I as defined above, hi some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention. All temperatures are degrees Celsius unless otherwise noted. The assignment of stereochemistry at the stereogenic carbon center indicated by an ** in Structure G of Scheme 3 from the Pictet-Spengler cyclization reaction to elaborate the β-carboline nucleus was determined using the aid of nuclear Overhauser effect (NOE) NMR spectroscopy. For a thorough discussion of the theory and application of NOE NMR spectroscopy, reference is made to Ernst, R.R.; Bodenhausen, B.; Wokaun, A., “Principles of Nuclear Magnetic Resonances in One or Two Dimensions”, Oxford University Press, 1992; Neuhaus, D.; Williamson, M. P., “The Nuclear Overhauser Effect in Structural and Conformational Analysis, 2nd Edition”, in “Methods in Stereochemical Analysis”, Marchand, A. P. (series editor), John A. Wiley and Sons, New York 2000.
In Scheme 1 , substituted indoles A are treated with dimethylamine and paraformaldehyde in a Mannich reaction to form 3-(dimethylamino)methyl-indole B. Reaction of B with nitro ester C affords the 3-(indol-3-yl)-2-nitro-propionic acid, ethyl ester D which is reduced to tryptophan derivative E. Acylation of the amine in E and hydrolysis of the ester F affords the appropriately protected tryptophan derivative G. Separation of the isomers of F or G by chiral column chromatography yields the individual enantiomers.
In Scheme 2, substituted indole A is reacted with L-serine in the presence of acetic anhydride and acetic acid to form tryptophan B. Hydrolysis of the amide followed by amine protection affords the desired substituted tryptophan intermediate D.
In Scheme 3, substituted tryptophan derivative A is reacted with α-bromo-ketone B to afford ester C. Reaction with ammonium acetate effects cyclization to form substituted imidazole D. Removal of the N-Boc protecting group with acid yields indole imidazole E which is reacted with aldehydes or ketones F in a Pictet-Spengler cyclization to afford the desired product G.
(IR)-I -[4-(4-Fluorophenyl)- 1 H-imidazol-2-yl] -2-( 1 H-indol-3 -yl) ethanamine hydrochloride (370 mg, 1.037 mmol) [prepared by treatment of tert-butyl (lR)-2-(l H-indol-3 -yl)- l-(4-(4-fluorophenyl)-l H-imidazol-2-yl)- 1-ethylcarbamate with hydrochloric acid] was treated with pyridine (4 mL) followed by reaction with l-methyl-pyrazol-4-yl 5-methyl-l,2,4-triazol-3-yl ketone (Intermediate 22) (219 mg, 1.141 mmol). The reaction was heated under N2 (oil bath 7O0C) for 48 h followed by additional heating (oil bath 850C) for 3 d. The reaction mixture was concentrated and azeotroped with toluene. The residue was purified with preparative TLC eluting with 10% MeOH in CH2Cl2 to give (3i?)-[4-(4-fluorophenyl)-lH-imidazol-2-yl]-l-(5- methyl-1 ,2,4-oxadiazol-3-yl)-l-(l-methyl-pyrazol-4-yl)-2,3,4,9-tetrahydro-lH-β-carboline as a mixture of diastereoisomers which were separated by chiral ΗPLC. The isomers were characterized by an analytical chiral AD column eluting with 20% IPA in heptane. (3i?)-[4-(4- Fluorophenyl)- 1 H-imidazol-2-yl] – 1 -(5 -methyl- 1 ,2,4-oxadiazol-3 -yl)-( 1 R)-( 1 -methyl-pyrazol-4- yl)-2,3,4,9-tetrahydro-lH-β-carboline (faster eluting isomer: retention time 18.13 min): 1H NMR (500 MHz, MeOH-(I4): δ 7.74 (m, 2H), 7.65 (s, IH), 7.52 (m, 2H), 7.37 (m, 2H), 7.13 (m, 3H), 7.04 (s, IH), 4.47 (dd, IH), 3.87 (s, 3H), 3.24 (dd, IH), 3.16 (dd, IH), 2.63 (s, 3H). LC-MS: m/z 495.3 (M + H)+ (2.56 min).
(3i?)-[4-(4-Fluorophenyl)-lH-imidazol-2-yl]-l-(5-methyl-l,2,4-oxadiazol-3-yl)-(lS)-(l-methyl- pyrazol-4-yl)-2,3,4,9-tetrahydro-l//-β-carboline (slower eluting isomer: retention time 24.62 min): 1H NMR (500 MHz, MeOH-Cl4): δ 7.73 (m, 2H), 7.54 (d, IH), 7.48 (s, IH), 7.43 (s, IH),
7.40 (d, IH), 7.36 ( brs, IH), 7.13 (m, 3H), 7.06 (t, IH), 4.40 (dd, IH), 3.84 (s, 3H), 3.26 (dd, IH), 3.16 (dd, IH), 2.63 (s, 3H). LC-MS: m/z 495.3 (M + H)+ (2.61 min).
The relative stereochemistry of the two diastereoisomers was determined by nuclear Overhauser effect (nθe) NMR spectroscopy. The slower eluting diastereisoomer afforded an nOe signal between the C-3 and C-5 hydrogens on the C-I pyrazole and the C-3 hydrogen on the β-carboline and the faster eluting product did not. Therefore, the diastereoisomer that eluted first from the preparative chiral HPLC purification was assigned as the c/s-isomer (imidazole and pyrazole are cis) and the slower eluting isomer as the trørøs-isomer.
Dobbelaar, P. H.; Du, W.; Guo, L.; Hagmann, W. K.; He, S.; Jian, T.; Liu, J.; Nargund, R. P.; Pasternak, A.; Shah, S. K.; Truong, Q. T.; Ye, Z.; Dellureficio, J.; Bakshi, R.WO/2009/011836 A1, 2009.
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