Preparation of two D2 partial agonists in C‐14 and stable isotope labeled forms

Abstract

In support of a program to develop a treatment for diseases resulting from an imbalance in dopamine levels, two drug candidates, 1 and 2, were prepared in stable isotope and C‐14 labeled forms. Both compounds contained an aminothiazole ring, and the C‐14 label was introduced into the ring using KS14CN. However, the use of KS14CN to form [14C]‐2 gave poor results; therefore, benzoyl [14C]isothiocyanate was used instead, which led to a much improved yield. The stable isotope labeled forms were prepared with the label in the side chain from [2H5]ethyl iodide for [2H5]‐1 and from 1‐[13C]methyl [15N2]pyrazole[13C]carboxaldehyde, which was prepared in turn from [carbonyl‐13C]DMF, [15N2]hydrazine sulfate, and [13C]methyliodide for [13C2, 15N2]‐2. Copyright © 2012 John Wiley & Sons, Ltd.

Multiple labeling of a potent CX3CR1 antagonist for the treatment of multiple sclerosis

“…The reduction was improved by the action of microwaves at 140 C, to give a total yield of 6.4% from potassium [ 14 C]cyanide and a specific If there would be a need for isotopic modification in the core of 1, the two-position will be the top choice, as proposed in Scheme 6, which works fine with standard chemicals. 10…”

“…The residue was purified by chromatography on silica gel (20 g) using a gradient of ethyl acetate in dichloromethane. Pooled fractions were concentrated to give [4-14 C]1 (44 mg, 229 MBq) at a specific activity of 2.1 GBq/mmol and a total yield of 5% from [2][3][4][5][6][7][8][9][10][11][12][13][14]…”

“…14 C]-(R)-2-amino-4-methylpentan-1-ol trifluoroacetate (18)[4][5][6][7][8][9][10][11][12][13][14] C]-(R)-tert-butyl 1-hydroxy-4-methylpentan-2-ylcarbamate (17, 500 mg, 2.28 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (10 mL) was stirred overnight at 21 C. The mixture was concentrated to give 530 mg of 18, consistent with the reference material.…”

Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery

“…[33] To diversify heavy drugs, various d n -alkylated reagents, such as d 3 -methyl, d 2 -ethyl, d 2 -phenethyl, and other d 2 -alkyl-substituted compounds, have been prepared, and their pharmaco-kinetics evaluated (Figure 1C). [34][35][36][37][38][39][40][41][42][43] For example, 1-d 2 -ethylamine (CH 3 CD 2 NH 2 ), possessing two deuterium atoms at the α-position to the nitrogen atom, was prepared by the reductive deuteration of CH 3 CN using LiAlD 4 . [43] Similarly,1-d 2 -phenethylamine (PhCH 2 CD 2 NH 2 ) was prepared by reducing the corresponding nitrile using NaBD 4 , [34] and the (d 2 -alkyl)alcohol derivative was prepared by BD 3 • THFmediated reduction of the corresponding ester substrate.…”