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Regioselective synthesis of imidazo [1, 2-a] pyrimidines

A pyrimidine, selected technology, applied in the field of regioselective synthetic pathways, can solve the problem of limited products

Pending Publication Date: 2022-04-29
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the scope of this method is limited to α,β-unsaturated aldehydes and ketones, which means that the products are limited to unsubstituted or alkylated imidazopyrimidines

Method used

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  • Regioselective synthesis of imidazo [1, 2-a] pyrimidines
  • Regioselective synthesis of imidazo [1, 2-a] pyrimidines
  • Regioselective synthesis of imidazo [1, 2-a] pyrimidines

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Experimental program
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example

[0073] General information

[0074] All new compounds passed 1 H NMR, 13 C NMR, IR, melting point and HRMS for characterization.

[0075] 1 H. 13 C. 19 F and 31 P NMR spectra were recorded at room temperature on a Bruker 400 MHz instrument.

[0076] Unless otherwise stated, all 1 H NMR spectra are expressed in parts per million (ppm) relative to the residual chloroform signal (δ 7.26), methanol (δ 3.31), DMSO (δ 2.50) or acetic acid (δ 2.04) in the deuterated solvent unit to measure. 1 Data for HNMR are reported as follows: chemical shift, multiplicity (br = broad signal, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet) , coupling constant and integral in Hertz.

[0077] Unless otherwise stated, all 13 C NMR spectra are relative to deuterated chloroform (δ77.06), methanol-d 4 (δ49.00), DMSO-d 6 (δ39.53) or acetic acid-d 4 (δ20.0) reported in ppm and in full 1 Obtained with H decoupling.

[0078] all 19 F NMR spectra were all in f...

example 1

[0086] Example 1: 2-(1-(Benzo[4,5]imidazo[1,2-a]pyridin-3-yl)piperidin-4-yl)ethyl-1,1,2,2-d44 -Synthesis of tosylate

[0087] Example 1 describes a representative synthesis of a molecule using the step of conjugating acrylamide to phosphorylated imidazole.

[0088] Step 1 – Formation of diethyl (1H-benzo[d]imidazol-2-yl)phosphoramidate

[0089]

[0090] The reactor was charged with 1H-benzo[d]imidazol-2-amine (0.7882 kg, 6.002 mol, 1.00 equiv) followed by MeCN (5.333 L) under nitrogen. To this mixture was then added N-methylimidazole (0.6693 kg, 8.103 mol, 1.35 eq) followed by MeCN (0.460 L) to rinse the reaction vessel. The slurry was then stirred at 20°C for a minimum of 15 minutes. Next, add PCl(O)(OEt) dropwise over 1 hour 2 (1.4070 kg, 8.154 mol, 1.35 equiv), keeping the internal temperature below 30°C. PCl(O)(OEt) 2 After the addition was complete, MeCN (0.455 L) was added to rinse the reaction vessel. The slurry was then stirred at 20°C for a minimum of 12 hou...

example 2

[0095] Example 2: 2-(1-(Benzo[4,5]imidazo[1,2-a]pyridin-3-yl)piperidin-4-yl)ethyl-1,1,2,2-d44 -Synthesis of tosylate

[0096] Step 1 – Preparation of (1H-benzo[d]imidazol-2-yl) diethyl phosphoramidate

[0097]

[0098] Charge the flask with 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (5.55 g, 23.8 mmol, 0.31 equiv ) and MeCN (35.0 mL). Stir the mixture until smooth. Then diethyl hydrogen phosphate (10.3 g, 75.1 mmol, 9.69 mL, 1.00 eq) and Et 3 N (15.2 g, 150.2 mmol, 20.9 mL, 2.00 eq), the flask was heated to 85 °C and stirred for 30 minutes, at which point precipitation occurred. The jacket was then cooled to 0 °C, and 1H-benzo[d]imidazol-2-amine (10.0 g, 75.1 mmol, 1.00 eq) dissolved in THF (35.0 mL) was charged to the flask. The reaction mixture was then warmed to 15°C-25°C and stirred for 1 hour. After the completion of the reaction was confirmed, the reaction was quenched with water (100.0 mL), and then extracted with two portions of ethyl acetate (200.0 mL). T...

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Abstract

The present disclosure provides a method of regioselective synthesis of an imidazo-pyrimidine compound of formula (XXa) or (XXb), the method comprising the step of coupling a first compound of formula XX-P1a or XX-P1b with a second compound of formula XX-P2. The cyclization reaction of imidazo [1, 2-a] pyrimidine-amine generated between beta-ethoxy acrylamide and phosphorylated aminoimidazole depends on the guiding effect from the phosphorylated aminoimidazole in the ring and the phosphorylated aminoimidazole outside the ring. According to the reaction, the 2-amino or 4-amino structure isomer of the imidazo [1, 2-a] pyrimidine is generated in a good yield and a regioselectivity range of 90: 10 to 99: 1. The reactions can be used to synthesize a variety of tracer molecules for neurological condition research, such as where R3 and R4 together with the imidazole ring atom to which they are bonded form a benzene ring, and the product is a substituted benzimidazopyrimidine. The reaction may be summarized to form imidazo [1, 2-a] pyrimidines substituted at its 2-and 4-positions with alkoxy or thioalkyl groups.

Description

[0001] priority statement [0002] This application claims the benefit of priority under 35 U.S.C. § 119(E) to U.S. Provisional Application Serial No. 62 / 845,840, filed May 9, 2019, and U.S. Provisional Application Serial No. 62 / 937,069, filed November 18, 2019, Both provisional applications are hereby incorporated by reference in their entirety. technical field [0003] The techniques described herein relate generally to organic synthesis, and more particularly to regioselective synthetic routes to molecules containing substituted imidazo-pyrimidine groups. Background technique [0004] The imidazo-pyrimidine moiety is a fused-ring heterocyclic functional group frequently encountered in organic chemistry. It serves as a core member or part of a scaffold of so-called "small organic molecules" that are important in drug discovery as well as in therapeutic and diagnostic applications. In particular, the benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine scaffold (3-fused ring system)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55C07F9/2454C07B59/002C07B2200/05
Inventor K·B·P·克拉格N·A·怀特张海明F·戈斯林W·纳克P·D·奥谢
Owner F HOFFMANN LA ROCHE & CO AG
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