Synthesis method of N-deuterated methylindole compounds
A deuterated methyl indole and synthetic method technology, applied in the field of synthesis of deuterium-containing compounds, can solve the problems of unfavorable industrial scale-up production, difficult experimental operation, high price, etc., and achieve the benefits of industrial scale-up production and low operation difficulty , easy storage effect
Active Publication Date: 2018-04-24
TETRANOV PHARMA CO LTD
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Problems solved by technology
However, the deuterated methyl iodide reagent has the following disadvantages: it is expensive, highly toxic, volatile, and requires low-temperature storage, which causes difficulties in experimental operations and is not conducive to industrial scale-up production.
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Embodiment 1
[0036]
[0037] Preparation of target compound Ⅲ-1:
[0038] 65.3g of indole was dissolved in 500mL of acetonitrile, NaOH 67.2g was added at room temperature, and then 116g of formula II-1 (TsOCD 3 ) in 500 mL of acetonitrile, stirred overnight at room temperature. After the LC monitors that the reaction is complete, add 1000 mL of a mixed solvent with a volume ratio of petroleum ether / ethyl acetate=10 / 1, filter, and dissolve the filtrate with 1000 mL of a mixed solvent with a volume ratio of petroleum ether / ethyl acetate=5 / 1. After washing with water, the organic phase was dried and then concentrated to obtain the compound N-deuteromethylindole with a purity of >95% and a deuteration rate of >99.5%. The NMR data are as follows:
[0039] 1 H NMR (400MHz, CDCl 3 ,ppm):δ=7.62(d,J=9.2Hz,1H),7.31(dd,J=8.2Hz,0.8Hz1H),7.23-7.19(m,1H),7.12-7.08(m,1H),7.02 (d, J=3.1 Hz, 1H), 6.48 (dd, J=3.1 Hz, 0.7 Hz, 1H).
[0040] Referring to the above examples, a series of compounds were ...
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The invention belongs to the technical field of synthesis of deuterium-containing compounds and particularly discloses a synthesis method of N-deuterated methylindole compounds. The synthesis method of N-deuterated methylindole compounds comprises steps as follows: a compound shown in a formula I and a compound shown in a formula II are stirred for a reaction in an organic solvent in the presenceof alkali, and N-deuterated methylindole compounds shown in a formula III are synthesized. The provided synthesis method of the N-deuterated methylindole compounds is mild in reaction condition and easy to operate and facilitates industrial magnified production. Deuterated methanol sulfonate shown in the formula II of a deuterated reagent has the characteristics of being cheap, low in toxicity andeasy to store. Therefore, the synthesis method is low in cost, simple to operate and favorable for industrial magnified production. According to the provided synthesis method of the N-deuterated methylindole compounds, the reaction of a reaction product is thorough, few side reactions are caused, the product yield is high and aftertreatment is simple.
Description
technical field [0001] The invention relates to the technical field of synthesis of deuterium-containing compounds, in particular to a synthesis method of N-deuteromethylindole compounds. Background technique [0002] Deuterium, a stable isotope of hydrogen (H), generally has very low toxicity. Since the deuterium atom is twice as heavy as the hydrogen atom, the carbon-deuterium bond (C—D) has a lower vibration zero point energy than the carbon-hydrogen bond (C—H), which means that the carbon-deuterium bond is more stable than the carbon-hydrogen bond. The isotope effect on order kinetics is approximately 9-fold at 37°C (kH / kD=9). Deuterated drugs replace part of the hydrogen atoms in the drug molecule with deuterium atoms, and the activity of the drug molecule remains basically unchanged. At the same time, the kinetic isotope effect can be used to block the metabolic site and prolong the half-life of the drug, thereby reducing the therapeutic dose. Improve the pharmacokin...
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IPC IPC(8): C07D209/08
CPCC07D209/08C07B2200/05
Inventor 吴豫生耿阳牛成山梁阿朋
Owner TETRANOV PHARMA CO LTD