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Method for synthesizing deuterated compound in aqueous phase solvent

A technology of deuterated compounds and water-phase solvents, applied in the field of isotope labeling chemical synthesis, can solve the problems of difficult acquisition of deuterium sources, decreased deuteration rate, difficult operation, etc., and achieves the effects of good applicability, simple operation and low cost

Active Publication Date: 2021-05-11
HUAZHONG UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

But these methods mostly have the following disadvantages: expensive, toxic and / or unstable, flammable and explosive reagents (for example: NaBD) need to be used 4 ,LiAlD 4 ,DCOONa,n-Bu 3 SnD), the deuterium source is not easy to obtain and requires a large excess (Si-D substances, deuterium gas), and the reaction needs to be in an expensive deuterated solvent (for example: deuterated acetone, deuterated tetrahydrofuran, deuterated alcohol, deuterated acids ) etc.
Therefore it is also foreseeable that H 2 The introduction of O will result in D 3 PO 2 The deuteration rate of the participating free radical deuteration reactions is severely reduced (J.Org.Chem.2015, 80, 10025 and J.Phys.Chem.1964, 68, 544)
So the reported deuterated hypophosphorous acid (D 3 PO 2 ) or its salt participation deuterium method all need to strictly avoid water ( 1 h 2 O) exists, and needs to consume a large amount of deuterium water, thus also causes difficult operation, poor economy

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  • Method for synthesizing deuterated compound in aqueous phase solvent
  • Method for synthesizing deuterated compound in aqueous phase solvent
  • Method for synthesizing deuterated compound in aqueous phase solvent

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preparation example Construction

[0041] Generally speaking, the synthetic method of deuterated compound of the present invention comprises the following steps:

[0042] (1) mix the compound shown in formula (I), the deuterium source containing phosphorus-deuterium bond shown in formula (II), initiator, alkali and water phase solvent, obtain the reaction raw material mixed system to react; Reaction general formula is:

[0043]

[0044] Among them, R 1 All are selected from at least one of alkyl, aryl, and acyl; X is selected from at least one of iodine, bromine, chlorine, diazo, and xanthate (shown in formula I as halogenated, heavy Nitrogen salt or xanthate (Xanthate)); Z is selected from at least one of oxygen atom and sulfur atom; R 2 , R 3 At least one of salt compounds selected from deuterium atoms, alkyl groups, aryl groups, hydroxyl groups, alkoxy groups, phenol groups, and hydroxyl groups forming acids, R 2 and R 3 Can be the same or different.

[0045] The method for synthesizing deuterated co...

Embodiment 1

[0058] Embodiment 1: the synthesis of compound 2a

[0059]

[0060] a), iodo compound 1a (152mg), deuterated calcium hypophosphite (Ca(D 2 PO 2 ) 2 ,69.6mg, 0.8equiv), sodium bicarbonate (NaHCO 3 , 84.0mg, 2.0equiv), initiator azobisisobutylamidine hydrochloride (AIBA, 27mg, 0.2equiv) were weighed in 10mL reaction bottle, then add water (H 2 O, 2.0ml), react at 80 degrees Celsius. After the iodo compound 1a was consumed, the reaction was terminated (5h), and the solvent water was distilled off under reduced pressure. The obtained crude product was acetylated under the conditions of acetic anhydride and triethylamine, and after acylation, the crude product was extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, washed with saturated sodium thiosulfate solution, and dried over anhydrous sodium sulfate. The crude product was concentrated to obtain compound 2a (142.0 mg) after separation and purification by column chroma...

Embodiment 2

[0071] Embodiment 2: the synthesis of compound 2b

[0072]

[0073] Iodo compound 1b (173.1mg), deuterated calcium hypophosphite (Ca(D 2 PO 2 ) 2 ,104.5mg, 1.2equiv), sodium bicarbonate (NaHCO 3 , 84.0mg, 2.0equiv), initiator azobisisobutylamidine dihydrochloride (AIBA, 27mg, 0.2equiv) were weighed in 10mL reaction flask, then add water and tert-butanol (H 2 O, 1.0ml of tert-butanol), reacted at 80 degrees Celsius, terminated the reaction (5h) after the iodide compound 1b was consumed, extracted the crude product with ethyl acetate 3 times, combined the organic phases, washed with saturated brine, and saturated thio Washed with sodium sulfate solution, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, separated and purified by column chromatography to obtain compound 2b (102.4 mg), with a yield of 93% and a deuterated rate of 99%.

[0074] Compound 2b is a colorless oily substance.

[0075] 1 H NMR (600MHz, CDCl 3)δ7.39–7.25 (m, 5H), 4.78 (...

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Abstract

The invention belongs to the technical field of isotope labeling chemical synthesis, and discloses a method for synthesizing a deuterated compound in an aqueous phase solvent. The method is based on the following chemical reaction equation: a halide, diazonium salt or Xanthate shown in a formula (I), a material containing a phosphorus-deuterium bond shown in a formula (II), an initiator, alkali and a solvent are mixed and react to obtain a reduced deuterated product shown in a formula (III), wherein the solvent is water (1H2O) or a mixed solvent consisting of water and an organic solvent. By researching and improving the types of raw materials for constructing a reaction system and adopting the material containing the phosphorus-deuterium bond shown in the formula (II) as a deuterium source, compared with the prior art, the method can effectively solve the problems that the reaction conditions are strict, the adopted deuterium source is seriously excessive, strict anhydrous (1H2O) is needed and / or the reaction needs to be carried out in a deuterated solvent in the preparation process of the deuterated compound.

Description

technical field [0001] The invention belongs to the technical field of isotope labeling chemical synthesis, and more specifically relates to a method for synthesizing deuterated compounds in an aqueous solvent. Background technique [0002] Deuterium (D, also known as heavy hydrogen) is one of two stable isotopes of hydrogen. Deuterium makes up only about 0.02% (or 0.03% on a mass basis) of all naturally occurring hydrogen. However, the use of deuterium-labeled compounds has important implications in many scientific fields such as spectroscopy, analytical chemistry, organic chemistry, and pharmacy. Specifically, deuterated solvents widely used in spectroscopy are used in nuclear magnetic resonance spectroscopy (NMR) to overcome the interference of solvent signals to the signals of substances to be tested; in the field of analytical chemistry, deuterium-labeled compounds can be used as non-interfering internal standard substances In the field of organic chemistry, the resea...

Claims

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Application Information

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IPC IPC(8): C07H1/00C07H15/04C07H9/04C07D493/04C07C51/347C07C63/06C07C63/04C07C65/10C07C57/32C07C63/70C07C65/21C07C29/58C07C33/22C07C41/24C07C43/205C07C67/30C07C69/80C07D295/194C07H13/04C07D309/30C07B59/00
CPCC07H1/00C07H15/04C07H9/04C07D493/04C07C51/347C07C29/58C07C41/24C07C67/30C07D295/194C07H13/04C07D309/30C07B59/001C07B59/005C07B59/002C07B2200/05C07C63/06C07C63/04C07C65/10C07C57/32C07C63/70C07C65/21C07C33/22C07C43/205C07C69/80C07B59/00
Inventor 万谦宋泽金曾静孟令奎
Owner HUAZHONG UNIV OF SCI & TECH
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