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Beta-deuterated valproic acid preparation method

A deuterated valproic acid and deuterated technology, which is applied in the field of preparation of antiepileptic drug beta-deuterated valproic acid, can solve the problems of high price of reducing agent deuterated lithium aluminum hydride, no experimental operation, harsh reaction conditions, etc. , to achieve the effect of high yield, low environmental pollution and high selectivity

Active Publication Date: 2018-07-13
ZHEJIANG UNIV
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Problems solved by technology

[0011] This method requires the use of a platinum catalyst and i-PrOH-d 8 As a deuterated reagent, it is expensive and has no selectivity for the deuterated site. It cannot orient the hydrogen atom at the β-position of the important metabolic site in the deuterated valproic acid molecule, and is not suitable for the specific metabolic site β of valproic acid. bit research, so the applicability of this method is limited
[0012] 2. Using α-deuterated 1-bromopropane and ethyl cyanoacetate as raw materials, under the action of sodium propoxide and sodium hydroxide, decarboxylate by heating to generate the corresponding deuterated 4-cyanoheptane, deuterated hydroxide Sodium hydrolyzes the cyano group, and after acidification, finally obtains polydeuterated valproic acid, but the general formula of the synthetic route is only given in the text, there is no specific experimental operation and the deuterated rate of the described polydeuterated valproic acid (Julie F etc., Deuterated 2-Propylpentanoic Acid Compounds, WO 2010 / 062656A2.); the reaction formula is shown in formula 3:
[0018] The price of the reducing agent deuterated lithium aluminum hydride in this method is also very expensive, and the reaction requires a strict anhydrous and oxygen-free system, and the reaction conditions are relatively harsh

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Embodiment 1

[0055] The preparation method of embodiment 1, β-deuterated valproic acid comprises the following steps successively:

[0056] (1) Directed deuteration reaction:

[0057] Weigh 4.13g (15.26mmol, 1eq.) of 8-aminoquinoline valproic acid amide and 0.68g (3.05mmol, 0.2eq.) of palladium acetate into a sealed tube, add 8.3ml of heavy water, and seal the tube at 140°C State reaction 48h.

[0058] After the reaction, add 20ml of water, then add ethyl acetate (3 × 30ml) for extraction, combine the organic phase - ethyl acetate layer, wash with saturated brine (30ml), then dry with 6g of anhydrous sodium sulfate, rotary evaporator Concentrate under reduced pressure, the concentration temperature is 30-40°C, the vacuum degree is not lower than -0.07MPa, concentrate until there is no obvious drop, and the concentrate is separated and purified by silica gel chromatography (the eluent is PE:EA=15:1 ), the intermediate product deuterated 8-aminoquinoline valproic acid amide 3.97g was obtai...

Embodiment 2

[0078] Embodiment 2, repeated application

[0079] Weigh the 8-aminoquinoline (115mg, 0.80mmol) and N,N-dimethyl-4-aminopyridine (13mg, 0.1mmol) recovered in Example 1 into a three-necked reaction flask, and add Anhydrous dichloromethane (10 mL), and triethylamine (135 μL, 0.96 mmol, 1.2 equiv) were added, the reaction system was cooled to 0° C., and valproyl chloride (130 mg, 0.80 mmol) was added dropwise. The reaction system was stirred overnight at room temperature. Add 20 mL of water to quench the reaction, extract with dichloromethane (3×20 mL), combine the dichloromethane layers, dry over anhydrous sodium sulfate, filter with suction, concentrate, and separate and purify by silica gel chromatography (petroleum ether: ethyl acetate=15: 1) 195 mg of 8-aminoquinoline valproic acid amide was obtained as a white solid, with a yield of 90%.

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Abstract

The invention discloses a beta-deuterated valproic acid preparation method, which sequentially comprises: carrying out an intramolecular valproyl carbon skeleton beta-site directed deuteration reaction on 8-aminoquinoline valpromide in D2O by using palladium acetate as a catalyst to generate deuterated 8-aminoquinoline valpromide, wherein the deuteration reaction is performed in a sealed state; and carrying out a hydrolysis reaction on the deuterated 8-aminoquinoline valpromide in an organic solvent under the action of an alkali under a normal pressure reflux condition, and carrying out acidification treatment to obtain beta-deuterated valproic acid. According to the present invention, the method has advantages of high selectivity, simple reaction post-treatment, easily available raw materials and environmental protection, and provides the efficient and accurate method for the efficient synthesis of beta-deuterated valproic acid.

Description

technical field [0001] The invention belongs to a method for synthesizing deuterated drugs, in particular to a method for preparing antiepileptic drug β-deuterated valproic acid. Background technique [0002] Deuterium reaction has a wide range of applications in the pharmaceutical industry. First of all, because of the characteristic radioactive absorption of the isotope-labeled drug by deuteration reaction, specific β-nuclear detectors can be used to detect and track the position, quantity and transformation of the drug in the body. Theoretical research in science and other related disciplines provides an effective and reliable experimental basis. Secondly, in exploring the mechanism of some organic reactions, the deuterium atom can be tracked by deuterating the hydrogen at a specific position in the reactant, which can be used as a basis to explain some difficult-to-study organic chemical reaction mechanisms (Thomas G et al., Using Deuterium in Drug Discovery: Leaving t...

Claims

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Application Information

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IPC IPC(8): C07C51/06C07C53/128
CPCC07B2200/05C07C51/06C07D215/40C07C53/128
Inventor 章国林赵冬红罗浩帆俞永平
Owner ZHEJIANG UNIV
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