A selective deuterated preparation method for deuterated alcohol

Abstract

The present invention discloses a method for selectively deuterating a deuterated alcohol. The reaction raw materials include alcohol, heavy water, and Raney nickel. The reaction is carried out at 100-120°C for 50-100 hours to obtain a deuterated alcohol in which the hydrogen on the carbon connected to the hydroxyl group is deuterated. The alcohol, heavy water, and Raney nickel are added in an amount of 1 mol: 1-100 mol: 100-200 g. The method achieves a high degree of deuteration and a high yield, and selective deuteration at a specific position is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of deuterated compound production, and in particular to a selective deuterated preparation method of deuterated alcohol. Background Art

[0002] As understanding of deuterated organic compounds increases, their importance is growing. In the field of medicinal chemistry, the substitution of deuterium for some hydrogen atoms in drug molecules can affect their absorption, distribution, metabolism, and excretion. These effects were recognized by scientists in the 1970s and 1980s and applied to pharmaceuticals in the early 21st century. Due to their unique advantages in improving drug metabolism and pharmacokinetic properties, they are now a hot area in new drug development. Deuterated reagents are often used as pharmaceutical intermediates in the synthesis of deuterated drugs.

[0003] Tetradeuterium glycol is a deuterated pharmaceutical intermediate used in the synthesis of deuterated drugs. For example, Chinese invention patent publication number WO2009005069A1 (application number PCT / JP2008 / 061924), "A method for deuteration using a ruthenium catalyst," discloses a method for preparing tetradeuterium glycol. 0.25 mmol of ethylene glycol and 20 wt% of 5% Ru / C (15.03 mg) are suspended in 2 mL of heavy water. The hydrogen pressure is maintained at 1 atm, and the mixture is heated and stirred at 80°C for 24 hours. After hydrogen exchange, tetradeuterium glycol is obtained. This method is a hydrogen-deuterium exchange method, but its disadvantages include the use of a large excess of a deuterium source, hydrogen activation that may lead to reverse exchange, and the reaction requiring a certain pressure. This also places high demands on equipment, making it unsuitable for industrial production.

[0004] The invention of WO2011017108A2 discloses a cyclopropyl modulator of a P2Y12 receptor, which discloses a synthetic route for deuterated n-propanol used as an intermediate. The synthetic route comprises five steps, namely, preparation of iodomethane, i.e., reaction of deuterated methanol-d4 with hydroiodic acid to produce deuterated iodomethane-d3; methylation reaction, i.e., reaction of dimethyl malonate with iodomethane-d3 under the action of sodium hydride to produce deuterated dimethyl methylmalonate; deuterium exchange reaction, i.e., reaction of deuterated dimethyl methylmalonate with methanol-d4 as a deuterium source under the action of triethylamine to produce perdeuterated dimethyl methylmalonate; decarboxylation reaction, i.e., reaction of perdeuterated dimethyl methylmalonate with heavy water and deuterated dimethyl sulfoxide as deuterium sources under the action of sodium chloride to produce deuterated methyl propionate; and reduction reaction, i.e., reaction of deuterated methyl propionate with lithium tetradeuterium aluminum as a reducing agent to produce deuterated n-propanol. Although the patent discloses a synthetic route for deuterated n-propanol, it has the following deficiencies:

[0005] 1) Using deuterated DMSO and deuterated lithium aluminum tetrahydride as deuterium sources is costly;

[0006] 2) The reaction steps are too many and do not conform to the design concept of green chemical synthesis;

[0007] 3) Multiple switching of different deuterium sources between different reaction steps increases the difficulty of process operation. Summary of the Invention

[0008] The object of the present invention is to provide a selective deuterated preparation method of deuterated alcohol, which has high deuteration degree and high yield and realizes selective deuteration at specific positions.

[0009] The technical solution adopted by the present invention to solve its technical problem is:

[0010] A selective deuterated preparation method for deuterated alcohols comprises reacting raw materials including alcohol, heavy water and Raney nickel, reacting at 100-120° C. for 50-100 hours to obtain deuterated alcohols in which the hydrogen on the carbon connected to the hydroxyl group is deuterated; the added amounts of the alcohol, heavy water and Raney nickel satisfy the ratio of 1 mol: 1-100 mol: 100-200 g.

[0011] Through research, the inventors discovered that using Raney nickel can achieve selective deuteration of specific alcohols with high deuteration degrees. This reaction involves deuterating the hydrogen atoms on the carbon atoms to which the hydroxyl groups are attached via an HD exchange reaction. First, the alcohol undergoes catalytic dehydrogenation under the action of Raney nickel to produce an aldehyde. Next, the aldehyde undergoes hydrogenation under the action of deuterium-rich Raney nickel to produce the target product, achieving hydrogen-deuteration at specific positions.

[0012] The reaction raw materials also include an auxiliary agent, with the alcohol and auxiliary agent added in an amount of 3 to 10 g per 1 mol. Adding a certain amount of the auxiliary agent to the reaction system not only improves the separation of the deuterated alcohol from the heavy water, reducing the separation difficulty, but also adjusts the pH of the reaction system, enhances the catalytic activity of the Raney nickel, and shortens the reaction time.

[0013] The auxiliary agent is selected from at least one of potassium phosphate, potassium carbonate, potassium acetate, sodium acetate, potassium hydroxide, and sodium hydroxide.

[0014] The auxiliary agent is a mixture of potassium phosphate and potassium carbonate in a mass ratio of 1:1 to 3.

[0015] The alcohol is one of ethylene glycol, n-propanol and n-butanol.

[0016] The deuterated alcohol is one of the following molecular structural formulas:

[0017]

[0018] The beneficial effects of the present invention are: by controlling the addition amounts of alcohol, heavy water, and Raney nickel, and controlling the reaction temperature, deuterated alcohol with a high deuteration degree and a high yield is finally achieved; the deuteration degree of the deuterated alcohol is ≥95% and the yield is ≥85%, and the reaction operation is simple, meeting the requirements of green chemistry, and can realize process scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The synthetic route of tetradeuterated ethylene glycol of Examples 1-5 of the present invention is as follows;

[0020] Figure 2 The synthetic route of deuterated n-propanol of Examples 6-10 of the present invention is shown in FIG.

[0021] Figure 3 The synthetic route of deuterated n-butanol of Examples 11-15 of the present invention is as follows;

[0022] Figure 4 The synthetic route diagram of Comparative Example 2 is shown below:

[0023] Figure 5 This is the synthetic route diagram of Comparative Example 3. DETAILED DESCRIPTION

[0024] The technical solution of the present invention is further described in detail below through specific embodiments.

[0025] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following examples, unless otherwise specified, are all conventional methods in the art.

[0026] Example:

[0027] The present invention provides 15 examples for preparing tetradeuterated ethylene glycol, specifically, the reaction system consists of alcohol, heavy water, Raney nickel, and an auxiliary agent, and the reaction is carried out at 100-120° C. for 50-100 hours to obtain a deuterated alcohol ( Figure 1-3 ); the addition amounts of alcohol, heavy water, and Raney nickel satisfy 1 mol: 1-100 mol: 100-200 g: 3-10 g.

[0028] The additives are selected from potassium phosphate and potassium carbonate. The weight ratio of potassium phosphate to potassium carbonate is 1:1 to 3. Key process parameters are shown in Table 1.

[0029] The following tests were performed on the obtained embodiments and comparative examples:

[0030] 1) Deuterium substitution degree:

[0031] The deuterium substitution degree of the obtained examples and comparative examples was detected by proton nuclear magnetic resonance spectroscopy and calculated using the following formula:

[0032]

[0033] Wherein, A is the hydrogen peak area of ​​the deuterated sample, D is the degree of deuteration, m1 is the added mass of the deuterated sample in g, n1 is the number of H atoms to be deuterated in the deuterated sample, M1 is the relative molecular mass of the sample before deuteration in g, m2 is the added mass of the internal standard in g, n2 is the number of H atoms in the deuterated sample, and M2 is the relative molecular mass of the internal standard.

[0034] 2) Purity detection: gas chromatography is used for detection.

[0035] 3) Yield detection: The calculation formula is theoretical weight / actual weight*%.

[0036] The specific test results are shown in Table 2.

[0037] Table 1 Key parameter control of the embodiment of preparing deuterated alcohol of the present invention

[0038]

[0039] Table 2 Test results of the embodiments of the present invention and comparative examples

[0040]

[0041]

[0042] The difference between Comparative Example 1 and Example 1 is that no auxiliary agent is added, which makes it difficult to separate tetradeuterated ethylene glycol from heavy water, increases the separation difficulty, and reduces the yield.

[0043] The difference between Comparative Example 2 and Example 11 is that Pt / C is used instead of Raney nickel, which cannot achieve the same high-efficiency and selective deuteration as the present invention, and the degree of deuteration is significantly reduced.

[0044] The difference between Comparative Example 3 and Example 11 is that Pd / C is used instead of Raney nickel, which cannot achieve the same high-efficiency and selective deuteration as the present invention, and the degree of deuteration is significantly reduced.

[0045] The analytical data of tetradeuterated ethylene glycol (ethylene glycol-d4) are as follows: 1H NMR (399 MHz, Chloroform-d) δ5.45 (s, 2H), δ3.65 (s, 0.02H) MS (EI) 62.04.

[0046] The embodiment described above is only a preferred solution of the present invention and does not limit the present invention in any form. Other variations and modifications are possible without exceeding the technical solution described in the claims.

Claims

1. A method for selectively deuterating a deuterated alcohol, characterized in that: The reaction raw materials include alcohol, heavy water and Raney nickel, which react at 100-120° C. for 50-100 hours to obtain deuterated alcohol in which the hydrogen on the carbon connected to the hydroxyl group is deuterated; the added amounts of the alcohol, heavy water and Raney nickel meet the following ratio: 1 mol: 1-100 mol: 100-200 g; The alcohol is one of ethylene glycol, n-propanol, and n-butanol; The reaction raw materials also include an auxiliary agent, and the addition amount of the alcohol and the auxiliary agent satisfies 1 mol: 3 to 10 g; The auxiliary agent is selected from at least one of potassium phosphate and potassium carbonate.

2. The selective deuterated preparation method of a deuterated alcohol according to claim 1, characterized in that: The auxiliary agent is a mixture of potassium phosphate and potassium carbonate in a mass ratio of 1:1 to 3.

3. The selective deuterated preparation method of a deuterated alcohol according to claim 1, characterized in that: The deuterated alcohol is one of the following molecular structural formulas: 。

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