Preparation method of deuterated paraformaldehyde

Abstract

The invention provides a preparation method of deuterated paraformaldehyde. Specifically, the invention provides a preparation method of deuterated polyformaldehyde, which comprises the following steps: (S1) deuterating dibromomethane; (S2) synthesis of deuterated methylene diacetate; and (S3) synthesizing the deuterated polyformaldehyde.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing deuterated paraformaldehyde. Background Art

[0002] Deuterated formaldehyde or deuterated polyformaldehyde Deuterated formaldehyde, as a common chemical raw material, has important uses in the pharmaceutical field and is becoming increasingly important for the development of deuterated drugs. Currently, there is no large-scale preparation method for deuterated formaldehyde in industry. There is an urgent need for a method for synthesizing deuterated formaldehyde with mild conditions, low equipment requirements and costs, and high production efficiency to solve the problems currently encountered in the design and synthesis of deuterated drugs. Summary of the invention

[0003] The purpose of the present invention is to provide a novel method for preparing deuterated paraformaldehyde.

[0004] In a first aspect of the present invention, a method for preparing deuterated polyoxymethylene is provided, characterized in that it comprises the steps of:

[0005] (S1) Deuterated dibromomethane,

[0006]

[0007] Includes steps:

[0008] (S1.1) performing N rounds of deuteration reaction; wherein N is an integer from 2 to 10 (preferably, N is an integer from 2 to 7, more preferably, N is 2, 3, 4 or 5, and most preferably, N is 3 or 4);

[0009] and,

[0010] The first round of deuteration reaction comprises the steps of: providing a reaction mixture containing dibromomethane, heavy water, a base and a phase transfer catalyst, performing a deuteration reaction, separating the liquids, and obtaining deuterated or partially deuterated dibromomethane;

[0011] The Nth round of deuteration reaction comprises the steps of: providing a reaction mixture containing partially deuterated dibromomethane obtained in the N-1th round of deuteration reaction, heavy water, a base and a phase transfer catalyst, performing a deuteration reaction, separating the liquids, and obtaining deuterated or partially deuterated dibromomethane;

[0012] (S1.2) post-treating the deuterated or partially deuterated dibromomethane obtained from the Nth round of deuteration reaction to obtain deuterated dibromomethane;

[0013] wherein the base is selected from the group consisting of alkali metal deuterium oxides, alkali metal salts of alcohols, or combinations thereof;

[0014] (S2) Synthesis of deuterated methylene diacetate,

[0015]

[0016] It includes the steps of:

[0017] reacting deuterated dibromomethane and acetate in an inert organic solvent in the presence of a crown ether and an iodide to obtain methylene diacetate; and

[0018] (S3) Synthesis of deuterated polyoxymethylene:

[0019]

[0020] Wherein, n is 1 to 10000 (preferably, 1n is 115 to 35; more preferably, n is 20);

[0021] It includes the steps of:

[0022] A mixture of deuterated methylene diacetate, hydrochloric acid and water is provided and reacted to obtain deuterated polyoxymethylene.

[0023] In another preferred embodiment, the phase transfer catalyst is selected from the following group: crown ethers, polyethers, quaternary ammonium salts, cyclodextrins, or combinations thereof.

[0024] In another preferred embodiment, the crown ethers include: 18-crown-6, 21-crown-7, and 15-crown-5.

[0025] In another preferred embodiment, the polyether includes: oligoethylene glycol.

[0026] In another preferred embodiment, the phase transfer catalyst is a crown ether.

[0027] In another preferred embodiment, the quaternary ammonium salt includes: tetrabutylammonium bromide and dodecyltrimethylammonium chloride.

[0028] In another preferred embodiment, the phase transfer catalyst is selected from the following group: 18-crown-6, 15-crown-5, oligoethylene glycol, tetrabutylammonium bromide, dodecyltrimethylammonium chloride, cyclodextrin, or a combination thereof.

[0029] In another preferred embodiment, the phase transfer catalyst is 18-crown-6.

[0030] In another preferred embodiment, the alkali metal deuterium oxide is selected from the group consisting of sodium deuterium oxide, potassium deuterium oxide, or a combination thereof.

[0031] In another preferred embodiment, the alkali metal salt of alcohol is selected from the following group: sodium salt of alcohol, potassium salt of alcohol, or a combination thereof.

[0032] In another preferred embodiment, the alkali metal salt of alcohol is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, or a combination thereof.

[0033] In another preferred embodiment, in step (S1), the base is sodium deuteride or sodium tert-butoxide.

[0034] In another preferred embodiment, each round of deuteration reaction further includes the step of measuring the deuteration degree of the lower layer product.

[0035] In another preferred embodiment, each round of deuteration reaction further includes the step of taking the upper layer of liquid and reusing it as a deuterium source.

[0036] In another preferred embodiment, the reuse of the heavy water deuterium source includes the steps of: providing a reaction mixture containing the obtained upper layer liquid and dibromomethane of the same mass as the separated deuterated or partially deuterated dibromomethane, performing a deuteration reaction, separating the liquids, and obtaining deuterated or partially deuterated dibromomethane.

[0037] In another preferred embodiment, the molar ratio of the base to heavy water is 1:2 to 1:50 (preferably 1:5 to 1:35, more preferably 1:10 to 1:30, and most preferably 1:15 to 22).

[0038] In another preferred embodiment, when the base is an alkali metal deuterium oxide, the molar ratio of the base to heavy water is 1:2 to 1:50 (preferably 1:5 to 1:35, more preferably 1:10 to 1:30, and most preferably 1:16 to 18).

[0039] In another preferred embodiment, when the base is an alkali metal salt of an alcohol, the molar ratio of the base to heavy water is 1:2 to 1:50 (preferably 1:5 to 1:35, more preferably 1:10 to 1:30, and most preferably 1:18 to 20).

[0040] In another preferred embodiment, in the first round of deuteration reaction, the molar ratio of dibromomethane to the deuterium source in the reaction mixture is 1:(0.1-15); preferably, 1:(3-10); wherein the deuterium source refers to the sum of all deuterium-containing compounds (such as heavy water and alkali metal deuterium oxides) in the reaction mixture.

[0041] In another preferred embodiment, in the first round of deuteration reaction, in the reaction mixture, when the base is an alkali metal deuterium oxide, the molar ratio of dibromomethane to the deuterium source is 1:(0.1-15); preferably, 1:(3-10); optimally, 1:8-9; wherein the deuterium source refers to the sum of heavy water and the base in the reaction mixture.

[0042] In another preferred embodiment, in the first round of deuteration reaction, in the reaction mixture, when the base is an alkali metal salt of an alcohol, the molar ratio of dibromomethane to the deuterium source is 1:(0.1-15); preferably, 1:(3-10); optimally, 1:3-4; wherein the deuterium source refers to heavy water in the reaction mixture.

[0043] In another preferred embodiment, in the Nth round of deuteration reaction, the molar ratio of dibromomethane to the deuterium source in the reaction mixture is ≥ the molar ratio in the first round of deuteration reaction.

[0044] In another preferred embodiment, in the second round of deuteration reaction, in the reaction mixture, when the base is an alkali metal deuterium oxide, the molar ratio of dibromomethane to the deuterium source is 1:(0.1-15); preferably, 1:(3-10); optimally, 1:8-9; wherein the deuterium source refers to the sum of heavy water and the base in the reaction mixture.

[0045] In another preferred embodiment, in the third round of deuteration reaction and / or the fourth round of deuteration reaction, in the reaction mixture, when the base is an alkali metal deuterium oxide, the molar ratio of dibromomethane to the deuterium source is 1:(0.1-15); preferably, 1:(3-10); optimally, 1:7-8; wherein the deuterium source refers to the sum of heavy water and the base in the reaction mixture.

[0046] In another preferred embodiment, in the second round of deuteration reaction and / or the third round of deuteration reaction and / or the fourth round of deuteration reaction, in the reaction mixture, when the base is an alkali metal salt of an alcohol, the molar ratio of dibromomethane to the deuterium source is 1:(0.1-15); preferably, 1:(3-10); optimally, 1:3-4; wherein the deuterium source refers to heavy water in the reaction mixture.

[0047] In another preferred embodiment, in each round of deuteration reaction, the amount of phase transfer catalyst in the reaction mixture is 3-7 mol% (preferably 4-6 mol%, more preferably 5±0.5 mol%), based on the total mass of dibromomethane or deuterated or partially deuterated dibromomethane.

[0048] In another preferred embodiment, in each round of deuteration reaction, deuterated or partially deuterated dibromomethane is the lower layer product.

[0049] In another preferred embodiment, in step (S1.2), the post-treatment is used to purify and dry the obtained deuterated or partially deuterated dibromomethane.

[0050] In another preferred embodiment, in step (S1.2), the post-treatment includes extraction with water and drying with anhydrous salt (anhydrous sodium sulfate).

[0051] In another preferred embodiment, in step (S1.2), the post-treatment includes azeotropic distillation with water.

[0052] In another preferred embodiment, in step (S1), the reaction temperature of the deuteration reaction is 80-120°C; preferably, 90-100°C; more preferably, 95-105°C; most preferably, 100°C.

[0053] In another preferred embodiment, in step (S1), the deuteration reaction is carried out under reflux.

[0054] In another preferred embodiment, in step (S1), the reaction time of each round of deuteration reaction is 5 to 40 hours; preferably, 10 to 30 hours; more preferably, 15 to 24 hours.

[0055] In another preferred embodiment, when the base is an alkali metal deuterium oxide, the heavy water and the base are provided in the form of a heavy water solution of the alkali metal deuterium oxide.

[0056] In another preferred embodiment, the heavy aqueous solution of alkali metal deuterium oxide is prepared by a method comprising the following steps: adding an alkali metal hydride to heavy water for reaction, and performing post-treatment to obtain a heavy aqueous solution of alkali metal deuterium oxide.

[0057] In another preferred embodiment, the alkali metal hydride is selected from the following group: sodium hydride, potassium hydride, or a combination thereof.

[0058] In another preferred embodiment, in the preparation of the heavy aqueous solution of alkali metal deuterium oxide, the post-treatment includes: drying and extraction to remove organic impurities (such as mineral oil).

[0059] In another preferred embodiment, when N≥4, the deuteration rate of the product of step (S1) is ≥95%; preferably, ≥98%; most preferably, ≥99.4%.

[0060] In another preferred embodiment, when N≥4, the yield of the product in step (S1) is ≥55%, preferably, ≥65%.

[0061] In another preferred embodiment, in step (S2), the crown ether is selected from the following group: 18-crown-6, 21-crown-7, 15-crown-5, or a combination thereof.

[0062] In another preferred embodiment, in step (S2), the iodide is selected from the following group: potassium iodide, sodium iodide, or a combination thereof.

[0063] In another preferred embodiment, in step (S2), the molar ratio of crown ether to iodide is 1:0.8-1.2; preferably, 1:0.9-1.1; more preferably, 1:1.

[0064] In another preferred embodiment, in step (S2), the crown ether is 18-crown-6, and the iodide is potassium iodide.

[0065] In another preferred embodiment, in step (S2), the molar ratio of 18-crown-6 to potassium iodide is 1:0.8-1.2; preferably, 1:0.9-1.1; more preferably, 1:1.

[0066] In another preferred embodiment, in step (S2), the acetate is selected from the following group: sodium acetate, potassium acetate, ammonium acetate, or a combination thereof.

[0067] In another preferred embodiment, in step (S2), the amount of crown ether used is 1-20 mol% (preferably, 4-15 mol%; more preferably, 3-7 mol%; most preferably, 5±0.5 mol%), based on the total molar amount of deuterated dibromomethane.

[0068] In another preferred embodiment, in step (S2), the amount of iodide used is 1-20 mol% (preferably, 4-15 mol%; more preferably, 3-7 mol%; most preferably, 5±0.5 mol%), based on the total molar amount of deuterated dibromomethane.

[0069] In another preferred embodiment, in step (S2), the molar ratio of deuterated dibromomethane to acetate is 1:(1-5); preferably, 1:(2-4); most preferably, 1:2-3.

[0070] In another preferred embodiment, in step (S2), the reaction time of the reaction is 5 to 48 hours; preferably, 24 hours.

[0071] In another preferred embodiment, in step (S2), the reaction temperature of the reaction is 60-100°C; preferably, 70-90°C; more preferably, 75-85°C; most preferably, 80°C.

[0072] In another preferred embodiment, in step (S2), the organic inert solvent is selected from the group consisting of acetonitrile, acetone, N'N-dimethylformamide, or a combination thereof.

[0073] In another preferred embodiment, in step (S2), the organic inert solvent is acetonitrile.

[0074] In another preferred embodiment, in step (S2), the mass volume ratio of deuterated dibromomethane to the organic inert solvent is 1 g:1-1.2 mL.

[0075] In another preferred embodiment, step (S2) includes the steps of providing a mixture of deuterated dibromomethane, acetate, catalyst 2 and an inert organic solvent, heating to the desired reaction temperature, reacting under stirring to obtain a reaction mixture, and separating by post-treatment to obtain deuterated methylene diacetate.

[0076] In another preferred embodiment, in step (S2), the post-treatment includes: cooling, filtering (such as by suction filtration), washing the obtained filter cake, taking the filtrate, and distilling under reduced pressure (-0.1 MPa, 100° C.) to obtain deuterated methylene diacetate.

[0077] In another preferred embodiment, in step (S3), the reaction temperature of the reaction is 80-120°C; preferably, 90-100°C; more preferably, 95-105°C; most preferably, 100°C.

[0078] In another preferred embodiment, in step (S3), the reaction time of the reaction is 15 to 40 hours; preferably, 18 to 30 hours; more preferably, 20 to 28 hours; most preferably, 24 hours.

[0079] In another preferred embodiment, in step (S3), the hydrochloric acid is an aqueous solution of hydrochloric acid.

[0080] In another preferred embodiment, in step (S3), the aqueous solution of hydrochloric acid is an aqueous solution of hydrochloric acid with a concentration of 0.3-12 mol / L or concentrated hydrochloric acid.

[0081] In another preferred embodiment, in step (S3), the volume ratio of hydrochloric acid to water is 1 to 20:1; preferably, 3 to 15:1; more preferably, 8 to 10:1; most preferably, 9:1.

[0082] In another preferred embodiment, in step (S3), the mass volume ratio of methylene diacetate to water is 1-10 g:1 ml; preferably, 2-6 g:1 ml; more preferably, 3-5 g:1 ml; most preferably, 4 g:1 ml.

[0083] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] Figure 1 The deuteration rate detection method of dibromodeuterane is shown. NMR (400M, DMSO-d6) of the blank group (CH2Br2).

[0085] Figure 2 The deuteration rate detection method of dibromodeuterane is shown. In the experimental group, the H NMR spectrum of the fourth round of deuteration reaction (400M, DMSO-d6).

[0086] Figure 3 The NMR spectra of the products after each of the four consecutive deuteration reactions in Example 2 are shown, and products with deuteration rates of 80%, 96.2%, 99.2%, and 99.5% are obtained, respectively, with acetonitrile (2-5 mM) as the internal standard ((500 M, DMSO-d6)).

[0087] Figure 4The NMR spectrum of the product after four consecutive deuteration steps after water washing (post-treatment method 1) is shown, showing a deuteration rate of 99.4%, with acetonitrile (2-5 mM) as the internal standard ((500 M, DMSO-d6)).

[0088] Figure 5 The deuterated rate detection method of deuterated methylene diacetate is shown. After adding dioxane (1:100000 molar ratio), the absolute concentration of the non-deuterated product can be calculated as 3.17E-10 mol.

[0089] Figure 6 The deuteration rate detection method of deuterated methylene diacetate is shown, and the H NMR spectrum (400M, DMSO-d6) after adding dioxane (1:125 molar ratio). The absolute total concentration of non-deuterated and deuterated products can be calculated from the characteristic signal of the methyl group, which is 4.2E-5 mol.

[0090] Figure 7 The NMR spectrum of the product after four consecutive deuteration treatments was shown after distillation column treatment (post-treatment method 2), showing a deuteration rate of 99.4%, with acetonitrile (2-5 mM) as the internal standard ((500 M, DMSO-d6)). DETAILED DESCRIPTION

[0091] The inventor has found a new method for preparing deuterated polyoxymethylene through extensive and in-depth research. The synthesis method of the present invention has mild conditions, simple operation, convenient post-processing, and high deuteration efficiency. Specifically, in the new preparation method of deuterated polyoxymethylene of the present invention, the phase transfer catalyst (such as crown ether) introduced in a specific molar ratio in the deuteration step (i.e., step (S1)) not only significantly improves the effect of the deuteration reaction, so that in each round of reaction, the deuteration balance can be reached in a short time under mild temperature conditions. 80%, 98% or even more than 99% can be reached after 3 or 4 rounds of deuteration reaction, and the separation loss is reduced and the product yield is improved. In addition, in the synthesis step of deuterated methylene diacetate (i.e., step (S2)), crown ether is introduced as a phase transfer catalyst and iodide, which significantly improves the reaction efficiency and improves the reaction yield. Further, the reaction also uses acetonitrile as a solvent, so that the desired product can be obtained by distilling off acetonitrile, which greatly simplifies the difficulty of post-processing. Based on this, the inventor has completed the present invention.

[0092] the term

[0093] Unless otherwise specified, the abbreviations or symbols in this application have the meanings well known to those skilled in the art.

[0094] As used herein, a~b refers to the range from a to b, including both values ​​of a and b.

[0095] As used herein, "mol %" means molar percentage.

[0096] Preparation method of deuterated polyoxymethylene

[0097] The present application aims at the deficiencies of the prior art, and provides a method for synthesizing deuterated formaldehyde. Dibromomethane is used as the starting material, and deuterated formaldehyde is obtained by sequentially undergoing hydrogen-deuterium exchange with heavy water, esterification with the participation of acetate, hydrolysis, and geminal diol dehydration. The raw materials of the reaction route are easily available, the conditions are mild, the yield is high, and the use of precious metal catalysts in the traditional route is avoided. The separation operation is simple, and it is easy to scale up industrial production.

[0098] In one embodiment, the present invention provides a method for preparing deuterated polyoxymethylene, comprising the following steps:

[0099] (S1) Deuterated dibromomethane,

[0100]

[0101] (S2) Synthesis of deuterated methylene diacetate,

[0102]

[0103] (S3) Synthesis of deuterated polyoxymethylene:

[0104]

[0105] Wherein, n is an integer from 1 to 10000; preferably, n is 5-100; more preferably, n is 15-35.

[0106] In another embodiment, the present invention provides a method for preparing deuterated polyoxymethylene, comprising the steps of:

[0107] (S1) Deuteration of dibromomethane, comprising the steps of:

[0108] (S1.1) performing N rounds of deuteration reaction; wherein N is an integer from 2 to 10 (preferably, N is an integer from 2 to 7, more preferably, N is 2, 3, 4 or 5, and most preferably, N is 3 or 4);

[0109] and,

[0110] The first round of deuteration reaction comprises the steps of: providing a reaction mixture containing dibromomethane, heavy water, a base and a phase transfer catalyst, performing a deuteration reaction, separating the liquids, and obtaining deuterated or partially deuterated dibromomethane;

[0111] The Nth round of deuteration reaction comprises the steps of: providing a reaction mixture containing partially deuterated dibromomethane obtained in the N-1th round of deuteration reaction, heavy water, a base and a phase transfer catalyst, performing a deuteration reaction, separating the liquids, and obtaining deuterated or partially deuterated dibromomethane;

[0112] (S1.2) post-treating the deuterated or partially deuterated dibromomethane obtained from the Nth round of deuteration reaction to obtain deuterated dibromomethane;

[0113] wherein the base is selected from the group consisting of alkali metal deuterium oxides, alkali metal salts of alcohols, or combinations thereof;

[0114] (S2) Synthesis of deuterated methylene diacetate, comprising the steps of:

[0115] reacting deuterated dibromomethane and acetate in an inert organic solvent in the presence of a crown ether and an iodide to obtain methylene diacetate; and

[0116] (S3) Synthesis of deuterated polyoxymethylene, comprising the steps of:

[0117] A mixture of deuterated methylene diacetate, hydrochloric acid and water is provided and reacted to obtain deuterated polyoxymethylene.

[0118] In other embodiments, steps (S1), (S2) and (S3) are as defined in the first aspect.

[0119] In one embodiment, the present invention provides a method for preparing deuterated polyoxymethylene, comprising the steps of:

[0120] (1) Deuteration of dibromomethane, comprising the steps of:

[0121] (1.1) providing a reaction mixture containing dibromomethane, a heavy aqueous solution of sodium deuteride and catalyst 1, performing a deuteration reaction, separating the liquids, and obtaining a lower layer product;

[0122] (1.2) providing a reaction mixture containing the lower layer product obtained in the previous step, a sodium deuteride heavy aqueous solution and catalyst 1, performing a deuteration reaction, separating the liquids, and obtaining a lower layer product; and

[0123] (1.3) repeating step (1.2) 0 to 10 times (preferably 1 to 5 times, more preferably 2 to 3 times) to obtain a lower layer product, which is deuterated dibromomethane;

[0124] (2) The synthesis of deuterated methylene diacetate comprises the steps of:

[0125] reacting deuterated dibromomethane and acetate in an inert organic solvent in the presence of a catalyst 2 to obtain methylene diacetate; and

[0126] (3) Synthesis of deuterated polyoxymethylene:

[0127] A mixture of deuterated methylene diacetate, hydrochloric acid and water is provided and reacted to obtain deuterated polyoxymethylene.

[0128] In another embodiment, the reaction conditions of steps (1), (2) and (3) are as defined above for steps (S1), (S2) and (S3), respectively.

[0129] In one embodiment, the present invention provides a synthetic method as shown in the following reaction scheme:

[0130]

[0131] In one embodiment, the present invention provides a synthetic method comprising the steps of:

[0132] Step 1: Deuteration of dibromomethane. Specifically, sodium hydride is carefully added to heavy water under an ice bath and stirred rapidly. After completion, hexane extracted mineral oil dried with anhydrous sodium sulfate is added to obtain a sodium deuteride heavy water solution. Catalyst 1 such as 18-crown-6 and dibromomethane are added to the solution, refluxed at 100°C for 24 hours, separated, the heavy water on the upper layer is collected for later use, and the dibromomethane on the lower layer is added to a new sodium deuteride heavy water solution after the degree of deuteration is detected, and the reaction is repeated.

[0133] Step 2: Synthesis of deuterated methylene diacetate. Specifically, deuterated dibromomethane, acetate, catalyst 2 and solvent such as acetonitrile are mixed, heated to 80°C, and mechanically stirred for 15 hours. After the reaction is completed, it is cooled to room temperature, the acetate is removed by suction filtration, the filter cake is rinsed with acetonitrile, and the filtrates are combined and distilled under reduced pressure (-0.1MPa, 100°C) to obtain deuterated methylene diacetate (colorless).

[0134] Preferably, step three: synthesizing deuterated formaldehyde is as follows: adding hydrochloric acid aqueous solution to deuterated methylene diacetate, reacting at 100° C. for 24 hours, and obtaining the deuterated formaldehyde product after distillation.

[0135] Preferably, in step 1, the content of sodium deuterium oxide in the sodium deuterium oxide heavy water solution is 10%wt, or the molar ratio of sodium deuterium oxide to heavy water is 1:18, and the molar ratio of dibromomethane, heavy water and catalyst 1 (such as 18-crown-6) is 1:4:0.05.

[0136] Preferably, in step one, the catalyst 1 used for phase transfer includes polyethers (such as oligoethylene glycol), crown ethers (such as 18-crown-6, 15-crown-5), quaternary ammonium salts (such as tetrabutylammonium bromide, dodecyltrimethylammonium chloride) and cyclodextrins.

[0137] Preferably, in step 1, the sodium deuterium oxide heavy water solution can be recycled after the reaction and separation to improve the utilization rate of the deuterium element and reduce the cost.

[0138] Preferably, in step 2, the molar ratio of deuterated dibromomethane, acetate and catalyst 2 is 1:3:0.05. The solvent can be selected from acetonitrile, acetone and N'N-dimethylformamide, etc., and 1-1.2 mL of organic solvent is required for each gram of deuterated dibromomethane.

[0139] Preferably, in step 2, the acetate used may be sodium acetate, potassium acetate, ammonium acetate, etc., and the catalyst 2 is used to improve the efficiency of nucleophilic substitution, and may be 18-crown-6, 15-crown-5, potassium iodide, sodium iodide, etc.

[0140] Preferably, in step 3, the concentration of hydrochloric acid can be between 1 and 12 M, but in order to ensure sufficient hydrolysis of the ester, the molar ratio of deuterated methylene diacetate to water in the hydrochloric acid should not be less than 1:2.

[0141] Preferably, in step 3, the specific operation of distillation is: placing the hydrolyzed reaction liquid in a distillation flask, connecting a condenser, a collecting flask and an exhaust gas treatment device. Connecting a water pump to perform reduced pressure distillation at 90°C, and collecting the solids remaining in the distillation flask. The liquid in the collecting flask is distilled again, and the operation is repeated. The solids in the distillation flask are combined, washed with cold water, and vacuum dried to obtain a polymer of deuterated formaldehyde.

[0142] The main advantages of the present invention include:

[0143] 1. The synthetic method of the present invention has relatively mild reaction conditions and is simple to operate. Simple operations such as extraction, separation, filtration and distillation can achieve product separation, and it is easy to scale up for preparation.

[0144] 2. The present invention uses simple industrial raw materials and can achieve a deuteration rate of 98.7%, or even above 99.4%, through 3 to 4 rounds of deuteration reactions.

[0145] 3. In the present invention, phase transfer catalysts are added in the first and second steps, so that each step is almost quantitatively converted without complicated separation and purification problems.

[0146] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are weight percentages and weight parts.

[0147] Example 1

[0148] Continuous Deuteration Synthesis of Deuterated Dibromomethane

[0149]

[0150] Preparation of 10% NaOD D2O solution: Place a three-necked flask containing 450g of heavy water (99.9% D) in an ice-salt bath. After the heavy water is cooled (≤0°C, to avoid ice formation affecting stirring), slowly add NaH (60%, 50g) while stirring the solution, and control the temperature of the reaction solution below 0°C during stirring. After the reaction is completed, add anhydrous n-hexane (150mL, dried and dehydrated with anhydrous Na2SO4 12 hours in advance) to extract, remove the upper organic layer, collect the lower heavy water phase, and repeat the extraction with anhydrous n-hexane twice. The heavy water phase is filtered with medium-speed filter paper to remove the residual black viscous impurities, thereby obtaining a sodium deuteride solution with a mass fraction of 10%.

[0151] First deuteration: Add dibromomethane (300 g, 1.73 mol), the above-prepared 10% NaOD in D2O solution (120 mL, 15.1 mol, based on the total molar amount of NaOD and D2O) and 18-crown-6 (22.5 g, 0.087 mol, 5% mol) to a 1L single-mouth round-bottom bottle. Set the oil bath temperature to 100°C. Stir the mixture under magnetic stirring and reflux for 15 hours. After the reaction is completed, cool it to room temperature and place it in a 4°C refrigerator. After 20 minutes, separate the liquids to obtain partially deuterated dibromomethane (280 g, deuteration rate 74.2%). Detect the deuteration rate. When it is close to the theoretical deuteration rate, the reaction is terminated. The calculation method of the deuteration rate at equilibrium is as follows: Assume that (partially deuterated) dibromomethane is a mol and the deuteration rate is b; heavy water with a deuteration rate of 99.9% is c mol; then the deuteration rate when the deuteration equilibrium is reached is: D% = (a*b+c) / (a+c).

[0152] Second deuteration: Repeat the above process, use 120mL of 10% NaOD in D2O solution (120mL, 15.1 mol, based on the total molar amount of NaOD and D2O), 18-crown-6 (20.1g, according to 5% mol of 280g of partially deuterated dibromomethane separated in the previous step), reflux reaction for 24 hours. 252g of partially deuterated dibromomethane was obtained, and the deuteration rate was 92.8%.

[0153] The third deuteration: Repeat the above process, use 100mL of 10% NaOD in D2O solution (100mL, 12.6 mol, based on the total molar amount of NaOD and D2O), 18-crown-6 (18.9g, according to 5% mol of 280g of partially deuterated dibromomethane separated in the previous step), reflux reaction for 24 hours, reflux reaction for 24 hours. 238g of partially deuterated dibromomethane was obtained, and the deuteration rate was 95.8%.

[0154] The fourth deuteration: Repeat the above process, use 100mL of 10% NaOD in D2O solution (100mL, 12.6 mol, based on the total molar amount of NaOD and D2O), 18-crown-6 (17.9g, according to 5% mol of the partially deuterated dibromomethane 280g separated in the previous step), reflux reaction for 24 hours. 203g of deuterated dibromomethane was obtained, and the deuteration rate was 98.7%.

[0155] After the above four consecutive deuteration reactions, the yield of dibromodeuterane was 67% and the deuteration rate was 98.7%. The deuterated dibromomethane obtained in the last step was extracted with deionized water (80 mL×3) and dried over anhydrous sodium sulfate to obtain 201 grams of deuterated product with a nuclear magnetic purity of 99.2%.

[0156] Example 2

[0157] Continuous Deuteration Synthesis of Deuterated Dibromomethane

[0158]

[0159] The first deuteration: Add dibromomethane (240g, 1.38mol), heavy water (96mL, 5.30mol), sodium tert-butoxide (25.6g, 0.27mol) and 18-crown-6 (19.2g, 0.073mol, 5%mol) to a 1L single-mouth round-bottom flask. Set the oil bath temperature to 100°C. Stir under magnetic reflux for 15h. After the reaction is completed, cool to room temperature and place in a 4°C refrigerator. After 20 minutes, separate the liquids to obtain partially deuterated dibromomethane (238g (containing tert-butanol impurities), with a deuteration rate of 80.1%, Figure 3 ), close to the equilibrium deuteration rate, the reaction terminates. The calculation method of the deuteration rate at equilibrium is as follows: Assume that (partially deuterated) dibromomethane is a mol, the deuteration rate is b; heavy water is c mol; then the deuteration rate when the deuteration equilibrium is reached is: D% = (a*b+c) / (a+c).

[0160] Second deuteration: Repeat the above process, add heavy water (96mL, 5.30mol), sodium tert-butoxide (25.6g, 0.27mol) and 18-crown-6 (19.2g, 0.073mol, 5%mol) to the partially deuterated dibromomethane, and reflux for 15 hours. 233g of partially deuterated dibromomethane was obtained, and the deuteration rate was 96.2% ( Figure 3 ).

[0161] The third deuteration: Repeat the above process, add heavy water (96mL, 5.30mol), sodium tert-butoxide (25.6g, 0.27mol) and 18-crown-6 (19.2g, 0.073mol, 5%mol) to the above partially deuterated dibromomethane, and reflux for 15 hours. 232g of partially deuterated dibromomethane was obtained, and the deuteration rate was 99.2% ( Figure 3 ).

[0162] The fourth deuteration: Repeat the above process, add heavy water (96mL, 5.30mol), sodium tert-butoxide (25.6g, 0.27mol) and 18-crown-6 (19.2g, 0.073mol, 5%mol) to the partially deuterated dibromomethane, and reflux for 15 hours. 227g of deuterated dibromomethane was obtained, and the deuteration rate was 99.4% ( Figure 3 ).

[0163] Post-treatment method 1: The deuterated dibromomethane obtained in the last step was extracted with deionized water (240 mL × 3) and dried over anhydrous sodium sulfate to obtain 135 g of deuterated product (58% yield, 99.4% deuteration rate ( Figure 4 ), NMR purity is 99.6%).

[0164] Post-treatment method 2 (rectification column, 7-layer tower plate): Deuterated dibromomethane was synthesized by continuous deuteration according to the same method as in Example 2. The deuterated dibromomethane obtained in the fourth time (135 g) was washed with saturated brine and added to a round-bottom flask. A binary azeotrope (30 g, distillation head temperature was 46 ° C) was obtained at 100-120 ° C. The product (91.8 g, distillation head temperature was 78 ° C) was obtained at 130 ° C (72% yield, 99.3% deuteration rate ( Figure 7 ), NMR purity 99.7%).

[0165] Example 3

[0166] The deuteration rate of dibromomethane was tested using acetonitrile as the internal standard. The calculation method for the theoretical deuteration rate at equilibrium is as follows: Assuming that (partially deuterated) dibromomethane is a mol and the deuteration rate is b; heavy water is c mol; then the deuteration rate when the deuteration equilibrium is reached is: D% = (a*b+c) / (a+c). Take 5μL of CH2Br2 and 5μL of the organic phase of the dibromodeuterane reaction solution respectively, and use them as blank groups ( Figure 1 ) and experimental group ( Figure 2 ), respectively added to 500 μL of CDCl3 or DMSO-d6 solution ([CH3CN] = 20 ~ 5mM, as internal standard), the NMR integrated area of ​​acetonitrile (at 2.0ppm) is recorded as 1, the NMR integrated areas of dibromomethane and dibromodeuterane remaining in the deuteration reaction are I and I0, respectively. The deuteration rate calculation formula is as follows:

[0167]

[0168] Taking the NMR result of the fourth deuteration in Example 1 as an example, it can be calculated that the deuteration rate is 98.7%.

[0169] Example 4

[0170] Recycling of deuterated water. "Recycling of deuterated water" in the deuteration reaction of dibromomethane means that the upper heavy water phase after the deuteration reaction of dibromomethane is used as a deuterium source to continue reacting with new dibromomethane to ensure the utilization rate of heavy water. The specific operation is as follows: weigh 100g (0.575mol) of dibromomethane, add 42mL of 10% NaOD (2.3mol) heavy water solution and 18-crown-6 (7.5g), and reflux at 100℃ for 24 hours. After the reaction system is cooled, separate and collect the deuterated dibromomethane mixed solution in the lower layer, then add the same mass of dibromomethane (100g), and start the second round under the same conditions. Refer to the same method to carry out the third and fourth rounds of deuteration. Using acetonitrile as the internal standard, the deuteration rates of dibromomethane were calculated by nuclear magnetic resonance hydrogen spectrum integration to be 79%, 47%, 32%, and 18% for different reuse times, and the cumulative utilization rates of deuterium atoms in heavy water were 21%, 53%, 68%, and 82%, respectively.

[0171] Example 5

[0172] Synthesis of Deuterated Methylene Diacetate

[0173] The reaction formula of the synthesis method is:

[0174]

[0175] Weigh deuterated dibromomethane (159 g, 0.9 mol), potassium acetate (253 g, 2.58 mol), potassium iodide (7.25 g, 0.045 mol, 5% eq) and 18-crown-6 (11.48 g, 0.045 mol, 5% eq) in a 1L three-necked flask, add acetonitrile (160 mL) and react in an oil bath at 80°C for 24 hours under mechanical stirring. After the reaction is completed, cool to room temperature, shake the reaction flask and transfer the reaction system to a suction filtration funnel. Use acetonitrile to transfer the solid and liquid in the remaining reaction flask (25 mL × 3), remove potassium acetate by suction filtration, rinse the filter cake with acetonitrile (25 mL × 3), and combine the filtrates.

[0176] Post-treatment method 1: The combined solution is subjected to vacuum rotary evaporation to remove acetonitrile. Pour the liquid in the eggplant-shaped bottle into a separatory funnel, then add saturated brine (50mL) to extract the liquid, collect the upper organic phase, and wash it twice with saturated brine (50mL) to obtain organic phase a. The lower aqueous phase of the previous step is transferred to a separatory funnel, and the oily liquid remaining in the eggplant-shaped bottle (transferred using 15mL of dichloromethane) is also transferred to a separatory funnel, extracted and separated, and the lower organic phase b1 is collected. The upper aqueous phase is extracted again with dichloromethane (15mL) to obtain the lower organic phase b2. Combine organic phases b1 and b2, and extract twice with saturated brine (30mL×2) to obtain the lower organic phase b. After mixing organic phases a and b, distill under reduced pressure at room temperature to obtain methylene diacetate-d2 (112g, 93%, light yellow liquid with a strong pungent odor), with a nuclear magnetic purity of >99%.

[0177] Post-treatment method 2: The solution after the filtrate is combined is distilled under reduced pressure (-0.1MPa, 100°C) to obtain a colorless liquid (102g, 85%) with a nuclear magnetic purity of >99%.

[0178] Example 6

[0179] Internal standard method: dioxane was used as the internal standard.

[0180] Prepare a deuterated solvent with a molar ratio of dioxane / CDCl3=1 / 100000: add 5ul of dioxane to 10ml of CDCl3, and dilute 50 times. Prepare a deuterated solvent with a molar ratio of dioxane / CDCl3=1 / 125: add 20ul of dioxane to 2.5ml of CDCl3.

[0181] Take 500 μL of the above deuterated solvent, add 5 μL of the deuterated methylene diacetate product, perform H NMR spectrum characterization, and calculate the integrated area. Determine the total content of non-deuterated and deuterated I 0(图) (like Figure 6 Display results) and the absolute value of the non-deuterated residue I (such as Figure 5The deuterium substitution rate is calculated to be 99.3%. The formula for calculating the deuterium substitution rate is as follows

[0182] Example 7

[0183] Synthesis of deuterated formaldehyde. The reaction formula of the synthesis method is:

[0184]

[0185] Weigh deuterated methylene diacetate (18 g, 0.13 mol), add water (4.5 mL) and concentrated hydrochloric acid (0.5 mL) and react at 100 ° C for 24 hours. After the reaction is completed, use a water pump to distill at 90 ° C under reduced pressure, and collect the white solid in the distillation flask. The fraction is distilled under reduced pressure again, and a total of 2.82 g of deuterated polyoxymethylene is obtained, with a yield of 66% and a degree of polymerization of 20 (iodine titration method).

[0186] In this embodiment, other concentrations of aqueous hydrochloric acid were also used for the reaction, including 0.3-12 mol / L, and the above reaction could occur.

[0187] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing deuterated polyoxymethylene, characterized in that: Includes steps: (S1) Deuterated dibromomethane, Includes steps: (S1.1) performing N rounds of deuteration reaction; wherein N is an integer from 2 to 10 (preferably, N is an integer from 2 to 7, more preferably, N is 2, 3, 4 or 5, and most preferably, N is 3 or 4); and, The first round of deuteration reaction comprises the steps of: providing a reaction mixture containing dibromomethane, heavy water, a base and a phase transfer catalyst, performing a deuteration reaction, separating the liquids, and obtaining deuterated or partially deuterated dibromomethane; The Nth round of deuteration reaction comprises the steps of: providing a reaction mixture containing partially deuterated dibromomethane obtained in the N-1th round of deuteration reaction, heavy water, a base and a phase transfer catalyst, performing a deuteration reaction, separating the liquids, and obtaining deuterated or partially deuterated dibromomethane; (S1.2) post-treating the deuterated or partially deuterated dibromomethane obtained from the Nth round of deuteration reaction to obtain deuterated dibromomethane; wherein the base is selected from the group consisting of alkali metal deuterium oxides, alkali metal salts of alcohols, or combinations thereof; (S2) Synthesis of deuterated methylene diacetate, It includes the steps of: reacting deuterated dibromomethane and acetate in an inert organic solvent in the presence of a crown ether and an iodide to obtain methylene diacetate; and (S3) Synthesis of deuterated polyoxymethylene: Wherein, n is an integer from 1 to 10000; It includes the steps of: A mixture of deuterated methylene diacetate, hydrochloric acid and water is provided and reacted to obtain deuterated polyoxymethylene.

2. The preparation method according to claim 1, characterized in that The phase transfer catalyst is a crown ether.

3. The preparation method according to claim 1, characterized in that: The crown ether is selected from the group consisting of 18-crown-6, 21-crown-7, 15-crown-5; and / or, The alkali metal deuterium oxide is selected from the group consisting of sodium deuterium oxide, methyl deuterium oxide, or a combination thereof; and / or, The alkali metal salt of alcohol is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, or a combination thereof.

4. The preparation method according to claim 1, characterized in that: The phase transfer catalyst is 18-crown-6; and / or, The base is sodium deuteride or sodium tert-butoxide.

5. The preparation method according to claim 1, characterized in that: Step (S1) further has one or more characteristics selected from the following group: (a) the molar ratio of the alkali to the heavy water is 1:2 to 1:50 (preferably 1:5 to 1:35, more preferably 1:10 to 1:30, and most preferably 1:15 to 22); (b) In the first round of deuteration reaction, the molar ratio of dibromomethane to the deuterium source in the reaction mixture is 1:(0.1-15); preferably, 1:(3-10); wherein the deuterium source refers to the sum of all deuterium-containing compounds (such as heavy water and alkali metal deuterium oxides) in the reaction mixture; (c) in the Nth round of deuteration reaction, the molar ratio of dibromomethane to the deuterium source in the reaction mixture is ≥ the molar ratio in the first round of deuteration reaction; and (d) in each round of deuteration reaction, the amount of the phase transfer catalyst in the reaction mixture is 3 to 7 mol % (preferably 4 to 6 mol %, more preferably 5±0.5 mol %), based on the total mass of dibromomethane or deuterated or partially deuterated dibromomethane; (e) in step (S1), the reaction temperature of the deuteration reaction is 80 to 120° C.; preferably, 90 to 100° C.; more preferably, 95 to 105° C.; most preferably, 100° C.; and (f) The reaction time of each round of deuteration reaction is 5 to 40 hours; preferably, 10 to 30 hours; more preferably, 15 to 24 hours.

6. The preparation method according to claim 1, characterized in that: Each round of deuterium substitution reaction also includes the steps of taking the upper layer of liquid and reusing it as a deuterium source.

7. The preparation method according to claim 1, characterized in that: In step (S2), The crown ether is selected from the group consisting of 18-crown-6, 21-crown-7, 15-crown-5, or a combination thereof; and / or, The iodide is selected from the group consisting of potassium iodide, sodium iodide, or a combination thereof; and / or, The molar ratio of crown ether to iodide is 1:0.8-1.2; preferably, 1:0.9-1.1; more preferably, 1:1; and / or, The organic inert solvent is selected from the group consisting of acetonitrile, acetone, N'N-dimethylformamide, or a combination thereof.

8. The preparation method according to claim 1, characterized in that: The crown ether is 18-crown-6, and the iodide is potassium iodide; and / or, The organic inert solvent is acetonitrile.

9. The preparation method according to claim 1, characterized in that: Step (S2) further has one or more characteristics selected from the group consisting of: (a) the amount of the crown ether is 1 to 20 mol% (preferably, 4 to 15 mol%; more preferably, 3 to 7 mol%; most preferably, 5 ± 0.5 mol%), based on the total molar amount of deuterated dibromomethane; (b) the amount of iodide is 1 to 20 mol% (preferably, 4 to 15 mol%; more preferably, 3 to 7 mol%; most preferably, 5 ± 0.5 mol%), based on the total molar amount of deuterated dibromomethane; (c) the molar ratio of deuterated dibromomethane to acetate is 1:(1-5); preferably, 1:(2-4); most preferably, 1:2-3; (d) The reaction time of the reaction is 5 to 48 hours; preferably, 24 hours; (f) the reaction temperature of the reaction is 60 to 100° C.; preferably, 70 to 90° C.; more preferably, 75 to 85° C.; most preferably, 80° C.; and (d) The mass volume ratio of deuterated dibromomethane and the organic inert solvent is 1 g:1-1.2 mL.

10. The preparation method according to claim 1, characterized in that: Step (S3) further has one or more characteristics selected from the group consisting of: (a) The reaction temperature of the reaction is 80-120°C; preferably, 90-100°C; more preferably, 95-105°C; most preferably, 100°C; (b) The reaction time of the reaction is 15 to 40 hours; preferably, 18 to 30 hours; more preferably, 20 to 28 hours; Optimally, 24 hours; (c) the hydrochloric acid is an aqueous solution of hydrochloric acid; (d) The aqueous solution of hydrochloric acid is an aqueous solution of hydrochloric acid with a concentration of 0.3-12 mol / L or concentrated hydrochloric acid. (e) the volume ratio of hydrochloric acid to water is 1 to 20:1; preferably, 3 to 15:1; more preferably, 8 to 10:1; most preferably, 9:1; and (f) The mass volume ratio of methylene diacetate to water is 1-10 g:1 ml; preferably, 2-6 g:1 ml; more preferably, 3-5 g:1 ml; most preferably, 4 g:1 ml.

Images