Continuous flow synthesis method of 4-(chloromethyl)-2, 2-dimethyl-1, 3-dioxolane

Abstract

The invention discloses a continuous flow synthesis method of 4-(chloromethyl)-2, 2-dimethyl-1, 3-dioxolane, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: dissolving a reaction raw material epoxy chloropropane in an organic solvent to prepare a component A; dissolving lewis acid in an organic solvent to prepare a component B; and mixing the component A and the component B at the same flow velocity, feeding the mixture into a continuous flow reactor, controlling the temperature at 20-60 DEG C, staying for 5-30 minutes, enabling the reaction mixture to flow out of the continuous flow reactor, and performing post-treatment to obtain the product 4-(chloromethyl)-2, 2-dimethyl-1, 3-dioxolame. According to the synthesis method disclosed by the invention, the continuous flow reactor is used for replacing the traditional dangerous kettle reaction, the reaction condition is mild, heat accumulation in the reaction is avoided, the safety risk is greatly reduced, and the reaction safety is extremely high; the reaction time is short, the production yield is high, the product quality is high, and industrial production is easy.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a continuous flow synthesis method for 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane. Background Art

[0002] 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (including its ( R )-、( S )- and racemic configurations) is an important class of organic synthesis intermediates. Its unique structural characteristics can be flexibly embedded in a variety of active molecular skeletons and has a wide range of application value in drug research and development. S )-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is the key chiral side chain fragment of the β-adrenergic receptor blocker Landiolol. R )-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane can be used to synthesize phthalimide glycidyl ester (CN109384773A), an important intermediate of rivaroxaban, and can also be used to construct the chiral glycerol skeleton in molecular structures such as nitroglycerin (CN107383085A). This type of compound can be used as a stereoisomer precursor in the synthesis of various nucleoside antiviral drugs (such as sofosbuvir) (CN108069933A; Nat. Commun. 2025, 16, 364). 4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane can be used to synthesize dipeptides, amino acid esters and A 2A Receptor antagonist prodrug (EP2379540B1, JP2012512203A, EP2185550B1), also used to synthesize vanillin and jasminoid acetal fragrances (JP2007302591A), and can also be used as a protective group to synthesize the side chain of paclitaxel ( Tetrahedron: Asymm. 2010, 21, 2619).

[0003] The known reported synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane was carried out in a tank reactor.

[0004] CN108069933A ( R )-epichlorohydrin as raw material, react with acetone, and generate the intermediate product (2,2-dimethyl-1,3-dioxolane-4 R ) methyl chloride; the kettle reaction synthesis route is as follows:

[0005] CN101012217A uses boron trifluoride ether as a catalyst and adds ( S )-epichlorohydrin and acetone are reacted at 10-60°C for 4-8 hours to obtain (2,2-dimethyl-1,3-dioxolane-4 S ) methyl chloride, the kettle reaction synthesis route is as follows:

[0006] However, the above method has a long reaction time, and the temperature rises sharply during the reaction, which is easy to cause material loss, posing a huge safety risk. In particular, the kettle reaction uses a large amount of boron trifluoride etherate, releases heat violently, and dissipates heat slowly, posing a huge safety hazard to industrial production.

[0007] Therefore, it is urgent to develop a new 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane synthesis process to improve production efficiency and reaction safety. Summary of the Invention

[0008] Purpose of the Invention: This invention addresses the shortcomings of existing technologies and provides a continuous flow synthesis method for the synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane. This method features mild conditions, high yield, and high product quality. The process is continuous, safe, and controllable, with high production efficiency and ease of industrialization.

[0009] Technical solution: The purpose of the present invention is achieved through the following technical solution: The present invention provides a continuous flow synthesis method for 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane, comprising the following steps: (1) Dissolve the reaction raw material epichlorohydrin in an organic solvent to prepare component A; dissolve the Lewis acid in an organic solvent to prepare component B; (2) Component A and component B are mixed at the same flow rate and then enter a continuous flow reactor. The temperature is controlled at 20-60°C. After staying for 5-30 minutes, the reaction mixture flows out of the continuous flow reactor and is post-treated to obtain the product 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane.

[0010] The continuous flow synthesis method of the present invention has only one step reaction. The epichlorohydrin solution and the Lewis acid solution are synchronously mixed by metering pumps and passed through a continuous flow reactor, and reacted at 20-60°C to obtain the product.

[0011] Preferably, 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane comprises R - Configuration, S -configuration or racemic configuration.

[0012] Preferably, the reaction raw materials are selected from S-Epichlorohydrin, R -Epichlorohydrin or racemic epichlorohydrin.

[0013] Preferably, in step (1), the organic solvent is selected from acetone.

[0014] Preferably, in step (1), the Lewis acid is selected from boron trifluoride etherate, ZnCl3, AlCl3, BCl3, trifluoromethanesulfonic acid or difluorophenylboric acid.

[0015] Preferably, in step (1), the molar ratio of epichlorohydrin to Lewis acid is 1:0.01 to 1:0.3.

[0016] Preferably, in step (1), the molar concentration of component A is 0.1-1.5M; the molar concentration of component B is 0.001-0.3M.

[0017] Preferably, in step (2), the residence time of component A and component B is 15 to 30 minutes.

[0018] In the continuous flow chemical synthesis reaction of the present invention, residence time is a key parameter that determines the reaction conversion rate and selectivity, and the flow rate of each component is adaptively adjusted as the residence time changes.

[0019] Preferably, the continuous flow reactor is a continuous flow coil reactor, and its material is FEP. Beneficial effects

[0020] (1) The present invention uses a continuous flow reactor to replace the traditional dangerous autoclave reaction, avoiding the accumulation of heat during the reaction, greatly reducing safety risks, and having extremely high reaction safety. The continuous flow synthesis method of the present invention has mild reaction conditions, short reaction time, high production yield, and high product quality.

[0021] (2) The product obtained by the continuous flow synthesis method of the present invention has stable quality and is very suitable for industrial production.

[0022] (3) The continuous flow synthesis method of the present invention uses commercial equipment, which is cheap and easy to obtain, and has flexible and efficient construction. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The present invention is a flow chart of the synthesis process of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane.

[0024] Figure 2 For the present invention R -4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane synthesis process flow chart.

[0025] Figure 3 For the present inventionS -4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane synthesis process flow chart. DETAILED DESCRIPTION

[0026] The technical solution of the present invention is described in detail below through specific embodiments, but the protection scope of the present invention is not limited to the embodiments.

[0027] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0028] The continuous flow reactor used in Examples 1 to 6 of the present invention is a continuous flow coil reactor, which is made of FEP with an ID of 0.8 mm. The coil volume of the continuous flow coil reactor is V=1.5 mL.

[0029] The purity of the compounds in Examples 1 to 7 of the present invention was determined by Shimadzu GC-2010 gas chromatograph.

[0030] Chromatographic column: DB-WAXETR (30 m × 0.32 mm × 1.0 μm).

[0031] Method: The initial column temperature was 50°C, maintained for 10 minutes, then increased to 220°C at a rate of 20°C per minute and maintained for 5 minutes. The carrier gas was nitrogen, the flow rate was 2.0 mL per minute, and the split ratio was 10:1. The injection volume was 1 μL, the injection port temperature was 220°C, and a hydrogen flame ionization detector was used with a detector temperature of 260°C.

[0032] Example 1 Synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane The synthetic route is as follows:

[0033] The synthetic process of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is shown in Figure 1 .

[0034] Synthesis method: (1) Dissolve epichlorohydrin (Compound 1, 1.0 equiv.) in acetone to prepare component A (1.0 M). Dissolve boron trifluoride etherate (0.2 equiv.) in acetone to prepare component B (0.2 M).

[0035] (2) Components A and B were mixed in a T-type mixer at the same flow rate of 0.05 mL / min and then flowed into a continuous flow coil reactor insulated at 50°C. After a residence time of 15 min, the reaction mixture was quenched with saturated sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain product 2. The product was collected for 180 min to obtain 1.22 g of product 2, with a yield of 90.04% and a purity of 99.133% (GC analysis).

[0036] 1 H NMR (400MHz, Chloroform-d) δ (ppm) 4.33 (ddd, J = 11.5, 6.5, 3.5 Hz,1H), 4.19 – 4.09 (m, 2H), 3.90 (dd, J = 8.8, 5.1 Hz, 1H), 3.60 (dd, J = 10.9, 4.9Hz, 1H), 3.49 (dd, J = 10.9, 7.7 Hz, 1H), 1.46 (s, 3H), 1.38 (s, 3H).

[0037] Example 2 Optimization of Synthesis Reaction Conditions for 4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane According to the synthesis method of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (Product 2) in Example 1, with reference to the parameter settings in Tables 1, 2, 3, 4, and 5, and the remaining parameter settings were the same as in Example 1, the optimized reaction conditions for Product 2 were investigated.

[0038] Table 1 studies the effects of different Lewis acids on the reaction.

[0039] The results showed that when the molar concentration of compound 1, the molar equivalent of Lewis acid, the temperature and the residence time were kept constant, the purity of the product was better than that of other Lewis acids when boron trifluoride etherate was used as the catalyst.

[0040] Table 1 Screening of Lewis acids

[0041] Table 2 studies the effect of the molar equivalent of Lewis acid on the reaction.

[0042] The results showed that, while maintaining constant molar concentration, temperature, and residence time of compound 1, at 0.05 equiv. of boron trifluoride etherate, compound 1 failed to react completely, resulting in a product purity of only 66.938%. At 0.2 equiv. of boron trifluoride etherate, the product purity increased to 99.015%. Further increases in the amount of boron trifluoride etherate reduced the product purity to 95.107%.

[0043] Table 2 Effect of the equivalent of boron trifluoride ether on the reaction

[0044] Table 3 studies the effect of residence time on the reaction.

[0045] The results showed that, while maintaining constant molar concentration, temperature, and molar equivalent of the Lewis acid, compound 1 did not react completely at a residence time of 5 minutes. At a residence time of 15 minutes, the purity of the product increased to 99.015%. Further increases in residence time reduced the purity of the product to 96.701%.

[0046] In the continuous flow chemical synthesis reaction of the present invention, residence time is a key parameter that determines the reaction conversion rate and selectivity, and the flow rate of each component is adaptively adjusted as the residence time changes.

[0047] Table 3 Effect of residence time on reaction

[0048] Table 4 studies the effect of the molar concentration of compound 1 on the reaction.

[0049] The results showed that maintaining a flow rate of 0.05 mL / min for components A and B, a residence time of 15 minutes, a reaction temperature of 50°C, and a catalyst molar equivalent of 0.2 allowed the product purity to exceed 99.00% when the molar concentration of compound 1 increased from 0.1 mol / L to 1.0 mol / L. However, increasing the molar concentration of compound 1 from 1.0 mol / L to 1.5 mol / L decreased the product purity to 95.580%, with the occurrence of side reactions. Considering the reaction flux, the 1.0 mol / L concentration condition was selected as the optimal concentration.

[0050] Table 4 Effect of the concentration of compound 1 on the reaction

[0051] Table 5 studies the effect of temperature on the reaction.

[0052] The results showed that when the catalyst molar equivalent, raw material molar concentration and residence time were kept constant and the reaction temperature was changed, the increase of temperature was beneficial to improving the purity of the product.

[0053] Table 5 Effect of temperature on reaction

[0054] Example 3 R Synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane R -4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane synthesis process is shown in Figure 2 .

[0055] Synthesis method: (1) Compound R Epichlorohydrin (compound 3, 1.0 equiv.) was dissolved in acetone to prepare component A (1.0 M). Boron trifluoride etherate (0.2 equiv.) was dissolved in acetone to prepare component B (0.2 M).

[0056] (2) Components A and B were mixed in a T-type mixer at the same flow rate of 0.05 mL / min and then flowed into a continuous flow coil reactor insulated at 50°C. After a residence time of 15 min, the reaction mixture was collected and quenched with saturated sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain product 4. The reaction mixture was collected for 180 min to obtain 1.14 g of product 4, with a yield of 84.13% and a purity of 99.081% (GC analysis).

[0057] 1 H NMR (400 MHz, Chloroform-d) δ (ppm) 4.33 (ddt, J = 7.6, 6.2, 5.0 Hz,1H), 4.15 – 4.11 (m, 1H), 3.90 (dd, J = 8.7, 5.1 Hz, 1H), 3.59 (dd, J = 10.9, 4.8Hz, 1H), 3.48 (dd, J = 10.9, 7.6 Hz, 1H), 1.48 – 1.44 (m, 3H), 1.38 (d, J =0.8 Hz, 3H).

[0058] Example 4 R Optimization of the Synthesis Conditions of 4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane According to the synthesis method of product 4 in Example 3, refer to the parameter settings in Tables 6, 7, 8, and 9, and set the remaining parameters the same as in Example 3 to investigate the optimized reaction conditions of product 4.

[0059] Table 6 studies the effect of the molar equivalent of Lewis acid on the reaction.

[0060] The results showed that, while maintaining constant molar concentration, temperature, and residence time of compound 3, compound 3 did not react completely at 0.05 equiv. of boron trifluoride etherate. At 0.2 equiv. of boron trifluoride etherate, the product purity increased to 99.461%. Further increases in the amount of boron trifluoride etherate reduced the product purity to 95.845%.

[0061] Table 6 Effect of the equivalent of boron trifluoride ether on the reaction

[0062] Table 7 studies the effect of residence time on the reaction.

[0063] The results showed that, while maintaining constant molar concentration, temperature, and Lewis acid equivalents of compound 3, compound 3 did not react completely at a residence time of 5 minutes. At a residence time of 15 minutes, the product purity increased to 99.461%. Further increases in residence time reduced the product purity to 96.620%.

[0064] In the continuous flow chemical synthesis reaction of the present invention, residence time is a key parameter that determines the reaction conversion rate and selectivity, and the flow rate of each component is adaptively adjusted as the residence time changes.

[0065] Table 7 Effect of residence time on reaction

[0066] Table 8 studies the effect of the molar concentration of compound 3 on the reaction.

[0067] The results showed that maintaining a flow rate of 0.05 mL / min for component A and component B, a residence time of 15 minutes, a reaction temperature of 50°C, and a catalyst molar equivalent of 0.2 equiv. Increasing the molar concentration of compound 3 from 0.1 mol / L to 1.0 mol / L resulted in product purity exceeding 99.00%. However, increasing the molar concentration of compound 3 from 1.0 mol / L to 1.5 mol / L decreased the product purity to 95.889%, indicating incomplete conversion. Considering the reaction flux, the 1.0 mol / L concentration was selected as the optimal concentration.

[0068] Table 8 Effect of the concentration of compound 3 on the reaction

[0069] Table 9 studies the effect of temperature on the reaction.

[0070] The results showed that when the catalyst molar equivalent, the molar concentration of compound 3 and the residence time were kept constant and the reaction temperature was changed, the increase in temperature was beneficial to improving the purity of the product.

[0071] Table 9 Effect of temperature on reaction

[0072] Example 5 S Synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane S The synthetic process flow chart of -4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is shown in Figure 3 .

[0073] Synthesis method: (1) Compound S Epichlorohydrin (compound 5, 1.0 equiv.) was dissolved in acetone to prepare component A (1.0 M). Boron trifluoride etherate (0.2 equiv.) was dissolved in acetone to prepare component B (0.2 M).

[0074] (2) Components A and B were mixed in a T-type mixer at the same flow rate of 0.05 mL / min and then flowed into a continuous flow coil reactor insulated at 50°C. After a residence time of 15 min, the reaction mixture was quenched with saturated sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain product 6. The product was collected for 180 min to obtain 1.33 g of product 6, with a yield of 98.15% and a GC purity of 99.269%.

[0075] 1 H NMR (400 MHz, Chloroform-d) δ (ppm) 4.33 (ddt, J = 7.6, 6.2, 5.0 Hz,1H), 4.15 – 4.11 (m, 1H), 3.90 (dd, J = 8.7, 5.1 Hz, 1H), 3.59 (dd, J = 10.9, 4.8Hz, 1H), 3.48 (dd, J = 10.9, 7.6 Hz, 1H), 1.46 (s, 3H), 1.38 (s, 3H).

[0076] Example 6 S Optimization of Synthesis Conditions of 4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane According to the synthesis method of product 6 in Example 5, refer to the parameter settings in Tables 10, 11, 12, and 13, and set the remaining parameters the same as in Example 5 to investigate the optimized reaction conditions of product 6.

[0077] Table 10 studies the effect of the molar equivalent of Lewis acid on the reaction.

[0078] Results showed that while maintaining constant molar concentration, temperature, and residence time, compound 5 did not react completely at 0.05 equiv. of boron trifluoride etherate. At 0.2 equiv. of boron trifluoride etherate, the product purity increased to 99.273%. Further increases in the amount of boron trifluoride etherate reduced the purity to 90.594%, as increasing the amount of boron trifluoride etherate resulted in the generation of impurities.

[0079] Table 10 Effect of the equivalent of boron trifluoride ether on the reaction

[0080] Table 11 studies the effect of residence time on the reaction.

[0081] The results showed that, while maintaining constant molar concentration, temperature, and molar equivalent of the Lewis acid, compound 5 did not react completely at a residence time of 5 minutes. When the residence time was increased to 15 minutes, the purity of the product increased to 99.273%. Further increases in the residence time decreased the purity of the product to 96.771%.

[0082] In the continuous flow chemical synthesis reaction of the present invention, residence time is a key parameter that determines the reaction conversion rate and selectivity, and the flow rate of each component is adaptively adjusted as the residence time changes.

[0083] Table 11 Effect of residence time on reaction

[0084] Table 12 studies the effect of the molar concentration of compound 5 on the reaction.

[0085] The results showed that maintaining a flow rate of 0.05 mL / min for components A and B, a residence time of 15 minutes, a reaction temperature of 50°C, and a catalyst molar equivalent of 0.2 equiv., the product purity reached its maximum when the molar concentration of compound 5 increased from 0.1 mol / L to 1.0 mol / L. However, when the molar concentration of compound 5 increased from 1.0 mol / L to 1.5 mol / L, the product purity dropped to 96.771%, indicating incomplete conversion.

[0086] Table 12 Effect of the concentration of compound 5 on the reaction

[0087] Table 13 studies the effect of temperature on the reaction.

[0088] The results showed that when the catalyst molar equivalent, the molar concentration of compound 5 and the residence time were kept constant and the reaction temperature was changed, the increase in temperature was beneficial to improving the purity of the reaction product.

[0089] Table 13 Effect of temperature on reaction

[0090] Example 7 (1) Compound S Epichlorohydrin (compound 5, 1.0 equiv.) was dissolved in acetone to prepare component A (1.0 M). Boron trifluoride etherate (0.2 equiv.) was dissolved in acetone to prepare component B (0.2 M).

[0091] (2) The continuous flow reactor is a continuous flow coil reactor, which is made of FEP, 1.6 mm ID, and the coil volume of the continuous flow coil reactor is V = 12.0 mL.

[0092] (3) Components A and B were mixed in a T-type mixer at the same flow rate of 0.4 mL / min and then flowed into a continuous flow coil reactor insulated at 50°C. After a residence time of 15 min, the reaction mixture was quenched with saturated sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain product 6. The product was collected for 60 min to obtain 5.08 g of product 6, with a yield of 98.38% and a GC purity of 99.215%.

[0093] The continuous flow synthesis method of the present invention solves the amplification effect existing in the traditional kettle process and verifies its excellent amplification ability; at the same time, the continuous flow amplification experiment further shows that this method has the potential for efficient and scalable production.

[0094] As described above, although the present invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the present invention itself. Various changes may be made to it in form and detail without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A continuous flow synthesis method for 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane, characterized in that: The following steps are involved: (1) Dissolve the reaction raw material epichlorohydrin in an organic solvent to prepare component A; dissolve the Lewis acid in an organic solvent to prepare component B; (2) Component A and component B are mixed at the same flow rate and then enter a continuous flow reactor. The temperature is controlled at 20-60°C. After staying for 5-30 minutes, the reaction mixture flows out of the continuous flow reactor and is post-treated to obtain the product 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane.

2. The continuous flow synthesis method according to claim 1, characterized in that 4-(Chloromethyl)-2,2-dimethyl-1-dioxolane includes R - Configuration, S -configuration or racemic configuration.

3. The continuous flow synthesis method according to claim 1, characterized in that The reaction raw materials are selected from S -Epichlorohydrin, R -Epichlorohydrin or racemic epichlorohydrin.

4. The continuous flow synthesis method according to claim 1, characterized in that In step (1), the organic solvent is selected from acetone.

5. The continuous flow synthesis method according to claim 1, characterized in that In step (1), the Lewis acid is selected from boron trifluoride etherate, ZnCl3, AlCl3, BCl3, trifluoromethanesulfonic acid or difluorophenylboric acid.

6. The continuous flow synthesis method according to claim 1, characterized in that In step (1), the molar ratio of epichlorohydrin to Lewis acid is 1:0.01 to 1:0.

3.

7. The continuous flow synthesis method according to claim 1, characterized in that In step (1), the molar concentration of component A is 0.1-1.5M; the molar concentration of component B is 0.001-0.3M.

8. The continuous flow synthesis method according to claim 1, characterized in that In step (2), the residence time of component A and component B is 15 to 30 minutes.

9. The continuous flow synthesis method according to claim 1, characterized in that The continuous flow reactor is a continuous flow coil reactor, and its material is FEP.

Images