A continuous flow process for the synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane

Abstract

The application discloses a continuous flow synthesis method of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane, and belongs to the technical field of drug synthesis. In the application, epichlorohydrin is dissolved in an organic solvent to prepare component A; a Lewis acid is dissolved in an organic solvent to prepare component B; component A and component B are mixed at the same flow rate, and then enter a continuous flow reactor, the temperature is controlled to be 20-60 DEG C, and after staying for 5-30 min, the reaction mixture flows out of the continuous flow reactor, and after treatment, the product 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is obtained. The synthesis method uses a continuous flow reactor to replace a traditional dangerous kettle type reaction, the reaction condition is mild, the heat accumulation in the reaction is avoided, the safety risk is greatly reduced, and the reaction safety is very high; the reaction time is short, the production yield is high, the product quality is high, and the industrial production is easy.

Description

TECHNICAL FIELD

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

[0002] 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (including three configurations of (R)-, (S)- and racemic) is an important intermediate in organic synthesis, which can be flexibly embedded into the skeletons of various active molecules due to its unique structural characteristics, and has wide application value in drug research and development. R (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is a key chiral side chain fragment of the beta-adrenergic receptor blocker Landiolol. S (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane can be used to synthesize an important intermediate of Rivaroxaban, phthalimide glycidyl ester (CN109384773A), and can also be used to construct the chiral glycerol skeleton in the molecular structure of nitroglycerin (CN107383085A). The compound can be used as a stereoisomeric precursor to participate in the synthesis of various nucleoside antiviral drugs (such as Sofosbuvir) (CN108069933A; S R 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 prodrugs (EP2379540B1, JP2012512203A, EP2185550B1), and can also be used to synthesize vanillin and heliotropin aldehyde acetal type fragrances (JP2007302591A), and can also be used as a protecting group to synthesize the side chain of paclitaxel (WO2007043398A1). Nat. Commun. 2010, 21, 2619). Tetrahedron: Asymm.

[0003] The known reported synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is completed in a kettle reactor.

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

[0005]

[0006] ​​​CN101012217A uses boron trifluoride diethyl ether as a catalyst, and adds (… S (2,2-Dimethyl-1,3-dioxolane-4-ethylhexylene) and acetone react at 10–60 °C for 4–8 hours to yield (2,2-dimethyl-1,3-dioxolane-4-ethylhexylene). S The following is the synthetic route for methyl chloride via a batch reactor:

[0007]

[0008] However, the above methods have long reaction times and are prone to material spillage due to the violent temperature rise during the reaction, posing significant safety risks. In particular, the large amount of boron trifluoride diethyl ether used in the batch reaction, the violent exothermic reaction, and the slow heat dissipation pose a huge safety hazard to industrial production.

[0009] Therefore, there is an urgent need to develop a novel synthetic process for 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane to improve production efficiency and reaction safety. Summary of the Invention

[0010] Objective of this invention: To address the shortcomings of existing technologies, this invention provides a continuous flow synthesis method for 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane. This method offers mild conditions, high yield, high product quality, continuous, safe, and controllable process, high production efficiency, and is easily scalable for industrial production.

[0011] Technical solution: The objective of this invention is achieved through the following technical solution:

[0012] This invention provides a continuous flow synthesis method for 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane, comprising the following steps:

[0013] (1) Dissolve the reactant epichlorohydrin in an organic solvent to prepare component A; dissolve the Lewis acid in an organic solvent to prepare component B;

[0014] (2) After mixing component A and component B at the same flow rate, the mixture is fed into a continuous flow reactor. The temperature is controlled at 20~60℃. After 5~30 min, the reaction mixture flows out of the continuous flow reactor and is post-processed to obtain the product 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane.

[0015] The continuous flow synthesis method of this invention involves only one reaction step. A solution of epichlorohydrin and a Lewis acid solution are simultaneously mixed using metering pumps and reacted in a continuous flow reactor at 20–60°C to obtain the product.

[0016] Preferably, 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane comprises R - Configuration, S - There are three configurations: unidirectional, racemic, and semi-unidirectional.

[0017] Preferably, the reaction raw material is selected from S - epichlorohydrin, R - epichlorohydrin or racemic epichlorohydrin.

[0018] Preferably, in step (1), the organic solvent is selected from acetone.

[0019] Preferably, in step (1), the Lewis acid is selected from boron trifluoride etherate, ZnCl3, AlCl3, BCl3, triflic acid or difluorobenzenesulfonic acid.

[0020] Preferably, in step (1), the molar ratio of epichlorohydrin to Lewis acid is 1:0.01-1:0.3.

[0021] 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.

[0022] Preferably, in step (2), the residence time of component A and component B is 15-30min.

[0023] In the continuous flow chemical synthesis reaction of the present application, the residence time is a key parameter for determining the reaction conversion rate and selectivity, and the flow rate of each component is adjusted adaptively with the change of the residence time.

[0024] Preferably, the continuous flow reactor is a continuous flow coil reactor, and the material is FEP. Advantages

[0025] (1) The present application uses a continuous flow reactor to replace the traditional dangerous kettle reaction, avoids the accumulation of heat in the reaction, greatly reduces the safety risk, and has very high reaction safety. The continuous flow synthesis method of the present application has mild reaction conditions, short reaction time, high production yield and high product quality.

[0026] (2) The product prepared by the continuous flow synthesis method of the present application has stable quality and is very suitable for industrial production.

[0027] (3) The continuous flow synthesis method of the present application uses commercial equipment, which is cheap and easy to obtain, and is flexible and efficient to build. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 The synthesis process flow chart of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane of the present application is shown in the figure.

[0029] Figure 2 The synthesis process flow chart of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane of the present application is shown in the figure. RSynthetic process flow chart of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane.

[0030] Figure 3 For the present invention S Synthetic process flow chart of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane. DETAILED DESCRIPTION

[0031] The technical solutions of the present application will be described in detail below through specific examples, but the protection scope of the present application is not limited to the examples.

[0032] The specific techniques or conditions not specified in the examples are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. The reagents or instruments not specified by the manufacturer are all conventional products that can be purchased through regular channels.

[0033] The continuous flow reactor used in Examples 1-6 of the present application is a continuous flow coil reactor with a material of FEP, 0.8 mm I.D., and a coil volume V = 1.5 mL.

[0034] The purity of the compounds in Examples 1-7 of the present application is determined by a Shimadzu GC-2010 gas chromatograph.

[0035] Chromatographic column: DB-WAXETR (30 m x 0.32 mm x 1.0 μm).

[0036] Method: The initial column temperature is 50°C, maintained for 10 minutes, and then increased to 220°C at a rate of 20°C per minute, maintained for 5 minutes, with nitrogen as the carrier gas at a flow rate of 2.0 mL per minute, and a split ratio of 10:1; the injection volume is 1 μL, the injection port temperature is 220°C, and a hydrogen flame ionization detector is used with a detector temperature of 260°C.

[0037] Example 1 Synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane

[0038] The synthetic route is as follows:

[0039]

[0040] The synthetic process flow chart of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is shown in Figure 1 .

[0041] Synthetic method:

[0042] (1) Compound epichlorohydrin (compound 1, 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).

[0043] (2) Component A and component B were mixed at the same flow rate of 0.05 mL / min through a T-type mixer, then entered a continuous flow coil reactor kept at 50°C, and flowed out after 15 min of residence time. The effluent reaction mixture was quenched with saturated sodium bicarbonate solution, dried with anhydrous Na2SO4, suction filtered, and distilled under reduced pressure to obtain product 2. Continuous collection was performed for 180 min, and 1.22 g of product 2 was obtained with a yield of 90.04% and a purity of 99.133% (determined by GC).

[0044] 1 H NMR (400MHz, Chloroform-d) delta (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).

[0045] Reaction condition optimization for synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane

[0046] According to the synthesis method of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (product 2) in Example 1, referring to the parameters in Table 1, Table 2, Table 3, Table 4, and Table 5, and setting the remaining parameters as in Example 1, the optimized reaction conditions of product 2 were investigated.

[0047] Table 1 studies the effect of different Lewis acids on the reaction.

[0048] The results show that when the molar concentration of compound 1, the molar equivalent of Lewis acid, the temperature, and the residence time are kept constant, the purity of the product is better when boron trifluoride etherate is used as a catalyst than when other Lewis acids are used.

[0049] Table 1 Screening of Lewis acids

[0050]

[0051] Table 2 studies the influence of the molar equivalent of Lewis acid on the reaction.

[0052] The results show that when the molar concentration of compound 1, temperature, and residence time are kept constant, compound 1 cannot be completely reacted when the amount of boron trifluoride etherate is 0.05 equiv., and the purity of the product is only 66.938%. When the amount of boron trifluoride etherate is 0.2 equiv., the purity of the product increases to 99.015%, and when the amount of boron trifluoride etherate continues to increase, the purity of the product decreases to 95.107%.

[0053] Table 2 Influence of the equivalent of boron trifluoride etherate on the reaction

[0054]

[0055] Table 3 studies the influence of residence time on the reaction.

[0056] The results show that when the molar concentration of compound 1, temperature, and the molar equivalent of Lewis acid are kept constant, compound 1 cannot be completely reacted when the residence time is 5 min. When the residence time is 15 min, the purity of the product increases to 99.015%, and when the residence time continues to increase, the purity of the product decreases to 96.701%.

[0057] In the continuous flow chemical synthesis reaction of the present application, residence time is a key parameter for determining the conversion rate and selectivity of the reaction, and the flow rate of each component is adjusted adaptively with the change of residence time.

[0058] Table 3 Influence of residence time on the reaction

[0059]

[0060] Table 4 studies the influence of the molar concentration of compound 1 on the reaction.

[0061] The results show that when the flow rate of component A and component B is 0.05 mL / min, the residence time is 15 min, the reaction temperature is 50°C, and the molar equivalent of the catalyst is 0.2, the purity of the product is more than 99.00% when the molar concentration of compound 1 increases from 0.1 mol / L to 1.0 mol / L, and the purity of the product decreases to 95.580% when the molar concentration of compound 1 increases from 1.0 mol / L to 1.5 mol / L, and a side reaction occurs. Considering the problem of reaction flux, the condition of 1.0 mol / L is selected as the optimal concentration condition.

[0062] Table 4 Influence of the concentration of compound 1 on the reaction

[0063]

[0064] Table 5 studies the influence of temperature on the reaction.

[0065] The results showed that keeping the catalyst molar equivalent, the molar concentration of the feedstock, and the residence time constant, changing the reaction temperature, and increasing the temperature, is beneficial to improving the purity of the product.

[0066] Table 5 Effect of temperature on the reaction

[0067]

[0068] Example 3 R Synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane

[0069] R The synthetic process of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is shown in [link to synthetic process]. Figure 2 .

[0070] Synthesis method:

[0071] (1) Compound R - Epichlorohydrin (compound 3, 1.0 equiv.) was dissolved in acetone to prepare component A (1.0 M). Boron trifluoride diethyl ether (0.2 equiv.) was dissolved in acetone to prepare component B (0.2 M).

[0072] (2) Components A and B were mixed at the same flow rate of 0.05 mL / min using a T-type mixer and then fed into a continuous flow coil reactor kept at 50 °C. After a residence time of 15 min, the mixture was discharged. The collected reaction mixture was quenched with saturated sodium bicarbonate solution, dried with anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain product 4. After continuous collection for 180 min, 1.14 g of product 4 was obtained, with a yield of 84.13% and a purity of 99.081% (GC detection).

[0073] 1 H NMR (400 MHz, Chloroform-d) delta (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).

[0074] Example 4R Optimization of reaction conditions for synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane

[0075] The reaction conditions for product 4 were optimized according to the synthesis method of product 4 in Example 3, referring to the parameters in Table 6, Table 7, Table 8, Table 9, and the rest of the parameters were set as in Example 3.

[0076] Table 6 studies the effect of the molar equivalent of Lewis acid on the reaction.

[0077] The results show that when the molar concentration of compound 3, temperature, and residence time are kept constant, compound 3 cannot react completely when the amount of boron trifluoride etherate is 0.05 equiv. When the amount of boron trifluoride etherate is 0.2 equiv., the purity of the product increases to 99.461%, and when the amount of boron trifluoride etherate continues to increase, the purity of the product decreases to 95.845%.

[0078] Table 6 Effect of the equivalent of boron trifluoride etherate on the reaction

[0079]

[0080] Table 7 studies the effect of residence time on the reaction.

[0081] The results show that when the molar concentration of compound 3, temperature, and the molar equivalent of Lewis acid are kept constant, compound 3 cannot react completely when the residence time is 5 min. When the residence time is 15 min, the purity of the product increases to 99.461%, and when the residence time continues to increase, the purity of the product decreases to 96.620%.

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

[0083] Table 7 Effect of residence time on the reaction

[0084]

[0085] Table 8 studies the effect of the molar concentration of compound 3 on the reaction.

[0086] The results show that the flow rate of component A and component B is kept at 0.05 mL / min, the residence time is 15 min, the reaction temperature is 50°C, and the molar equivalent of the catalyst is 0.2 equiv. When the molar concentration of compound 3 is increased from 0.1 mol / L to 1.0 mol / L, the purity of the product reaches more than 99.00%, and when the molar concentration of compound 3 is increased from 1.0 mol / L to 1.5 mol / L, the purity of the product decreases to 95.889%, and the conversion is not complete. Considering the problem of reaction flux, the condition of 1.0 mol / L is selected as the optimal concentration condition.

[0087] Table 8 Effect of concentration of compound 3 on the reaction

[0088]

[0089] Table 9 studies the effect of temperature on the reaction.

[0090] The results show that the molar equivalent of the catalyst, the molar concentration of compound 3, and the residence time are kept unchanged, and the reaction temperature is changed. The increase of the temperature is beneficial to improve the purity of the product.

[0091] Table 9 Effect of temperature on the reaction

[0092]

[0093] Example 5 S Synthesis of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane

[0094] S The synthesis process flow chart of 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is shown in Figure 3 .

[0095] Synthesis method:

[0096] (1) Compound S Epichlorohydrin (compound 5, 1.0 equiv.) is dissolved in acetone to prepare component A (1.0 M). Boron trifluoride etherate (0.2 equiv.) is dissolved in acetone to prepare component B (0.2 M).

[0097] (2) Component A and component B are mixed at the same flow rate of 0.05 mL / min through a T-type mixer, then enter a continuous flow coil reactor kept at 50°C, and flow out after a residence time of 15 min. The reaction mixture flowing out is quenched with saturated sodium bicarbonate solution, dried with anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain product 6. Continuous collection is carried out for 180 min, and 1.33 g of product 6 is obtained with a yield of 98.15% and a GC purity of 99.269%.

[0098] 1 H NMR (400 MHz, Chloroform-d) delta (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).

[0099] Example 6 S Optimization of reaction conditions for the synthesis of -4- (chloromethyl) -2, 2-dimethyl-1, 3-dioxolane

[0100] According to the synthesis method of product 6 in Example 5, referring to the parameter settings in Table 10, Table 11, Table 12, Table 13, and the rest of the parameter settings are the same as Example 5, the optimized reaction conditions of product 6 are investigated.

[0101] Table 10 studies the effect of molar equivalents of Lewis acid on the reaction.

[0102] The results show that: keeping the molar concentration of compound 5, temperature, residence time constant, when the amount of boron trifluoride ether is 0.05 equiv., compound 5 cannot react completely. When the amount of boron trifluoride ether is 0.2 equiv., the purity of the product increases to 99.273%, and the increase of the amount of boron trifluoride ether will produce impurities.

[0103] Table 10 Effect of equivalents of boron trifluoride ether on the reaction

[0104]

[0105] Table 11 studies the effect of residence time on the reaction.

[0106] The results show that: keeping the molar concentration of compound 5, temperature, molar equivalents of Lewis acid constant, when the residence time is 5 min, compound 5 cannot react completely. When the residence time increases to 15 min, the purity of the product increases to 99.273%, and the increase of the residence time will reduce the purity of the product to 96.771%.

[0107] In the continuous flow chemical synthesis reaction of the present application, the residence time is a key parameter determining the conversion rate and selectivity of the reaction, and the flow rate of each component is adjusted adaptively with the change of the residence time.

[0108] Table 11 Effect of residence time on the reaction

[0109]

[0110] Table 12 Effect of the molar concentration of compound 5 on the reaction was studied.

[0111] The results show that: keeping the flow rate of component A and component B at 0.05 mL / min, the residence time at 15 min, and the reaction temperature at 50°C, and the molar equivalent of the catalyst at 0.2 equiv., when the molar concentration of compound 5 increases from 0.1 mol / L to 1.0 mol / L, the purity of the product reaches a maximum value; when the molar concentration of compound 5 increases from 1.0 mol / L to 1.5 mol / L, the purity of the product decreases to 96.771%, and the reaction cannot be completely converted.

[0112] Table 12 Effect of the concentration of compound 5 on the reaction

[0113]

[0114] Table 13 Effect of temperature on the reaction was studied.

[0115] The results show that: keeping the molar equivalent of the catalyst, the molar concentration of compound 5, and the residence time unchanged, and changing the reaction temperature, the increase of the temperature is beneficial to improve the purity of the reaction product.

[0116] Table 13 Effect of temperature on the reaction

[0117]

[0118] Example 7

[0119] (1) Compound 1 was prepared according to the following reaction scheme: S -Epoxy chloropropane (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).

[0120] (2) The continuous flow reactor was a continuous flow coil reactor with a material of FEP, 1.6 mm I.D., and the coil volume V of the continuous flow coil reactor was 12.0 mL.

[0121] (3) Component A and Component B were both at the same flow rate of 0.4 mL / min, mixed by T-type mixer, then entered the continuous flow coil reactor which was kept at 50°C, and flowed out after 15 min residence time. The reaction mixture was quenched by saturated sodium bicarbonate solution, dried by anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain product 6. The collection was continued for 60 min, and 5.08 g of product 6 was obtained with a yield of 98.38% and a GC purity of 99.215%.

[0122] The continuous flow synthesis method of the present application solves the scale-up effect of the traditional tank process, and verifies the excellent scale-up ability. At the same time, the continuous flow scale-up experiment further shows that the method has high efficiency and the potential for large-scale production.

[0123] As described above, although the present application has been shown and described with respect to certain preferred embodiments, it is to be understood that the application is not to be limited to the specific embodiments set forth above. Various changes in form and detail can be made without departing from the spirit and scope of the application as defined in the appended claims.

Claims

1. A continuous flow process for the synthesis of 4-(chloromethyl)-2,2-dimethyl- 1,3-dioxolane, characterized in that, The method comprises the following steps: (1) dissolving the reaction raw material epichlorohydrin in an organic solvent to prepare component A; dissolving a Lewis acid in an organic solvent to prepare component B; (2) mixing component A and component B at the same flow rate, then entering a continuous flow reactor, controlling the temperature at 50 DEG C, and staying for 15 min, then the reaction mixture flows out of the continuous flow reactor, and the product 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane is obtained through post-treatment; The reaction starting materials are selected from S - epichlorohydrin, R - epichlorohydrin or racemic epichlorohydrin; In step (1), the organic solvent is selected from acetone; In step (1), the Lewis acid is selected from boron trifluoride etherate; In step (1), the molar ratio of epichlorohydrin to Lewis acid is 1:0.2; In step (1), the molar concentration of component A is 0.5, 0.7, 1.0 M; and the molar concentration of component B is 0.1-0.2 M; The continuous flow reactor is a continuous flow coil reactor, and the material thereof is FEP.

2. The continuous flow synthesis process of claim 1, wherein, 4-(chloromethyl)-2,2-dimethyl-1-dioxolane includes R - configuration, S - configuration or racemic three configurations.

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