Purification method of spiropyran derivative optically active additive

Abstract

The present invention relates to a method for purifying a spiropyran derivative optically active additive, belonging to the field of photochromic materials. A spiropyran derivative optically active additive A containing an impurity Z is reacted with maleic anhydride in an organic solvent and in the presence of a base, followed by quenching with water, and filtering and beating to obtain the spiropyran derivative optically active additive A. The method utilizes the different steric hindrances between the impurity alcohol Z and the product quaternary alcohol A to react the reaction mixture with maleic anhydride. The impurity Z reacts with the maleic anhydride to generate an organic salt ZZ, while the target molecule A remains unaffected. After quenching the reaction, the impurity Z in the reaction mixture is removed by filtration, thereby avoiding the traditional column chromatography process, greatly simplifying the operation, and saving time and cost.

Description

Technical Field

[0001] The invention relates to a method for purifying a spiropyran derivative optically active additive, and belongs to the field of photochromic materials. Background Art

[0002] Photochromism refers to the reversible phenomenon in which certain compounds change color rapidly when exposed to light and then revert to their original color when the light is removed and the compound is placed in darkness. Photochromism has a history of over a century. In 1904, it was discovered that succinate esters condense with aromatic aldehydes or ketones to produce products called fulgides, which exhibit optical color change. At the time, this was extensively studied as a component of dye synthesis. The first successful commercial application was in the 1960s, when American Corning scientists Amistead and Stooky first discovered the reversible photochromic properties of silver halide glass. Subsequently, extensive research into its mechanism and applications led to the development of photochromic glasses.

[0003] Due to its high cost and complex processing technology, it is not suitable for the production of large-scale photochromic glass, limiting its commercial application in the architectural field. Since then, the application focus of silver halide photochromism has shifted to inexpensive and lightweight polymer-based materials. These organic photochromic materials have advantages such as high resolution, direct display, and repeated use. They have great potential applications in modern science and technology and daily life, such as photosensitive catalysts, anti-counterfeiting materials, self-developing cameras, various radiation dosimeters and protective materials, anti-counterfeiting and decorative materials, computer memory components, coatings, cosmetics, molecular switches, polymer lens materials, etc. At the same time, the photochromism of organic systems is often accompanied by many processes related to photochemical reactions, which lead to certain changes in molecular structure, including valence isomerism, cis-trans isomerism, bond cleavage, polymerization, oxidation-reduction, and pericyclic reactions. These materials also have important applications in the field of photochemistry.

[0004] Spiropyran compounds It has good performance, simple synthesis and wide application, but its industrial production involves the reaction from pyrone Q to quaternary alcohol A after addition.

[0005]

[0006] Literature (J. Am. Soc. Chem. 2006, 128, 9998-9999) reported that the addition reaction of strong bases such as Grignard reagents or alkyllithium to aromatic ketones is accompanied by the formation of a competitive reduction byproduct, impurity Z, due to β-hydrogen transfer from the alkyl group R5. The same problem was observed during repeated preparations of the target molecule A. Whether using Grignard reagent or alkyllithium addition, or supplementing with various proportions of Lewis acid, the byproduct impurity Z was unavoidable. Because the optically active additive and the corresponding reduction byproduct have minimal structural differences and similar properties, column chromatography purification is required, resulting in low yields and significantly increased production costs.

[0007] With the widespread use of pyran optically active additives in photosensitive catalysts, cosmetics, photochromic glass, and even photochromic glasses, they are expected to gain increasing market favor and possess enormous market potential. Therefore, optimizing existing production processes and designing simpler, more feasible large-scale production processes to increase yields and reduce costs are of great practical significance and economic value. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to remove a small amount of impurity Z from an optically active additive A derived from a spiropyran derivative. By utilizing the different steric hindrances between the tertiary alcohol impurity Z and the quaternary alcohol product A, the reaction mixture is reacted with maleic anhydride in the presence of triethylamine as an acidifying agent to produce an organic salt ZZ, while the target molecule A remains unaffected. The impurity Z is then removed from the reaction mixture by quenching and filtration, avoiding the traditional column chromatography step, greatly simplifying the operation, and saving time and cost.

[0009] The efficient purification method of the optically active additive of spiropyran derivatives of the present invention is represented by the following reaction equation:

[0010]

[0011] Wherein: R1 and R2 are each independently selected from C1-C4 alkyl (preferably methyl); R3 and R4 are each independently selected from C1-C3 alkoxy (preferably methoxy); R5 is selected from C4-C8 alkyl (preferably n-pentyl).

[0012] The efficient purification method of the optically active spiropyran derivative additive of the present invention comprises the following steps: reacting a spiropyran derivative optically active additive A containing impurity Z with maleic anhydride in an organic solvent and in the presence of a base, quenching with water, filtering to obtain a crude product, and slurrying to obtain the optically active spiropyran derivative additive A.

[0013] Furthermore, in the above technical solution, the organic solvent is selected from DMF, DMA, NMP, DMSO and the like.

[0014] Furthermore, in the above technical solution, the molar ratio of impurity Z to the spiropyran derivative optically active additive A is 0.01-0.50:1.

[0015] Furthermore, in the above technical solution, the base is selected from triethylamine, diisopropylethylamine, pyridine and the like.

[0016] Furthermore, in the above technical solution, the molar ratio of the spiropyran derivative optically active additive A, maleic anhydride and base is 1:0.5-1.0:1-1.5.

[0017] Furthermore, in the above technical solution, the pulping solvent is selected from methanol, ethanol or isopropanol.

[0018] From the structural formulas of A and Z, we can see that the polarity difference between the two is small. Separation by column chromatography requires the consumption of a large amount of silica gel and eluent, which is time-consuming and labor-intensive. Industrial production is also not feasible.

[0019] By utilizing the steric effect of tertiary alcohol impurity Z and quaternary alcohol A as a breakthrough, the mixture containing impurities is reacted with maleic anhydride. Since quaternary alcohol A has large steric hindrance and does not react, the impurity ZZ that can react with the tertiary alcohol impurity Z is converted into water-soluble impurity and removed.

[0020] Furthermore, in the above technical solution, the optically active additive A is prepared by the following method:

[0021]

[0022] Compound Q undergoes an addition reaction with an alkyl magnesium halide or an alkyl lithium in tetrahydrofuran or toluene solvent at low temperature to obtain a reaction mixture A+Z, wherein: the target molecule is A and the impurity is Z.

[0023] The positive progress of the present invention is that: by researching literature, a simple new method for removing the reduced impurity Z in pyran optically active additives has been successfully developed, avoiding the column chromatography method of the traditional process, greatly improving production efficiency, saving costs, and enhancing the market competitiveness of such products. DETAILED DESCRIPTION

[0024] The present invention is further illustrated by the following examples, but the invention is not limited to the scope of these examples. Experimental methods and conditions not specified in the following examples were performed according to conventional methods and conditions, or according to the product specifications. The following examples are based on R1=R2=Me; R3=R4=OMe; and R5=n-pentyl. All reagents and raw materials used in the present invention are commercially available.

[0025] Example 1

[0026] Step A: Preparation of pyran derivative precursor ketone Q

[0027] According to the literature steps (Journal of Chemical Research 2018, 42 , 447-452), 101.5 g of pyran derivative precursor ketone Q (R1=R2=Me; R3=R4=OMe) was synthesized as a light red powdery solid with a yield of 75%. 1 HNMR (400 MHz, CDCl3) d 8.17 (d, J = 9.6 Hz, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.66(d, J = 9.6 Hz, 1H) 7.57 (d, J = 2.4 Hz, 1H), 7.43 (m, 4H), 7.18 (m, 2H), 6.88 (d, J= 8.8 Hz, 4H), 6.30 (d, J = 11.2Hz, 1H), 3.97 (s, 3H), 3.87 (s,3H), 3.79 (s, 6H); LC-MS: 525.2 (M+1).

[0028] Step B: Preparation of optically active additive A (R5 is n-pentyl)

[0029] Pyran derivative precursor ketone Q (20.0 g, 38.2 mmol) was added to a 1L three-necked flask, followed by 200 mL of dry tetrahydrofuran. The mixture was cooled to below -50°C under nitrogen protection, and 2M n-pentylmagnesium chloride tetrahydrofuran solution (100 mL, 200 mmol) was added dropwise. After the addition was complete, the mixture was stirred and kept warm for 1 hour. TLC detected that the raw material had completely disappeared, and the reaction was stopped. The temperature was raised to 0°C, and 300 mL of ammonium chloride aqueous solution was slowly added dropwise, followed by 3M HCl solution, until the pH was 3~4. The organic layer was separated, and the aqueous layer was extracted once with 200 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a crude product. Under the optimal separation conditions, the product AR f =0.33, impurity ZR f =0.32 (dichloromethane / petroleum ether = 1 / 3), with a ratio of approximately 3:1. 400g of 200-300 mesh silica gel was added, and dichloromethane / n-heptane was used as the mobile phase for separation and purification. 6.5g of pure product A and 6.1g of a mixture of A and Z were obtained. Further column chromatography of the mixture afforded 3.1g of pure product. A second column chromatography yielded 9.6g of pure product A, for a yield of 42.2%. Confirmation data for product A are as follows:1 HNMR (400 MHz, CDCl3) d 8.33 (d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 7.84 (d, J = 6.8Hz, 1H), 7.45-7.25 (m, 7 H), 7.11 (d, J = 7.2 Hz, 1H), 6.83(d, J = 8.8 Hz,2H), 6.69 (d, J =8.8 Hz, 2H), 6.11 (d, J= 10.0 Hz, 1H), 3.74 (s, 3H), 3.63(s, 3H), 2.47 (s, 3H), 2.36 (s, 3H), 2.25 (m, 2H), 0.85 (m, 4H), 0.6 (m, 3H), 0.35 (m, 2H); LC-MS: 597.1 (M+1).

[0030] Example 2

[0031] Step A: Same as Example 1.

[0032] Step B: Preparation of optically active additive A (R5 is n-pentyl)

[0033] Pyran derivative precursor ketone Q (20.0 g, 38.2 mmol) was added to a 1L three-necked flask, followed by 200 mL of dry tetrahydrofuran. The mixture was cooled to below -50°C under nitrogen protection, and 1.6 M n-pentyllithium hexane solution (100 ml, 160 mmol, 4.2 eq) was added dropwise. After the addition was complete, the mixture was stirred and kept warm for 1 hour. TLC showed that the starting material had completely disappeared, and the reaction was stopped. 300 mL of ammonium chloride aqueous solution was slowly added dropwise, followed by 3M HCl solution until the pH reached 3-4. The organic layer was separated, and the aqueous layer was extracted with 200 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a crude product. Under the optimal separation conditions, the product AR f =0.33, impurity ZR f =0.32 (dichloromethane / petroleum ether = 1 / 3) in a ratio of approximately 3:1. 400 g of 200-300 mesh silica gel was added, and dichloromethane / n-heptane was used as the mobile phase for separation and purification. 6.0 g of pure product A and 6.9 g of a mixture of A and Z were obtained. The mixture was further subjected to column chromatography to obtain 3.0 g of pure product. A second column chromatography yielded 9.0 g of pure product A, with a yield of 39.6%.

[0034] Example 3

[0035] Step A: Same as Example 1.

[0036] Step B: Add the pyran derivative precursor ketone Q (20.0 g, 38.2 mmol) from the previous step to a 1L three-necked flask, followed by 200 mL of dry tetrahydrofuran. Cool the mixture to below -50°C under nitrogen protection, and begin adding a 2M solution of n-pentylmagnesium chloride in tetrahydrofuran (100 mL, 200 mmol, 5.26 eq) dropwise. Once the addition is complete, continue stirring and incubating for 1 hour. Stop the reaction by TLC, check that the starting material has completely disappeared, and raise the temperature to 0°C. Slowly add 300 mL of ammonium chloride aqueous solution, followed by 3M HCl solution, until the pH reaches 3-4. Separate the organic layer, extract the aqueous layer with 200 mL of ethyl acetate, combine the organic phases, wash with saturated sodium bicarbonate solution and saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain the crude product. Under optimal separation conditions, the product AR f =0.33, impurity ZR f =0.32 (dichloromethane / petroleum ether=1 / 3), the ratio between the two is about 3:1.

[0037] The crude product was dissolved in 100 mL of DMF. Then, 4.0 g (39.6 mmol, 1.04 eq) of triethylamine and 2.5 g (21.55 mmol, 0.56 eq) of solid maleic anhydride were added. The mixture was allowed to react at room temperature for 1 hour. TLC indicated that the impurities had completely disappeared, while the target molecule remained unchanged. The reaction was stopped.

[0038] 200 mL of purified water was added dropwise to the reaction system, and solids gradually precipitated. Filtering afforded a filter cake. The filtrate contained impurity ZZ. The filter cake was dissolved in DCM, filtered, concentrated to dryness, and slurried with methanol. The mixture was dried at 50°C to afford 15.3 g of an off-white solid, A, in a 67.5% yield.

[0039] The above embodiments illustrate the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions merely illustrate the principles of the present invention. Various changes and improvements may be made to the present invention without departing from the scope of the present invention, and all such changes and improvements fall within the scope of protection of the present invention.

Claims

1. A method for purifying an optically active additive of a spiropyran derivative, characterized in that: The method comprises the following steps: reacting a spiropyran derivative optically active additive A containing impurity Z with maleic anhydride in an organic solvent and in the presence of a base, quenching with water, filtering to obtain a crude product, and beating the product to obtain the spiropyran derivative optically active additive A. The reaction equation is as follows: ; Wherein: R1 and R2 are each independently selected from C1-C4 alkyl; R3 and R4 are each independently selected from C1-C3 alkoxy; R5 is selected from C4-C8 alkyl.

2. The method for purifying the optically active additive of spiropyran derivative according to claim 1, characterized in that: The organic solvent is selected from DMF, DMA, NMP or DMSO.

3. The method for purifying the optically active additive of spiropyran derivative according to claim 1, characterized in that: The base is selected from triethylamine, diisopropylethylamine or pyridine.

4. The method for purifying the optically active additive of spiropyran derivative according to claim 1, characterized in that: The molar ratio of the impurity Z to the spiropyran derivative optically active additive A is 0.01-0.5:

1.

5. The method for purifying the optically active additive of spiropyran derivative according to claim 1, characterized in that: The molar ratio of the spiropyran derivative optically active additive A, maleic anhydride and base is 1:0.5-1.0:1.0-1.

5.

6. The method for purifying the optically active additive of spiropyran derivative according to claim 1, characterized in that: Methanol, ethanol or isopropanol solvent is used for pulping.

7. The method for purifying the optically active additive of spiropyran derivative according to claim 1, characterized in that: Compound Q undergoes an addition reaction with an alkyl magnesium halide or an alkyl lithium in tetrahydrofuran or toluene solvent at low temperature to obtain a reaction mixture A+Z, wherein: the target molecule is A and the impurity is Z; the reaction equation is expressed as follows: ; Wherein: R5 is selected from C4-C8 alkyl.

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