Synthesis method of hydroxyl pinacolone retinoate

Abstract

The invention discloses a synthesis method of hydroxyl pinacolone retinoate, and belongs to the technical field of organic synthesis.The synthesis method comprises the steps that firstly, retinoic acid and an acid binding agent are mixed and added into an organic solvent, stirring is conducted at the temperature of 50 DEG C till clarification is achieved, a material A is obtained, then 1-bromo pinacolone is dissolved with the organic solvent, and a material B is obtained; and adding the material A and the material B into a tubular reactor, reacting the mixed material for 50-120s at 50-80 DEG C, washing the reaction liquid with water, concentrating, adding a pulping solvent for pulping, and finally adding the pulping product into a crystallization solvent for recrystallization to obtain the hydroxyl pinacolone retinoate. According to the present invention, the tubular reactor is adopted to synthesize the hydroxyl pinacolone retinoate, the efficient mass and heat transfer effect enables the retinoic acid to be efficiently converted into the hydroxyl pinacolone retinoate during the reaction process, the use of phosphorus trichloride is avoided during the synthesis process, and the residue of the retinoic acid is effectively reduced through the multi-solvent mixing pulping and recrystallization;

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to hydroxypinazone retinate, specifically a method for synthesizing hydroxypinazone retinate. Background Technology

[0002] Hydroxypinazone retinyl ester (HPR) is a retinol derivative that regulates the metabolism of the epidermis and stratum corneum. It can delay aging, reduce sebum secretion, and lighten epidermal pigmentation, thus preventing skin aging, acne, and whitening / lightening dark spots. Compared to retinol, HPR is less irritating, more stable, and does not require enzymatic hydrolysis to take effect, making it a core active ingredient for gentle anti-aging and widely added to various cosmetics.

[0003] Currently, the main raw materials for the synthesis of hydroxypinazone retinate are mostly prepared by the condensation reaction of retinoic acid and monohalopinane. The factory production generally adopts a "two-step, three-reactor" mode, that is, first, the acyl chloride is prepared in reactor A, then the material is transferred to reactor B for esterification, and finally transferred to reactor C for recrystallization. However, frequent material transfer not only leads to solvent evaporation loss and hydrolysis of intermediates, but also increases the risk of personnel exposure to the polluted environment.

[0004] Chinese invention patent announcement CN114436924B discloses a method for synthesizing hydroxypinazone retinate. The method involves a two-step reaction in the same reactor, using phosphorus trichloride to convert retinoic acid into acyl chloride, followed by esterification with 1-hydroxypinazone, minimizing material transfer and intermediate purification.

[0005] However, the above method uses phosphorus trichloride, which is highly toxic and corrosive, requires sophisticated equipment, and generates a large amount of phosphorus-containing wastewater. Furthermore, it still uses an intermittent batch reactor, which has poor mass and heat transfer efficiency, resulting in high levels of retinoic acid residue, which is detrimental to subsequent refining and purification. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing hydroxypinazone retinate. The method uses a tubular reactor to synthesize hydroxypinazone retinate. The efficient mass and heat transfer allows retinoic acid to be converted into hydroxypinazone retinate in a high-efficiency manner during the reaction. Furthermore, the synthesis process avoids the use of phosphorus trichloride. At the same time, through multi-solvent mixing, pulping, and recrystallization, the residual amount of retinoic acid is extremely low, which facilitates subsequent purification.

[0007] The objective of this invention can be achieved through the following technical solutions: A method for synthesizing hydroxypinazone retinate, comprising the following steps: Step 1: Mix retinoic acid and acid-binding agent and add to organic solvent. Stir at 50°C until clear to obtain material A.

[0008] Step 2: Dissolve 1-bromopinazone in an organic solvent to obtain material B.

[0009] Step 3: Add material A from Step 1 and material B from Step 2 into a tubular reactor. React the mixture at 50-80℃ for 50-120s. Wash the reaction solution with water and concentrate it. Then add a pulping solvent to the concentrated product and pulp at 0-10℃ and 200-500rpm for 30-60min. After pulping, add the pulping product to a crystallization solvent for recrystallization and collect the crystals to obtain hydroxypinazone retinate.

[0010] The reaction process is as follows:

[0011] In this context, "A" represents retinoic acid and "B" represents 1-bromopinazone.

[0012] Furthermore, the molar ratio of retinoic acid and retinoic acid binder in material A is 1:3-5.

[0013] Furthermore, the ratio of retinoic acid to organic solvent in material A is 1 mol: 1.5 kg.

[0014] Furthermore, the ratio of 1-bromopinazone to organic solvent in material B is 1-2 mol: 0.3 kg.

[0015] Furthermore, the acid-binding agent is any one or more of DBU, triethylamine, and pyridine in any ratio.

[0016] Furthermore, the organic solvent is any one of toluene, n-hexane, and N-methylpyrrolidone.

[0017] Furthermore, the molar ratio of retinoic acid to 1-bromopinazone in the mixture is 1:1-2, preferably 1:1.5.

[0018] Furthermore, the ratio of crystallization solvent, pulping solvent, and retinoic acid is 5 mL: 1 mL: 1 g.

[0019] Furthermore, the crystallization solvent is anhydrous methanol or anhydrous ethanol.

[0020] Furthermore, the pulping solvent is any one or more of tetrahydrofuran, isopropanol, and n-heptane in any ratio, preferably isopropanol and n-heptane mixed in a volume ratio of 6:4.

[0021] The beneficial effects of this invention are: 1. The synthesis method of hydroxypinazone retinate of the present invention is simple to operate, the reaction is fast and safe, it does not involve expensive catalysts and complicated post-processing, the reagents are cheap and readily available, and the production efficiency and product purity are improved by operations such as pulping and recrystallization.

[0022] 2. The synthesis method of hydroxypinazone retinate of the present invention uses 1-bromopinazone for direct esterification, avoiding the use of highly toxic reagents such as phosphorus trichloride and the resulting waste problems. It solves the problem that the process cannot be continuously scaled up in the presence of high-salt and high-phosphorus wastewater, and greatly meets the needs of industrial scale-up production.

[0023] 3. The synthesis method of this invention uses a continuous flow tubular reactor instead of a traditional batch reactor, enabling continuous production. In the presence of an acid-binding agent, a conversion rate of 99.5% can be achieved within 90 seconds, with a total yield of 80%, proving that the phosphorus-free system can still achieve efficient esterification. Furthermore, the efficient mass and heat transfer effect of the tubular reactor helps to convert hydroxypinazone retinate and reduce the generation of by-products. Combined with multi-solvent mixing, pulping, and recrystallization operations, the residual retinoic acid is strictly controlled (no residual retinoic acid was detected at the detection limit of 10 ppm), facilitating further purification. Attached Figure Description

[0024] Figure 1 The 1H NMR spectrum of hydroxypinazone retinate in Example 5 of this invention; Figure 2 This is the liquid chromatography-mass spectrum of hydroxypinazone retinate in Example 5 of the present invention; Figure 3 This is a chromatogram of the retinoic acid control in the retinoic acid residue detection test of this invention; Figure 4 This is a chromatogram of hydroxypinazone retinate in Example 4 of the present invention. Detailed Implementation

[0025] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0026] Example 1: This example provides a method for synthesizing hydroxypinazone retinate, the steps of which are as follows: S1: Mix 300g of retinoic acid (1.0mol) and 1665.3g of acid-binding agent DBU (5.0mol) into 1.5kg of toluene (i.e., organic solvent), heat to 50℃, stir and mix until clear, and transfer to raw material tank A to obtain material A.

[0027] S2: Dissolve 268.2g of 1-bromopinazone (1.5mol) in 0.3kg of toluene (i.e., organic solvent), stir and mix evenly, and transfer to raw material tank B to obtain material B.

[0028] S3: Material A and material B were pumped into a tubular reactor using a constant flow pump. The reaction temperature was 50℃ and the residence time was 50s. The reaction liquid was collected at the receiving port. HPLC analysis showed that the retinoic acid conversion rate was 66.53%. The reaction liquid was washed with water and concentrated to obtain a dark yellow solid (i.e., the concentrated product). The obtained solid was added to 300mL of a slurry solvent (tetrahydrofuran) and slurried at 0℃ and 200rpm for 30min. After slurrying, the slurry product was added to 1.5L of anhydrous ethanol for recrystallization. The crystals were collected to obtain hydroxypinazone retinate with a purity of 97.25% and a yield of 49.23%.

[0029] Example 2: This example provides a method for synthesizing hydroxypinazone retinate, the steps of which are as follows: S1: Mix 300g of retinoic acid (1.0mol) and 303.1g of triethylamine (3.0mol), an acid-binding agent, and add them to 1.5kg of toluene (i.e., organic solvent). Heat to 50℃, stir and mix until clear, and transfer to raw material tank A to obtain material A.

[0030] S2: Dissolve 268.5g of 1-bromopinazone (1.5mol) in 0.3kg of toluene (i.e., organic solvent), stir and mix evenly, and transfer to raw material tank B to obtain material B.

[0031] S3: Materials A and B are pumped into a tubular reactor using constant flow pumps. The reaction temperature is 80℃ and the residence time is 120s. The reaction liquid is collected at the receiving port. HPLC analysis shows that the retinoic acid conversion rate is 82.5%. The reaction liquid is washed with water and concentrated to obtain a dark yellow solid (i.e., the concentrated product). 300mL of pulping solvent (isopropanol) is added, and the mixture is pulped at 10℃ and 350rpm for 45min. After pulping, the pulping product is added to 1.5L of anhydrous ethanol for recrystallization. The crystals are collected to obtain hydroxypinazone retinate with a purity of 98.43% and a yield of 67.7%.

[0032] Example 3: This example provides a method for synthesizing hydroxypinazone retinate, the steps of which are as follows: S1: Mix 300g of retinoic acid (1.0mol) and 237g of acid-binding agent pyridine (3.0mol) into 1.5kg of toluene (i.e., organic solvent), heat to 50℃, stir and mix until clear, and transfer to raw material tank A to obtain material A.

[0033] S2: Dissolve 179g of 1-bromopinazone (1mol) in 0.3kg of toluene (i.e., organic solvent), stir and mix evenly, and transfer to raw material tank B to obtain material B.

[0034] S3: Materials A and B are pumped into a tubular reactor using constant flow pumps. The reaction temperature is 50℃ and the residence time is 90s. The reaction liquid is collected at the receiving port. HPLC analysis shows that the retinoic acid conversion rate is 89.5%. The reaction liquid is washed with water and concentrated to obtain a dark yellow solid (i.e., the concentrated product). 300mL of a slurrying solvent (n-heptane) is added, and the mixture is slurried at 5℃ and 300rpm for 60min. After slurrying, the slurry product is added to 1.5L of anhydrous ethanol for recrystallization. The crystals are collected to obtain hydroxypinazone retinate with a purity of 98.82% and a yield of 72.5%.

[0035] Example 4: This example provides a method for synthesizing hydroxypinazone retinate, the steps of which are as follows: S1: Mix 300g retinoic acid (1.0mol) and 237g acid-binding agent pyridine (3.0mol) into 1.5kg n-hexane (i.e. organic solvent), heat to 50℃, stir and mix until clear, transfer to raw material tank A to obtain material A.

[0036] S2: Dissolve 358g of 1-bromopinazone (2mol) in 0.3kg of n-hexane (i.e., organic solvent), stir and mix evenly, and transfer to raw material tank B to obtain material B.

[0037] S3: Materials A and B are pumped into a tubular reactor using constant flow pumps. The reaction temperature is 80℃ and the residence time is 120s. The reaction liquid is collected at the receiving port. HPLC analysis shows that the retinoic acid conversion rate is 93.62%. The reaction liquid is washed with water and concentrated to obtain a dark yellow solid (i.e., the concentrated product). 300mL of a slurry solvent (isopropanol and n-heptane in a volume ratio of 6:4) is added, and the mixture is slurried at 5℃ and 500rpm for 45min. After slurrying, the slurry product is recrystallized in 1.5L of anhydrous ethanol. The crystals are collected to obtain hydroxypinazone retinate with a purity of 99.60% and a yield of 79.58%.

[0038] Example 5: This example provides a method for synthesizing hydroxypinazone retinate, the steps of which are as follows: S1: Mix 300g retinoic acid (1.0mol) and 237g acid-binding agent pyridine (3.0mol) into 1.5kg N-methylpyrrolidone (i.e. organic solvent), heat to 50℃, stir and mix until clear, transfer to raw material tank A to obtain material A.

[0039] S2: Dissolve 268.5g of 1-bromopinazone (1.5mol) in 0.3kg of N-methylpyrrolidone (i.e., organic solvent), stir and mix evenly, and transfer to raw material tank B to obtain material B.

[0040] S3: Materials A and B are pumped into a tubular reactor using constant flow pumps. The reaction temperature is 60℃ and the residence time is 90s. The reaction liquid is collected at the receiving port. HPLC analysis shows that the retinoic acid conversion rate is 98.46%. The reaction liquid is washed with water and concentrated to obtain a dark yellow solid (i.e., the concentrated product). 300mL of a slurry solvent (isopropanol and n-heptane in a volume ratio of 6:4) is added, and the mixture is slurried at 5℃ and 300rpm for 45min. After slurrying, the slurry product is added to 1.5L of anhydrous ethanol for recrystallization. The crystals are collected to obtain hydroxypinazone retinate with a purity of 99.73% and a yield of 80.71%.

[0041] Example 6: This example provides a method for synthesizing hydroxypinazone retinate, the steps of which are as follows: S1: Mix 300g retinoic acid (1.0mol) and 237g acid-binding agent pyridine (3.0mol) into 1.5kg n-hexane (i.e. organic solvent), heat to 50℃, stir and mix until clear, transfer to raw material tank A to obtain material A.

[0042] S2: Dissolve 268.5g of 1-bromopinazone (1.5mol) in 0.3kg of n-hexane (i.e., organic solvent), stir and mix evenly, and transfer to raw material tank B to obtain material B.

[0043] S3: Materials A and B are pumped into a tubular reactor using constant flow pumps. The reaction temperature is 70℃ and the residence time is 100s. The reaction liquid is collected at the receiving port. HPLC analysis shows that the retinoic acid conversion rate is 89.5%. The reaction liquid is washed with water and concentrated to obtain a dark yellow solid (i.e., the concentrated product). 300mL of a slurry solvent (isopropanol and n-heptane in a volume ratio of 6:4) is added, and the mixture is slurried at 5℃ and 350rpm for 50min. After slurrying, the slurry product is added to 1.5L of anhydrous ethanol for recrystallization. The crystals are collected to obtain hydroxypinazone retinate with a purity of 99.54% and a yield of 72.8%.

[0044] Example 7: This example provides a method for synthesizing hydroxypinazone retinate. The difference from Example 6 is that isopropanol is used as the pulping solvent in step S3. The final product is hydroxypinazone retinate with a purity of 98.60% and a yield of 71.42%.

[0045] In the above embodiments, anhydrous methanol can also be used as a solvent for recrystallization in addition to anhydrous ethanol. The tubular reactor is made of stainless steel with a polytetrafluoroethylene liner, has an inner diameter of 5 mm and a length of 2 m. In practical industrial applications, the suitable inner diameter range is 5-20 mm, and the suitable length range is 2-50 m.

[0046] As can be seen from the above examples, the purity of hydroxypinazone retinate in Example 5 was the highest, reaching 99.73%, and its 1H NMR spectrum is shown below. Figure 1 As shown, the liquid phase mass spectrum is as follows: Figure 2 As shown.

[0047] Commercially available analytical grade retinoic acid was used as a control, and hydroxypinazone retinate from Example 4 was used as the test sample to detect retinoic acid residues. The detection limit was 10 ppm.

[0048] The chromatogram of retinoic acid as a reference is as follows: Figure 3 As shown, the retinoic acid eluted at 13.302 min. The chromatogram of hydroxypinazone retinate in Example 4 is shown below. Figure 4 As shown, there are no obvious peaks at 11.773 min, 14.013 min, and 13.302 min, indicating that retinoic acid residues were not detected at the detection limit of 10 ppm.

[0049] Analysis of the data from Examples 1-7 and Comparative Example 1 revealed that the products from Examples 4-6 had high purity, all >99.5%, reaching a high level in the industry. The only difference between Example 7 and Example 6 was that the pulping solvent was replaced by a single isopropanol instead of a multi-solvent solvent. Combined with the purity data of the products from Examples 1-3, it indicates that the multi-solvent pulping solvent can improve the purity of the hydroxypinazone retinate product. This may be because the mixture of isopropanol and n-heptane in a 6:4 ratio can better dissolve impurities during the pulping process, reducing co-crystallization impurities and thus improving the purity of the crystalline product.

[0050] Comparative Example 1: The difference from Example 4 is that in step S3, material A and material B were pumped into a batch reactor for reaction. The reaction was stopped after 2 hours. HPLC analysis showed that the conversion rate of retinoic acid was 83.62%, the purity of hydroxypinazone retinate was 97.90%, the yield was 72.15%, and the residual retinoic acid was 285 ppm.

[0051] Comparative Example 1 uses a batch reactor, which requires a longer reaction time (2h > 120s) compared to the tubular reactor used in Example 4. This indicates that the excellent mass and heat transfer effect of the tubular reactor can achieve the reaction in a residence time of seconds (120s). In Comparative Example 1, the conversion rate of retinoic acid decreased, and the yield and purity of hydroxypinazone retinate also decreased. The retinoic acid residue also increased compared to Example 4. This may be because the shorter residence time can reduce the occurrence of side reactions. Combined with pulping and recrystallization operations, it synergistically reduces the retinoic acid residue and improves the purity of the product.

[0052] It should be noted that, in this document, terms such as “comprising,” “including,” or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0053] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention.

Claims

1. A method for synthesizing hydroxypinazone retinate, characterized in that, The steps are as follows: Step 1: Mix retinoic acid and acid-binding agent and add to organic solvent, stir at 50°C until clear, to obtain material A; Step 2: Dissolve 1-bromopinazone in an organic solvent to obtain material B; Step 3: Add material A from Step 1 and material B from Step 2 into a tubular reactor. React the mixture at 50-80℃ for 50-120s. Wash the reaction solution with water and concentrate it. Then add a pulping solvent to the concentrated product and pulp at 0-10℃ and 200-500rpm for 30-60min. Add the pulping product to a crystallization solvent for recrystallization and collect the crystals to obtain hydroxypinazone retinate. The molar ratio of retinoic acid to 1-bromopinazone in the mixture is 1:1-2.

2. The method for synthesizing hydroxypinazone retinate according to claim 1, characterized in that, The molar ratio of retinoic acid to 1-bromopinazone in the mixture is 1:1.

5.

3. The method for synthesizing hydroxypinazone retinate according to claim 1, characterized in that, The molar ratio of retinoic acid and retinoic acid binder in material A is 1:3-5.

4. The method for synthesizing hydroxypinazone retinate according to claim 3, characterized in that, The acid-binding agent is any one or more of DBU, triethylamine, and pyridine in any ratio.

5. The method for synthesizing hydroxypinazone retinate according to claim 1, characterized in that, The ratio of retinoic acid to organic solvent in material A is 1 mol: 1.5 kg; the ratio of 1-bromopinazone to organic solvent in material B is 1-2 mol: 0.3 kg.

6. The method for synthesizing hydroxypinazone retinate according to claim 5, characterized in that, The organic solvent is any one of toluene, n-hexane, and N-methylpyrrolidone.

7. The method for synthesizing hydroxypinazone retinate according to claim 1, characterized in that, The ratio of the crystallization solvent, the pulping solvent, and the retinoic acid is 5 mL: 1 mL: 1 g.

8. The method for synthesizing hydroxypinazone retinate according to claim 7, characterized in that, The crystallization solvent is anhydrous methanol or anhydrous ethanol.

9. The method for synthesizing hydroxypinazone retinate according to claim 7, characterized in that, The pulping solvent is any one or more of tetrahydrofuran, isopropanol, and n-heptane in any ratio.

10. The method for synthesizing hydroxypinazone retinate according to claim 9, characterized in that, The pulping solvent is obtained by mixing isopropanol and n-heptane in a volume ratio of 6:4.

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