A method for preparing retinoic acid

Abstract

The present invention provides a method for preparing tretinoin. The Wittig reaction product of [3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-2,4-pentadienyl]-triphenylphosphonium salt (Compound of Formula II) and 5-hydroxy-4-methyl-2-furanone (Compound of Formula III), namely the mixture of C11,13-dicis-tretinoin (Compound of Formula IV) and isotretinoin (Compound of Formula V), is subjected to two-step isomerization reactions: copper-catalyzed isomerization reaction (a) and iodine-catalyzed isomerization reaction (b) to prepare tretinoin by a one-pot method. This preparation method can avoid heavy metal pollution, has high selectivity, low cost, and the raw materials are easy to obtain or prepare, and is suitable for the industrial production of tretinoin.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for preparing retinoic acid. Background Art

[0002] Retinoic acid (English name: Tretinoin), also known as all-trans retinoic acid, has a chemical structure as shown in Formula I. It is used topically in different dosage forms such as cream, gel, or solution to treat acne and is approved for the treatment of acute promyelocytic leukemia.

[0003] The nonatetraenoic acid fragment in the structure of retinoic acid exists in an all-trans configuration. One of the key links in its preparation is to effectively construct this structure. Currently, the preparation methods of retinoic acid reported in the literature mainly include the following routes:

[0004] US3746730A discloses a process for preparing retinoic acid by hydrolysis and oxidation using retinoic acid acetate as a raw material. This process requires a large amount of silver oxide as an oxidant, which is costly. EP0563825A2 improves this process by adopting a step-by-step oxidation method, i.e., retinoic acid is obtained by hydrolysis of retinoic acid acetate to prepare retinol, retinol is oxidized by Oppenauer oxidation to obtain retinal, and then retinoic acid is obtained by oxidation with chlorite. The improvement avoids the use of expensive silver oxide, but the aldehyde oxidation yield is only about 50%, which is low. This route requires the use of all-trans retinoic acid acetate with high purity as a raw material, which is not conducive to material acquisition and cost control.

[0005]

[0006] CN102775338A discloses a one-pot process for Wittig reaction and isomerization reaction. [3-methyl-5-(2,6,6-trimethylcyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt (compound of formula II) and β-formylcrotonic acid undergo a Wittig reaction under the action of a base, and the obtained product is isomerized after the pH value is adjusted by adding a palladium catalyst.

[0007]

[0008] In CN101774954A, a phosphonium salt compound of formula II and β-formyl crotonate butyl ester are used as raw materials, and Wittig reaction is performed to obtain a mixture of retinoic acid butyl ester and C11-cis-retinoic acid butyl ester; after the mixture is further hydrolyzed, a composite catalyst of palladium nitrate, triphenylphosphine and triethylamine is added to catalyze the preparation of retinoic acid.

[0009] The above two patent applications actually both apply for the palladium-catalyzed isomerization of a mixture of C11-cis-retinoic acid (compound of formula VI) and retinoic acid (compound of formula I). ​​Palladium belongs to the 2B class element. The use of palladium catalyst not only increases the cost, but also increases the risk of heavy metal pollution. Moreover, the raw material β-formylcrotonic acid (or ester) is not easily available in the market.

[0010] In CN102558007A, phosphonium salt (II compound) and 5-hydroxy-4-methyl-2-furanone are used as raw materials, and a mixture of C11-cis-retinoic acid and retinoic acid is obtained through a Wittig reaction of strong base sodium methoxide. The mixture is isomerized under the action of iodine to obtain retinoic acid.

[0011]

[0012] This patent application provides a method for preparing retinoic acid that avoids heavy metal pollution. The process includes preparing trans-structured β-formylcrotonic acid from furanone (compound of formula III) with a strong base, which needs to be used in excess. It reports that the yield of the two-step Wittig reaction and isomerization reaction is no more than 60%, which is relatively low. At the same time, the use of the strong base sodium methoxide requires the control of moisture in the reaction, otherwise the substrate is difficult to effectively convert. Summary of the invention

[0013] The present invention provides a method for preparing retinoic acid, which avoids the introduction of heavy metals during the reaction process, has high reaction selectivity and low cost, and the raw materials are easy to obtain, so the method is suitable for the industrial production of retinoic acid.

[0014] The technical scheme of the present invention is a method for preparing retinoic acid, which uses a mixture of C11,13-dicis-retinoic acid and isotretinoin as raw materials, and performs a two-step isomerization reaction to prepare retinoic acid with an all-trans configuration product in one pot;

[0015] S1. A copper catalyst is added to a mixture of C11,13-dicis-retinoic acid and isotretinoin to perform a first step isomerization reaction to obtain a mixture of isotretinoin and retinoic acid;

[0016] S2. The material obtained in step S1 is directly added with iodine to carry out a second step isomerization reaction, and the all-trans configuration product retinoic acid is obtained in one pot.

[0017] Furthermore, the C11,13-dicis-retinoic acid and isotretinoin mixture is a Wittig reaction product of [3-methyl-5-(2,6,6-trimethylcyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt and 5-hydroxy-4-methyl-2-furanone. In the specific reaction process, KOH is used as a base and isopropanol is used as a solvent for the Wittig reaction.

[0018] Furthermore, the copper catalyst used in S1 is cuprous iodide, cuprous chloride, cuprous bromide, cupric sulfate, cuprous oxide, preferably cuprous iodide.

[0019] Furthermore, the molar ratio of the copper catalyst to the [3-methyl-5-(2,6,6-trimethylcyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt is 0.001-0.3:1.

[0020] The amount of iodine used in the second step isomerization reaction does not have a significant effect on the reaction and is not specifically limited. The amount used is usually 0.01 to 0.2 equivalents of [3-methyl-5-(2,6,6-trimethylcyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt.

[0021] Furthermore, in the two-step isomerization reaction, the solvent used is ethyl acetate, isopropyl acetate, C1-4 alcohol, acetonitrile; preferably ethanol and acetonitrile.

[0022] Furthermore, the reaction temperature in S1 is 30-80° C., preferably 50-60° C. The temperature in the first step of isomerization reaction has a certain influence on the reaction. If the temperature is low, the conversion of C11,13-dicis-retinoic acid is slow. If the temperature is too high, the isomerization reaction is fast, but the impurities increase significantly.

[0023] Furthermore, the reaction time in S1 is controlled by detecting the reaction using an HPLC method, and the reaction is stopped when the content of C11, C13-di-cis-retinoic acid in the unisomerized material is less than 1%.

[0024] Furthermore, the reaction temperature in S2 is 10-50° C., and the reaction time is 12-48 hours. The time of the second step isomerization reaction mainly affects the content of the isomeric impurity isotretinoin in the product, but since conventional crystallization post-treatment has a good ability to remove this impurity, the reaction time can be in a wider range.

[0025] Further, after the two-step isomerization reaction is completed, the reaction solution is crystallized to obtain retinoic acid; and recrystallization purification is required for follow-up. Specifically, after the reaction is completed, the reaction mixture is cooled and crystallized, or distilled and crystallized, or part of deionized water is added, cooled and crystallized, and filtered. The solid obtained is retinoic acid, with a yield of more than 70% (based on 5-hydroxy-4-methyl-2-furanone, including Wittig reaction and isomerization reaction), a purity of more than 95%, and the main impurities are isomeric impurities A and impurity D (not more than 2.0% and 1.0%, respectively). In addition to isomeric impurities, the total amount of other impurities is not more than 0.5%. Subsequent recrystallization purification can adopt conventional dissolution and crystallization operations, adding ethyl acetate or ethanol to dissolve, filter, and crystallize to obtain high-purity retinoic acid.

[0026] The present invention also relates to retinoic acid prepared by the method.

[0027] The existing methods for preparing retinoic acid are mainly achieved through Wittig reaction and isomerization reaction, which are all isomerization of C11-cis-retinoic acid. These processes all require the construction of C13-trans configuration before the Wittig reaction, or the use of trans-structured β-formyl crotonic acid (or ester) as a raw material, or the use of raw material 5-hydroxy-4-methyl-2-furanone to prepare trans-structured β-formyl crotonic acid on site. Since the raw material 5-hydroxy-4-methyl-2-furanone can be obtained from the market and has a lower cost, it is more suitable as a material for the Wittig reaction. It can react with phosphonates to prepare a C13-cis retinoic acid mixture (i.e., a mixture of C11,13-dicis-retinoic acid and isotretinoic acid) with high yield. This mixture is currently used for palladium catalysis or photocatalysis to prepare isotretinoin (the C13-cis isomer of retinoic acid). There is no report on the preparation of all-trans retinoic acid by isomerization reaction of C11,13-dicis-retinoic acid. In addition, in the current preparation of retinoic acid compounds, the isomerization of double bonds is mainly carried out through three methods: palladium catalysis, iodine catalysis, and photoreaction, and there is no report on copper catalysis.

[0028] The present invention adopts a one-pot method of copper catalyst-catalyzed isomerization reaction and iodine-catalyzed isomerization reaction, which effectively realizes the preparation of retinoic acid with a C13-cis structure. This is not only a safer and more effective catalytic system, but also provides a new method for preparing retinoic acid. The preparation of retinoic acid does not require the advance construction of the C13-trans configuration and does not require heavy metal catalysis.

[0029] The reaction formula involved in the present invention is as follows:

[0030]

[0031] Compared with the prior art, the present invention has the following advantages:

[0032] The method for preparing retinoic acid provided by the present invention adopts a two-step isomerization reaction in one pot, and the catalysts used are copper catalyst and iodine, respectively, which avoids heavy metal pollution, has high safety, and low catalyst cost; the details are shown in Table 1 below.

[0033] unit price unit price Cuprous iodide About 1000 yuan / Kg Palladium acetate 500-600 Yuan / g iodine About 2000 yuan / Kg Palladium nitrate 500-600 Yuan / g

[0034] The isomerization reaction of the present invention has high selectivity, and the content of the retinoic acid (formula I compound) product obtained by isomerization is more than 95%, and the main impurities are known isomer impurities A and impurity D, which are easily removed by conventional treatment, and the total yield of Wittig reaction and isomerization reaction is more than 70%. The intermediates of the two-step isomerization reaction do not need to be separated or additionally operated, and the operation is simple and the conditions are mild. The process selects the Wittig reaction product of [3-methyl-5-(2,6,6-trimethylcyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt (formula II compound) and 5-hydroxy-4-methyl-2-furanone (formula III compound), that is, C11,13-dicis-retinoic acid (formula IV compound) and isotretinoin (formula V) mixture as the starting material. These two materials are now easy to obtain, the Wittig reaction process is relatively mature, and no stronger base is needed, which is convenient for preparation and operation. The entire process is suitable for the industrial production of retinoic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the HPLC spectrum of the product obtained in Example 1(1).

[0036] Figure 2 This is the HPLC spectrum of the cuprous iodide isomerization reaction in Example 1(2).

[0037] Figure 3 This is the HPLC spectrum of the isomerization product retinoic acid in Example 1(2).

[0038] Figure 4 This is the hydrogen NMR spectrum of retinoic acid obtained in Example 1. DETAILED DESCRIPTION

[0039] The embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0040] High performance liquid chromatography (HPLC) method: chromatographic column: C18 alkyl silica gel column (150*4.6mm, 3um); mobile phase: methanol-water-glacial acetic acid solution (5:225:770); flow rate: 1.0mL / min; wavelength: 355nm.

[0041] Embodiment 1:

[0042] (1) Preparation of a mixture of C11,13-dicis-retinoic acid (compound of formula IV) and isotretinoin (compound of formula V)

[0043] Under nitrogen protection, a mixture of 1.0L isopropanol, 231.0g phosphonium salt (compound of formula II), and 50.0g 5-hydroxy-4-methyl-2-furanone (compound of formula III) was stirred to dissolve. The mixture was cooled to -25°C, and the temperature was maintained at -20°C to -25°C, and a cold isopropanol solution of potassium hydroxide (2N, 550mL) was added dropwise. After the addition, the mixture was stirred for 1 hour.

[0044] Deionized water and n-hexane were added for extraction. The temperature of the aqueous phase was controlled at 0°C to 10°C, phosphoric acid was added dropwise to adjust the pH value to about 4, and ethyl acetate / petroleum ether (1:4) was added to extract until the aqueous phase had no obvious UV absorption. The organic phases were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 258 g of product (theoretical yield 131.7 g), which was set aside. HPLC detection showed that C11,13-dicis-retinoic acid was 76.27%, isotretinoin was 19.50%, and the total of the two was 95.77% ( Figure 1 ).

[0045] (2) Preparation of Retinoic Acid (Compound of Formula I)

[0046] Under nitrogen protection, 20 g of the mixed acid mixture prepared according to Example 1 (1) was added with 150 mL of ethanol and 0.6 g of cuprous iodide, stirred, and heated to 50-60° C. for reaction. After 12 hours, the HPLC control showed that the content of C11,13-dicis-retinoic acid was 0.39%, the total content of isotretinoin and retinoic acid was 92.71%, the content of isomeric impurity B was 2.49%, and the content of isomeric impurity D was 1.47% ( Figure 2 ).

[0047] The reaction mixture was cooled to 20-25°C, 0.6 g of iodine was added, and the temperature was controlled at 20-30°C and stirred for about 24 hours. The temperature was cooled to -10-0°C and stirred for 1 hour. Filtered, the solid obtained was vacuum dried to obtain 8.8 g of isomerized product retinoic acid. Starting from the Wittig reaction feed, the total yield of the Wittig reaction and isomerization reaction was 76.5% (excluding possible residual cuprous iodide inorganic salt) based on 5-hydroxy-4-methyl-2-furanone. HPLC purity 98.84%, the main impurity isomer impurity A (isoretinoic acid) content was 0.78%, and the isomer impurity D content was 0.15% ( Figure 3 ).

[0048] (3) Purification

[0049] Under nitrogen protection, 8 g of isomerized retinoic acid solid was added to 200 mL of ethyl acetate, heated until basically dissolved, 0.3 g of activated carbon was added, stirred for about 15 minutes, and filtered. The filtrate was evaporated to remove part of the solvent, cooled to 0-10 ° C and stirred for 2 hours. Filtered, the filter cake was vacuum dried to obtain 6.5 g of solid purified retinoic acid, with a yield of 81.3% and an HPLC purity of 99.63%.

[0050] The NMR data of the obtained solid ( Figure 4 ): 1 H-NMR (400 MHz, DMSO-d6): δ12.02 (s, 1H), 7.03 (dd, 1H), 6.41 (d, 1H), 6.26 (m, 2H), 6.16 (d, 1H), 5.78 (s, 1H), 2.28 (s, 3H), 2.01 (m, 5H), 1.69 (s, 3H), 1.58 (m, 2H), 1.45 (m, 2H), 1.02 (s, 6H). This spectrum and data are consistent with the structure of retinoic acid.

[0051] Example 2

[0052] (1) Preparation of retinoic acid (compound of formula I)

[0053] Under nitrogen protection, 320 g of the mixed acid mixture prepared according to Example 1 (1) was added with 2.5 kg of acetonitrile and 8.0 g of cuprous iodide, stirred, and heated to 50-60° C. for reaction. After 12 hours, HPLC control showed that the content of C11,13-dicis-retinoic acid was 0.20%, the total content of isotretinoin and retinoic acid was 92.88%, the content of isomeric impurity B was 1.76%, and the content of isomeric impurity D was 2.92%.

[0054] The reaction mixture was cooled to 15-20°C, 9.0 g of iodine was added, and the temperature was controlled at 15-25°C and stirred for about 24 hours. A certain amount of deionized water was added, and the temperature was cooled to 0-10°C and stirred for about 2 hours. Filtered, the solid was vacuum dried, and 170.6 g of isomerized product retinoic acid was obtained. Calculated from the start of Wittig reaction feeding, the total yield of Wittig reaction and isomerization reaction was 77.0% (minus the possible residual cuprous iodide inorganic salt). HPLC purity was 95.97%, the content of the main impurity isomer impurity A (isoretinoic acid) was 1.95%, and the content of isomer impurity D was 0.58%.

[0055] (2) Purification

[0056] Under nitrogen protection, 50g of the isomerized retinoic acid solid was added to 1.3L of anhydrous ethanol, heated until basically dissolved, and 2.0g of activated carbon was added. Stir for about 15 minutes and filter. Cool down, add an appropriate amount of deionized water, and stir at 0-10℃ for 2 hours. Filter, vacuum dry the filter cake to obtain 42.0g of solid, with a yield of 84% and a HPLC purity of 99.51%.

[0057] Example 3

[0058] (1) Preparation of retinoic acid (compound of formula I)

[0059] Under nitrogen protection, 10 g of the mixed acid mixture prepared according to Example 1 (1) was added with 50 mL of ethyl acetate and 0.36 g of cuprous oxide, stirred, and heated to about 65° C. for reaction. After 12 hours, HPLC control showed that the content of C11,13-dicis-retinoic acid was 0.47%, the total content of isotretinoin and retinoic acid was 95.76%, the content of isomeric impurity B was 2.19%, and the content of impurity D was 0.54%.

[0060] The reaction mixture was cooled to 10-20°C, 0.2 g of iodine was added, and the temperature was controlled at 10-20°C and stirred for about 48 hours. The mixture was cooled to about -5°C and stirred for 2 hours. The mixture was filtered and the solid was vacuum dried to obtain 4.1 g of isomerized product, retinoic acid. The total yield of the Wittig reaction and isomerization reaction was 73.3% (minus the possible residual copper inorganic salt) based on 5-hydroxy-4-methyl-2-furanone, calculated from the start of the Wittig reaction. The HPLC purity was 99.10%, and the main impurities were impurity A (isoretinoic acid) content of 0.63% and impurity D content of 0.08%.

[0061] Example 4

[0062] (1) Preparation of retinoic acid (compound of formula I)

[0063] Under nitrogen protection, 10 g of the mixed acid mixture prepared according to Example 1 (1) was added with 50 mL of isopropanol and 0.5 g of cuprous bromide, stirred, and heated to about 60° C. for reaction. After 16 hours, HPLC control showed that the content of C11,13-dicis-retinoic acid was 0.69%, and the total content of isotretinoin and retinoic acid was 93.86%.

[0064] The reaction mixture was cooled to 20-30°C, 0.3 g of iodine was added, and the temperature was controlled at 20-30°C and stirred for about 24 hours. The mixture was cooled to about -5°C and stirred for 2 hours. The solid was filtered and vacuum dried to obtain 4.3 g of isomerized product retinoic acid. The total yield of the Wittig reaction and isomerization reaction was 74.5% (excluding possible residual copper inorganic salts) based on the Wittig reaction feed. HPLC purity was 98.50%.

[0065] Comparative Example

[0066] (1) Preparation of a mixture of C11-cis-retinoic acid (compound of formula VI) and retinoic acid (compound of formula I)

[0067] Under nitrogen protection, 13.6 g of 5-hydroxy-4-methyl-2-furanone (compound of formula III), 26.2 g of sodium methoxide, and 120 ml of methanol were stirred at 35-40°C for about 2 hours, and then cooled to -5-0°C. A methanol solution of [3-methyl-5-(2,6,6-trimethylcyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt (compound of formula II) (50 g dissolved in 80 mL) was added dropwise. After addition, the mixture was kept warm for 4 hours, and then reacted at room temperature for 8 hours. Ice water and ethyl acetate / petroleum ether (1:4) were added for extraction, the pH of the aqueous layer was adjusted to 3-4, ethyl acetate / petroleum ether (1:3) was added for extraction, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 35.5 g of solid. HPLC showed that the contents of C11-cis-retinoic acid (compound of formula VI) and retinoic acid (compound of formula I) were 47.71% and 45.46%, respectively, and the total content of the two was 93.17%.

[0068] (2) Preparation of Retinoic Acid (Compound of Formula I)

[0069] Under nitrogen protection, 10 g of the solid (mixture of C11-cis-retinoic acid and retinoic acid) was added to 40 mL of ethanol, and 0.14 g of iodine was added. The mixture was stirred at 20-30 ° C for 48 hours, and then cooled to 5-10 ° C and stirred for 1 hour. Filter, wash the filter cake with ice ethanol, and vacuum dry to obtain retinoic acid. The total yield of Wittig reaction and isomerization reaction was 54.0%. HPLC purity was 97.64%, and the main impurities included impurity A (isoretinoic acid) content of 0.90% and impurity D content of 0.03%.

[0070] The above embodiments are only for illustrating the technical ideas and features of the present invention, and the contents are only preferred embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Within the technical scope disclosed by the present invention, equivalent changes or improvements made according to the technical solution and inventive concept of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of retinoic acid, characterized in that, the involved reaction formula is as follows: ； Using the compound of formula II [3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-2,4-pentadiene]-triphenylphosphonium salt and the compound of formula III 5-hydroxy-4-methyl-2-furanone as raw materials, using KOH as the base and isopropanol as the solvent for the Wittig reaction to obtain a mixture of the compound of formula IV C11,13-dicis-retinoic acid and the compound of formula V isotretinoin. The mixture undergoes two-step isomerization reactions to prepare the all-trans configuration product retinoic acid by one-pot method; S1. Add the mixture of C11,13-dicis-retinoic acid and isotretinoin to a copper catalyst for the first-step isomerization reaction. The reaction temperature is 30-80 °C to obtain a mixture of isotretinoin and retinoic acid; the molar ratio of the copper catalyst to the amount of [3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-2,4-pentadiene]-triphenylphosphonium salt used is 0.001-0.3:1; the copper catalyst is cuprous iodide, cuprous chloride, cuprous bromide, copper sulfate, cuprous oxide S2. Directly add iodine to the material obtained in step S1 for the second-step isomerization reaction. The reaction temperature is 10-50 °C and the reaction time is 12-48 hours. The all-trans configuration product retinoic acid is obtained by one-pot method; In the two-step isomerization reactions, the solvents used are ethyl acetate, isopropyl acetate, C1-4 alcohols or acetonitrile.

2. The method according to claim 1, characterized in that: wherein the mixture of C11,13-dicis-retinoic acid and isotretinoin is the Wittig reaction product of [3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-2,4-pentadiene]-triphenylphosphonium salt and 5-hydroxy-4-methyl-2-furanone.

3. The method according to claim 1, characterized in that: In the two-step isomerization reactions, the solvents used are ethanol or acetonitrile.

4. The method according to claim 1, characterized in that: The reaction temperature in S1 is 50-60 °C.

5. The method according to any one of claims 1-4, characterized in that: The reaction time in S1 is detected and controlled by HPLC method, and the reaction is stopped after the content of the non-isomerized material C11,C13-dicis-retinoic acid is below 1%.

6. The method according to any one of claims 1-4, characterized in that: After the two-step isomerization reactions are completed, the reaction solution is crystallized to obtain retinoic acid; recrystallization purification is required for subsequent follow-up.

7. The method according to claim 1, characterized in that: The copper catalyst used in S1 is cuprous iodide.

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