Method for preparing intermediates useful in the synthesis of voclosporine

Abstract

The present invention relates to a method for preparing an intermediate useful for the synthesis of voclosporine, an immunosuppressive active ingredient that is a calcineurin inhibitor.

Description

Technical Field

[0001] The present invention relates to a method for preparing an intermediate useful for the synthesis of voclosporin.

Background Art

[0002] Voclosporin (Formula 1) is an immunosuppressive active ingredient that is a calcineurin inhibitor obtained by derivatization of cyclosporin (Formula 2). By such derivatization, the calcineurin inhibitory ability and metabolic stability of voclosporin are higher than those of cyclosporin.

[0003]

Chemical Formula

[0004] Voclosporin is approved in Europe and the United States under the trademark "Lupkynis" TM (Lupkynis) and is used in combination with mycophenolate mofetil for the treatment of glomerulonephritis caused by systemic lupus erythematosus, also known as lupus nephritis. Furthermore, voclosporin has been adopted as a drug candidate in clinical trials for lesions such as focal segmental glomerulosclerosis, psoriasis, dry eye syndrome, non-infectious uveitis, dry keratoconjunctivitis, etc. and for kidney transplant patients.

[0005] Methods for preparing voclosporin are disclosed in International Publication No. 2003 / 033526, International Publication No. 2003 / 033527, and International Publication No. 2004 / 089960, and these methods include at least one step of forming or introducing a carbon-carbon double bond by a Wittig reaction, Peterson olefination, or the use of phospho- or titanium-allyl.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

[0007] [ka]

[0008] The aldehyde of formula 3 is an important intermediate in the above method and is obtained by ozonolysis of the compound of formula 4. Although such a procedure is commonly used in industrial processes, it has several limitations, such as compatibility with a limited number of solvents and use on a scale of several hundred grams. Furthermore, the eventual generation of undesirable peroxide species is particularly undesirable due to the associated formation of undesirable byproducts, as well as safety concerns stemming from the explosiveness of these species.

[0009] Given the interest in voclosporine and its potential usefulness, there is a need to develop alternative synthetic methods for this compound and, in particular, its intermediates / precursors. [Means for solving the problem]

[0010] The applicant has developed a method for preparing an aldehyde of formula 3, comprising the steps of converting a compound of formula 4 to a diol of formula 5, and subsequently isolating and oxidizing the diol of formula 5.

[0011] [ka]

[0012] [ka]

[0013] In the compounds of Formulas 3 to 5 and the carboxylic acid of 6 described below, the R group is selected from acetyl, chloroacetyl, trifluoroacetyl, pivaloyl, benzoyl, and preferably, R is acetyl.

Brief Description of the Drawings

[0014] [Figure 1] The X-ray diffraction (X-RPD) spectrum of the crystalline form V of the aldehyde of 3 is shown.

Mode for Carrying Out the Invention

[0015] The diol of Formula 5 is obtained by dihydroxylating the compound of Formula 4 using a metal catalyst containing a metal selected from the group consisting of Ru, Yb, Ce, Mn, Fe, Pd, and Os, and preferably using a catalyst selected from osmate, encapsulated osmium, and supported osmium. In addition to these preferably specified metal catalysts, the catalysts described in "Recent Advancements in the Development of Osmium Catalysts for Various Oxidation Reactions: A New Era?" in Comments on Inorganic Chemistry 2021 by Von Willingh G. and European Journal of Organic Chemistry 2021, 2021(6), 877 - 896 by Achard T. et al. can be used. "Isolation of the diol of Formula 5" means the separation of the compound from the reaction mixture, particularly the separation from the unreacted metal catalyst. According to a particularly preferred embodiment, the method according to the present invention involves the use of osmate, preferably K2OsO4·2H2O, Na2OsO4·2H2O.

[0016] The isolation of the diol of formula 5 is carried out by solvent extraction using a solvent selected from dichloromethane, butanol, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, toluene, and mixtures thereof.

[0017] The aldehyde of formula 3 is obtained by treating the diol of formula 5 with an oxidizing agent selected from NaIO4, IBX, Dess-Martin periodinane, KMnO4, Pb(OAc)4, CrO3, MnO2, pyridinium chlorochromate. Preferably, the oxidizing agent is selected from NaIO4, IBX, and Dess-Martin periodinane.

[0018] More specifically, the method for preparing the compound of formula 3 includes the following steps: a. Dissolving the compound of formula [4] in a mixture of an organic solvent S [1] and water to obtain a solution A; b. Adding a metal catalyst to solution A to obtain solution B, and stirring solution B until the compound of formula [4] is converted to the corresponding diol of formula [5]; c. Extracting solution B with an organic solvent S [2] to obtain an organic phase and an aqueous phase; d. Adding an aqueous solution of an oxidizing agent to the organic phase to obtain solution C, and stirring this solution until the diol of formula [5] is converted to the corresponding aldehyde of formula [3]; e. Extracting solution C with an organic solvent S [3] to obtain an organic phase and an aqueous phase; f. Isolating the aldehyde of formula [3] from the organic phase obtained in step e.

[0019] Typically, in step a, solvent S1 is a mixture of water and an organic solvent selected from methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, hexamethylphosphoramide, pyridine, tetrahydrofuran, and mixtures thereof. Preferably, the organic solvent is selected from acetone, acetonitrile, ethyl acetate, and tetrahydrofuran. More preferably, solvent S1 is a mixture of acetonitrile and water. Typically, the ratio of the organic solvent to water is 10:1 to 1:3, preferably 7:1 to 1:1. More preferably, the ratio is 5:1. In a particularly preferred embodiment, in step a, the compound of formula 4 is dissolved in a mixture of acetonitrile and water in a ratio of 5:1.

[0020] Typically, in step b, the metal catalyst is selected from catalysts containing a metal selected from the group consisting of Ru, Yb, Ce, Mn, Fe, Pd, and Os. Preferably, the catalyst is selected from osmium salts, encapsulated osmium, or supported osmium. More preferably, the catalyst is an osmium salt selected from K2OsO4·2H2O and Na2OsO4·2H2O, more preferably K2OsO4·2H2O. If K2OsO4·2H2O or Na2OsO4·2H2O is used in step b, a co-oxidant selected from the group consisting of N-methylmorpholine N-oxide, H2O2, triethylamine N-oxide, and KMnO4 is also added. Such a co-oxidant is necessary to regenerate the metal catalyst and enable the efficient use of the metal catalyst in catalytic amounts. The equivalent ratio of the compound of formula 4 to the metal catalyst is in the range of 5:0.001, preferably in the range of 3:0.005, and more preferably in the range of 1:0.01. The use of osmium salts, particularly K2OsO4·2H2O or Na2OsO4·2H2O, is especially preferred on an industrial scale because it avoids the use of OsO4, which is associated with problems such as high cost, toxicity, volatility, and non-recyclability.

[0021] Typically, the solvent S2 used in step c. is selected from dichloromethane, butanol, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, toluene, and mixtures thereof, preferably from dichloromethane, butanol, and methyl tert-butyl ether, and more preferably from dichloromethane. Furthermore, the organic phase obtained in step c. may optionally be washed with an aqueous solution containing a reducing agent, preferably sodium thiosulfate, sodium metabisulfite, or an aqueous solution of ascorbic acid, to remove any catalyst residue present.

[0022] The organic phase obtained in step c. can be concentrated by distillation under vacuum to obtain a volume equal to two-thirds of the initial volume, preferably half of the initial volume, and more preferably one-third of the initial volume. Then, before adding the aqueous solution of the oxidizing agent in step d., it can be diluted with a solvent selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, and mixtures thereof, preferably acetonitrile, by 5 to 10 times its volume. The oxidizing agent used in step d. can be selected from NaIO4, IBX, des-martin periodinane, KMnO4, Pb(OAc)4, CrO3, MnO2, and pyridinium chlorochromate, preferably from NaIO4, IBX, and des-martin periodinane.

[0023] Once it has been confirmed that diol 5 has disappeared from solution C using any method known to those skilled in the art, an aqueous solution containing a reducing agent selected from sodium thiosulfate, sodium metabisulfite, and ascorbic acid, preferably Na2S2O3, may be added to solution C to remove any oxidizing agent residue.

[0024] Typically, in step e, the organic solvent S3 is selected from pentane, hexane, cyclohexane, benzene, toluene, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, and dichloromethane, preferably from hexane, toluene, tetrahydrofuran, diethyl ether, and mixtures thereof, and more preferably from toluene. Furthermore, the organic phase obtained in step e is concentrated, preferably by distillation under vacuum, to obtain a volume equal to two-thirds of the initial volume, more preferably one-half of the initial volume, and even more preferably one-third of the initial volume.

[0025] Typically, in step f, the isolation of aldehyde 3 is carried out by adding an organic solvent S4 selected from pentane, hexane, cyclohexane, cyclopentane, heptane, methyl tert-butyl ether, diethyl ether, and mixtures thereof, preferably cyclohexane or heptane, more preferably heptane. This addition causes aldehyde 3 to precipitate in a crystalline form referred to as form V. The X-ray diffraction (X-RPD) spectrum of crystalline form V of aldehyde 3 shows a crystalline structure and contains characteristic reflections approximately equal to 8.0-8.7-10.08-11.4-11.8-12.9-14.5-16.1-16.5-17.2-18.0-18.2-18.5-18-9-19.8-20.2-21.7-25.7 (±0.2) at an angle 2θ° where the relative intensity is 5% or more. More specifically, the X-RPD spectrum of morphology V exhibits a crystalline structure and includes characteristic reflections approximately equal to 6.0-8.0-8.7-10.08-11.4-11.8-12.0-12.9-14.5-16.1-16.5-17.2-18.0-18.2-18.5-18-9-19.8-20.2-21.7-22.0-23.6-24.1-24.6-25.7-26.3-28.4-29.3-30.3-31.4-31.7-32.8-34.5-35.5-35.8-38.3 (±0.2) with relative intensity exceeding 1% at angles of 2θ°. More specifically, the X-RPD spectrum of morphology V shows the crystalline structure and includes characteristic reflections approximately equal to 6.0-8.0-8.7-10.08-11.4-11.8-12.0-12.9-14.5-16.1-16.5-17.2-18.0-18.2-18.5-18-9-19.8-20.2-21.7-22.0-23.6-24.1-24.6-25.7-26.3-28.4-29.3-30.3-31.4-31.7-32.8-34.5-35.5-35.8-38.3-42.6 (±0.2) at an angle of 2θ°. The X-RPD spectrum of crystalline morphology V of aldehyde 3 is shown in Figure 1.

[0026] Crystalline form V is particularly advantageous compared to the amorphous form of aldehyde 3 because it contains fewer impurities and prevents the formation of undesirable by-products.

[0027] The present invention makes it possible to obtain the aldehyde of formula 3 in two steps, namely by converting the compound of formula 4 to the diol of formula 5, followed by isolation of the latter and conversion to the aldehyde of formula 3 by oxidative cleavage. This method is highly advantageous compared to known methods, etc., because it provides the aldehyde of formula 3 in high yield and high purity. In particular, the present invention makes it possible to obtain the aldehyde of formula 3 in an amount of less than 1% of the accompanying carboxylic acid of formula 6, preferably less than 0.5%, 0.2%, 0.1%, 0.05%, or 0.02%. The amount of impurities is measured by HPLC analysis according to the method described in the "Materials and Methods" section.

[0028] [ka]

[0029] The extraction performed in step c. makes it possible to separate the diol of formula 5 from the unreacted metal catalyst. This separation step is very advantageous because the presence of the metal catalyst in the subsequent steps can accelerate the oxidation of the aldehyde of formula 3 to the carboxylic acid of formula 6. In fact, when the conversion of the compound of formula 4 to the compound of formula 3 is performed in a single step of treating the compound of formula 4 with OsO4 and NaIO4, the carboxylic acid of formula 6 is typically obtained in an amount of 5-15%. The presence of such a large amount of impurities is significant, as it particularly affects the reaction yield. Table 1 shows the content of the carboxylic acid of formula 6 obtained by oxidation of the compound of formula 4 in a single step and the content obtained by the method of the present invention.

[0030] [Table 1]

[0031] Furthermore, since the aldehyde of formula 3 cannot be separated from the carboxylic acid of formula 6 by simple precipitation or crystallization, other purification methods such as column chromatography must be employed to purify the aldehyde of formula 3. However, this process becomes longer and more laborious, and there is a possibility of further loss of the target product. [Examples]

[0032] [material and method] The diffraction patterns were recorded using a Bruker D2-Phaser diffractometer with the following parameters. Anode tube: Cu Voltage generator (kV): 30 Generator (mA): 10 Wavelengths λ1 and λ2 (Å): 1.54056, 1.54439 Intensity ratio (λ2 / λ1):0.500 Spinner: Off Angular range (2θ°): 2.00~50.00 Step size (2θ°): 0.020 Step time (seconds): 3.0

[0033] HPLC analysis was performed using an HPLC system consisting of a quaternary pump, a constant-temperature autosampler, a column compartment, and a 2998 PDA detector, with a 150 mm x 4.6 mm 2.5 μm Xselect CSH Fluoro-phenyl column, and solvent A (1% 0.2 M HCOONH4 solution / 99% water + 0.1% HCOOH) and solvent B (1% 0.2 M HCOONH4 solution / 99% CH3CN + 0.1% HCOOH) as mobile phases.

[0034] [Example 1: Method for preparing the aldehyde in formula 3] 65.0 g of acetylcyclosporine A (formula 4, R=acetyl) (52.2 mmol, 1.0 equivalent) was dissolved in a 5:1 CH3CN:H2O mixture (390 mL) at room temperature. Then, 194 mg of K2OsO4·2H2O (0.52 mmol, 0.01 equivalent) was added, and the resulting mixture was stirred for 30 minutes. Finally, 6.4 g of N-methylmorpholine N-oxide (54.8 mmol, 1.05 equivalent) was added, and the final mixture was heated at 30°C. After the starting material was completely converted to the corresponding 5 diols, the mixture was cooled to room temperature and diluted with water (260 mL) and CH2Cl2 (162 mL). The resulting two phases were separated, and the organic phase was washed twice with water (260 mL x 2) and concentrated to 130 mL under reduced pressure. The resulting residue was diluted with CH3CN (520 mL, 8x volume) and heated at 30°C. 22.5 g of NaIO4 (105.1 mmol, 2.0 equivalents) dissolved in water (130 mL, 2x volume) was added under stirring. After the diol of 5 was completely converted to the corresponding aldehyde of 3, the mixture was cooled to 20°C, and the reaction was stopped with 12.41 g of Na2S2O3 (78.6 mmol, 1.5 equivalents) dissolved in water (260 mL) while maintaining a constant temperature. The final mixture was extracted with toluene (195 mL) to separate the two phases. The organic layer was washed with water (260 mL) and brine (260 mL). The final solution was concentrated to 130 mL, and the product was precipitated by adding 260 mL of heptane. The resulting suspension was filtered, and the solid was washed once with heptane (65 mL). This solid was dried under vacuum at 50°C for 16 hours to obtain a white solid (53.9 g, yield = 83%, typical purity A% HPLC 96-98%).

[0035] [Example 2: Method for preparing the aldehyde in formula 3] Aldehyde synthesis 1.5 g of acetylcyclosporine (1.2 mmol, 1.0 equivalent) was dissolved in 9 mL of acetonitrile:water (5:1) mixture. Then, 200 mg of encapsulated osmium (osmium tetroxide encapsulated in a porous matrix of cross-linked polyurea, trademark "Os EnCat® 40") (0.3 mmol / g Os, 0.06 mmol, 0.05 equivalent) was added, and the resulting suspension was heated at 45°C. Subsequently, 280 mg of NMO (2.4 mmol, 2.0 equivalent) was added gradually.

[0036] [Table 2]

[0037] After the starting materials were completely converted, the mixture was filtered and 4.5 mL of toluene and 4.5 mL of a 10% aqueous solution of sodium metabisulfite were added. The resulting mixture was stirred for 16 hours. Then, phase separation was performed, the organic phase was distilled and diluted with 7.5 mL of acetonitrile. 385 mg of NaIO4 (1.8 mmol, 1.5 equivalents) dissolved in 1.5 mL of water was added, and the mixture was heated at 30°C. After the intermediate was completely converted to the desired product, the mixture was cooled to 20°C, and the reaction was stopped with 285 mg of Na2S2O3 (1.8 mmol, 1.5 equivalents) dissolved in 6 mL of water while maintaining a constant temperature. After phase separation, the organic phase was further washed with water, and the final solution was concentrated to 3 mL. 6 mL of heptane was added to precipitate the product. The resulting suspension was filtered, and the solids were washed once with 1.5 mL of heptane. This solid was dried under vacuum at 50°C for 16 hours to obtain a white solid (1.2 g, yield = 79%, typical purity A% HPLC ≥ 90%).

[0038] [Example 3 (Comparative Example): Method for preparing the aldehyde in formula 3] 5.58 g of acetylcyclosporine A (formula 4, R=acetyl) (4.48 mmol, 1.0 equivalent) was suspended in a 1:1 CH3CN:H2O mixture (55.8 mL + 55.8 mL) and heated at 30°C. Then, 50 mg of K2OsO4·2H2O (0.13 mmol, 0.03 equivalent) was added, and the mixture was stirred for 30 minutes. Finally, 2.01 g of NaIO4 (9.42 mmol, 2.1 equivalent) was added in three portions. After complete conversion, the reaction mixture was cooled to room temperature, and while maintaining a constant temperature, the reaction was stopped with 7.09 g of Na2S2O3 (44.86 mmol, 10.0 equivalent) dissolved in water (20 mL). The final reaction mixture was extracted with methyltetrahydrofuran (Me-THF) (110 mL) to separate the two phases. The aqueous phase was extracted again with Me-THF (110 mL), and the collected organic phase was concentrated to 100 mL. 500 mL of heptane was added to precipitate the product. The resulting suspension was filtered, and the solid (aldehyde 3) was washed twice with heptane (2 × 25 mL). This solid was dried under vacuum at 50°C for 16 hours to obtain a white solid.

Claims

1. Convert the compound in formula 4 to the diol in formula 5, 【Chemistry 1】 Next, a method for preparing the aldehyde of formula 3 by isolating and oxidizing the diol of formula 5, 【Chemistry 2】 A method in which R is selected from the group consisting of acetyl, chloroacetyl, trifluoroacetyl, pivaloyl, and benzoyl.

2. The method according to claim 1, wherein the diol of formula 5 is obtained by using a metal catalyst containing a metal selected from the group consisting of Ru, Yb, Ce, Mn, Fe, Pd, and Os.

3. The method according to claim 2, wherein the metal catalyst is selected from osmium salt, encapsulated osmium, and supported osmium.

4. The metal catalyst is K ２ OSO ４ ・2H ２ O or Na ２ OSO ４ ・2H ２ The method according to claim 3, wherein O.

5. The method according to claim 1, wherein the isolation of the diol of formula 5 is performed by solvent extraction, and the solvent is selected from dichloromethane, butanol, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, toluene, and mixtures thereof.

6. The oxidation of the diol of formula 5 is carried out using an aqueous solution of an oxidizing agent selected from NaIO ４ , IBX, Dess-Martin periodinane, KMnO ４ , Pb(OAc) ４ , CrO ３ , MnO ２ , pyridinium chlorochromate, according to claim 1

7. A method according to any one of claims 1 to 6, a. The step of dissolving the compound of formula 4 in a mixture of organic solvent S1 and water to obtain solution A; b. Adding a metal catalyst to solution A to obtain solution B, and stirring solution B until the compound of formula 4 is converted to the corresponding diol of formula 5; c. The step of extracting the solution B with an organic solvent S2 to obtain an organic phase and an aqueous phase; d. Adding the organic phase of the aqueous solution of the oxidizing agent to obtain solution C, and stirring the solution until the diol of formula 5 is converted to the corresponding aldehyde of formula 3; e. The step of extracting the solution C with an organic solvent S3 to obtain an organic phase and an aqueous phase; f. The step of isolating the aldehyde of formula 3 from the organic phase obtained in step e, A method that includes this.

8. In step b, N-methylmorpholine N-oxide, H ２ O ２ Triethylamine N-oxide, KMnO ４ The method according to claim 7, wherein a co-oxidant selected from the group consisting of the following is used.

9. The method according to claim 7, wherein the organic phase obtained in step c. and the solution C are treated with an aqueous solution containing a reducing agent selected from sodium thiosulfate, sodium metabisulfite, and ascorbic acid.

10. The method according to claim 7, wherein the isolation of the aldehyde 3 in step f. is carried out by adding an organic solvent S4 selected from pentane, hexane, cyclohexane, cyclopentane, heptane, methyl tert-butyl ether, diethyl ether, and mixtures thereof to the organic phase obtained in step e.

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