Preparation method of apremilast

Abstract

The invention discloses a synthesis method of a PDE4 inhibitor apremilast, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: taking 3-ethoxy-4-methoxystyrene as an initial raw material, and carrying out aziridine treatment on olefin to obtain an intermediate 1; carrying out nucleophilic ring opening on the intermediate 1 and methyl mercaptide to obtain an intermediate 2; then the intermediate 2 and a tartaric acid resolving agent are subjected to salification and alkali treatment reaction to obtain a chiral intermediate 3, and the intermediate 3 and 3-acetamino phthalic anhydride are subjected to condensation reaction to obtain an intermediate 4; and oxidizing the intermediate 4 to obtain apremilast. The invention develops a green and efficient synthesis process of apremilast, the target product is prepared through five-step reaction, the process breaks through the situation that a traditional route depends on high-pressure hydrogenation conditions and use of highly toxic reagents, normal-pressure operation and mild temperature are adopted in the whole process, and the requirement of low-temperature reaction is avoided. The safety in industrial production is improved to a great extent, and the method is more suitable for industrial continuous production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of preparation of pharmaceutical organic synthesis, and particularly relates to a preparation method of apremilast. BACKGROUND

[0002] Apremilast is an orally bioavailable PDE-4 and TNF-alpha inhibitor, IC 50 74nM and 77nM respectively. Apremilast is an orally administered, selective phosphodiesterase 4 (PDE4) inhibitor developed by Celgene Corporation, and the trade name is Otezla. On March 21, 2014, the U.S. FDA approved apremilast for the treatment of active PsA adult patients. The drug is the first PDE4 inhibitor approved by the FDA for the treatment of plaque psoriasis, and is used for the treatment of moderate to severe plaque psoriasis in adult patients who are suitable for phototherapy and systemic therapy. By regulating the intracellular cyclic adenosine phosphate level, the release of pro-inflammatory cytokines is inhibited, and the production of anti-inflammatory factors is promoted. In the aspect of patent protection, the development of new crystal forms or process optimization will become the focus of technical competition. New synthesis strategies for apremilast and its intermediates can provide better insights for finding new routes to achieve fast, scalable and convenient yield.

[0003] The chemical structure of apremilast is as follows:

[0004]

[0005] The original research company (patent document US6020358) reported a preparation method of apremilast, using 3-ethoxy-4-methoxybenzaldehyde as a raw material, and the synthesis route is as follows:

[0006]

[0007] The process mainly has the following problems:

[0008] 1) racemates are produced, which need to be subsequently separated, increasing the difficulty and cost of separation and purification, and generating a large amount of waste of inactive isomer which needs to be treated;

[0009] 2) The process has poor atom economy, and 50% of the synthesized product is an inactive isomer, which does not meet the principles of green chemistry and efficient synthesis;

[0010] 3) The condensation is carried out by refluxing in acetic acid, and the high-temperature strong acid environment may cause side reactions, and the high-boiling-point acetic acid is difficult to remove during post-processing, which may affect crystallization.

[0011] Patent document US10370329B2 reports a preparation method of apremilast, and the synthesis route is as follows:

[0012]

[0013] The main problems with this route are as follows:

[0014] 1) The splitting step is inefficient and results in huge yield loss, with a theoretical maximum yield of only 50% (for the required enantiomer).

[0015] 2) L-phenylalanine p-toluenesulfonamide and L-DTTA are both custom-designed chiral resolving agents and are expensive.

[0016] 3) Complex process: Multiple steps lead to long production cycles, complex operation, high equipment occupancy rate, and increased scale-up risk.

[0017] US Patent 9126906 discloses a method for synthesizing apremilast from dimethyl sulfoxide and 3-ethoxy-4-methoxybenzonitrile. The synthetic route is as follows:

[0018]

[0019] The main problems with this route are as follows:

[0020] 1) While avoiding the 50% theoretical yield cap and the cost / recovery issues inherent in the splitting step, the asymmetric hydrogenation route introduces new challenges.

[0021] 2) The use of expensive precious metal catalysts and chiral ligands requires strict control of the residual rhodium in the final API, which increases the complexity and cost of the process and may lead to yield loss.

[0022] 3) The use of n-butyllithium and high-pressure hydrogen in the reaction involves flammable and explosive risks, increasing the burden and cost of safety management. Summary of the Invention

[0023] The technical problem to be solved by this invention is to overcome the shortcomings of the existing technology and provide a new method for preparing apremilast. This method directly constructs the core framework through aziridineation, avoiding the use of highly toxic reagents. It is simpler than the traditional route and can obtain the apremilast product through five steps, which can effectively improve reaction efficiency and safety.

[0024] The technical solution adopted in this invention is: a method for preparing apremilast, comprising the following steps:

[0025] Step 1: Starting with 3-ethoxy-4-methoxystyrene, the olefin is aziridine-treated to obtain intermediate 1 as shown:

[0026]

[0027] Step 2: Intermediate 1 undergoes nucleophilic ring-opening with a methanethiol salt to obtain intermediate 2:

[0028]

[0029] Step 3: Intermediate 2 undergoes a salt-forming and alkali-treatment reaction with tartaric acid resolving agent to obtain chiral resolving product intermediate 3:

[0030]

[0031] Step 4: Intermediate 3 undergoes a condensation reaction with 3-acetamidophthalic anhydride to obtain intermediate 4.

[0032]

[0033] Step 5: Intermediate 4 is oxidized to obtain Apster:

[0034]

[0035] Its synthetic route is as follows:

[0036]

[0037] In this invention, the preparation method of the apremilast intermediate 1 preferably employs the following reaction conditions:

[0038] The solvent used is acetonitrile;

[0039] The catalyst used is MgO;

[0040] In this invention, the preferred method for preparing Apre intermediate 2 is as follows:

[0041] The solvent used was anhydrous DMF;

[0042] The nucleophile used was sodium methanethiol.

[0043] In this invention, the preferred method for preparing the apremilast intermediate 3 is as follows:

[0044] The solvent used was a mixture of dichloromethane and methanol;

[0045] The resolving agent used was L-di-p-methoxybenzoyl tartaric acid;

[0046] The solvent used in the alkali treatment is water;

[0047] The alkali used in the alkali treatment is sodium hydroxide or potassium hydroxide.

[0048] In this invention, the preferred method for preparing the apremilast intermediate 4 is as follows:

[0049] The solvent used is trifluoroacetic acid;

[0050] The alkaline saturated aqueous solution used is sodium carbonate.

[0051] In this invention, the preferred method for preparing apremilast is as follows:

[0052] The solvent used is methanol;

[0053] The catalyst used was TaCl5.

[0054] Compared with the prior art, the method of the present invention has the following beneficial effects:

[0055] This invention uses 3-ethoxy-4-methoxystyrene as a starting material, which is economical and readily available, reducing synthesis costs and improving economic efficiency. The reaction conditions are mild, avoiding high-risk reagents such as cyanide and ozone throughout the process, thus improving reaction safety and production efficiency. The one-pot protection / deacetylation of 3-acetamidophthalic anhydride reduces reaction steps and complex post-processing, improving production efficiency and making it suitable for industrial production. Detailed Implementation

[0056] The technical solution of the present invention will be further described below to enable those skilled in the art to further understand the present invention, without constituting a limitation on the rights of the present invention.

[0057] Example 1, Preparation method of intermediate 1:

[0058]

[0059] 1) In a reaction vessel, dissolve chloramine-T in an acetonitrile / water mixture and cool to 0°C in an ice bath. Slowly add 2.00 g of an acetonitrile solution of 3-ethoxy-4-methoxystyrene and stir for 30 minutes. Add MgO in portions, raise the temperature to room temperature, and react for 6 hours. TLC analysis shows that almost all the starting material has reacted, at which point the reaction is stopped. After the reaction is complete, filter to remove the solid, and quench the filtrate with saturated Na₂S₂O₃. Extract with ethyl acetate (3 × 50 mL), combine the organic phases, and dry over anhydrous Na₂SO₄. Concentrate under reduced pressure and purify by silica gel column chromatography, yield 75%. 1 H NMR (400MHz, CDCl3) δ7.70 (d, J = 8.3Hz, 2H), 7.30 (d, J = 8.0Hz, 2H), 6.85-6.75 (m, 3H), 3.85 (q, J = 7.0Hz, 2H) , 3.80 (s, 3H), 3.20 (dd, J = 6.5, 3.5Hz, 1H), 2.85 (dd, J = 6.5, 5.0Hz, 1H), 2.45 (s, 3H), 1.40 (t, J = 7.0Hz, 3H).

[0060]

[0061] 2) In a reaction vessel, dissolve chloramine-T in an acetonitrile / water mixture and cool to 0°C in an ice bath. Slowly add 2.00 g of a 3-ethoxy-4-methoxystyrene solution in acetonitrile and stir for 30 minutes. Add K₂CO₃ in portions, raise the temperature to room temperature, and react for 6 hours. TLC analysis shows that almost all the starting material has reacted; stop the reaction at this point. After the reaction is complete, filter to remove the solid, and quench the filtrate with saturated Na₂S₂O₃. Extract with ethyl acetate (3 × 50 mL), combine the organic phases, and dry over anhydrous Na₂SO₄. Concentrate under reduced pressure and purify by silica gel column chromatography, yield 70%. 1 H NMR (400MHz, CDCl3) δ7.70 (d, J = 8.3Hz, 2H), 7.30 (d, J = 8.0Hz, 2H), 6.85-6.75 (m, 3H), 3.85 (q, J = 7.0Hz, 2H) , 3.80 (s, 3H), 3.20 (dd, J = 6.5, 3.5Hz, 1H), 2.85 (dd, J = 6.5, 5.0Hz, 1H), 2.45 (s, 3H), 1.40 (t, J = 7.0Hz, 3H).

[0062] Example 2, Preparation method of intermediate 2:

[0063]

[0064] 1) Dissolve 2.00 g of intermediate 1 in anhydrous DMF in a reaction vessel and cool to 0°C in an ice bath. Slowly add CH3SNa solution for about 30 min. After the addition is complete, remove the ice bath and heat to room temperature with stirring. TLC is used to detect that almost all the starting material has reacted, and the reaction is stopped. After the reaction is complete, cool again to 0°C in an ice bath. Slowly add 100 mL of saturated NH4Cl solution in a fume hood. Continue stirring for 15 min until no gas is released. After quenching, filter to remove the solid, and quench the filtrate with saturated Na2S2O3. Extract with ethyl acetate (3 × 100 mL), combine the organic phases, and dry with anhydrous Na2SO4. Concentrate under reduced pressure and purify by silica gel column chromatography, yield 70%. 1 H NMR (400MHz, CDCl3): δ7.65(d,2H),7.30(d,2H,), 6.8--7.0(m,3H), 4.10(q,2H), 3. 85(s, 3H), 3.7-3.8(m, 1H), 3.1-3.3(m, 2H), 2.42(s, 3H), 2.10(s, 3H), 1.40(t, 3H).

[0065]

[0066] 2) Dissolve 2.00 g of intermediate 1 in anhydrous DMF in a reaction vessel and cool to 0°C in an ice bath. Slowly add CH3SAg solution for about 30 min. After the addition is complete, remove the ice bath, heat to room temperature, and stir the reaction. TLC is used to detect that almost all the starting material has reacted, and the reaction is stopped. After the reaction is complete, cool again to 0°C in an ice bath. Slowly add 100 mL of saturated NH4Cl solution in a fume hood. Continue stirring for 15 min until no gas is released. After quenching, filter to remove the solid, and quench the filtrate with saturated Na2S2O3. Extract with ethyl acetate (3 × 100 mL), combine the organic phases, and dry with anhydrous Na2SO4. Concentrate under reduced pressure and purify by silica gel column chromatography, yield 65%. 1 H NMR (400MHz, CDCl3): δ7.65 (d, 2H), 7.30 (d, 2H,), 6.8-7.0 (m, 3H), 4.10 (q, 2H), 3. 85(s, 3H), 3.7-3.8(m, 1H), 3.1-3.3(m, 2H), 2.42(s, 3H), 2.10(s, 3H), 1.40(t, 3H).

[0067] Example 3, Preparation method of intermediate 3:

[0068]

[0069] 1) 2.0 g (7.3 mmol) of intermediate 2 and 10 ml of a dichloromethane-methanol mixture (DCM:MeOH = 4:1) were added to the reactor. After observing that the reaction solution was clear, 3.4 g (8.1 mmol) of L-di-p-methoxybenzoyl tartaric acid was added, and the mixture was heated and stirred at 60 °C. After approximately 4 hours, the reaction solution was observed to be clear, and heating and stirring were stopped. Crystallization was allowed to occur. After 10 hours, the mixture was filtered, and the filter cake was washed with a small amount of dichloromethane to obtain 2.51 g of the resolved intermediate salt, with a yield of 49.6%.

[0070]

[0071] 2) Add 2.5 g (3.6 mmol) of the intermediate salt to the reactor, prepare 5 mL of 0.1 mol / L sodium hydroxide solution, add 10 mL of water to the reactor, and slowly add about 3 mL of the prepared sodium hydroxide solution dropwise. Stir the reaction at room temperature (about 25 °C) for 3 h, filter, and wash the filter cake with a small amount of water to obtain 0.93 g of intermediate 2, with a yield of 94% and an ee value of 99.0%. 1H NMR (500MHz, Chloroform-d) δ9.13 (s, 1H), 7.41 (dd, J=7.1, 1.5Hz, 1H), 7.28 (dd, J=8.6, 2.0Hz, 1H), 7.22 (dd, J=8.6, 0.7 Hz, 1H), 7.18 (d, J = 1.9Hz, 1H), 6.94 (s, 2H), 4.95-4.71 (m, 1H), 3.83 (s, 3H), 2.15 (d, J = 1.5Hz, 3H), 2.08 (d, J = 1.1Hz, 3H)·

[0072]

[0073] 3) Add 2.5 g (3.6 mmol) of the intermediate salt to the reactor, prepare 5 mL of 0.1 mol / L potassium hydroxide solution, add 10 mL of water to the reactor, and slowly add about 3 mL of the prepared potassium hydroxide solution dropwise. Stir the reaction at room temperature (about 25 °C) for 3 hours. After filtration, wash the filter cake with a small amount of water to obtain 0.96 g of intermediate 2, with a yield of 97% and an ee value of 98.7%. 1 H NMR (500MHz, Chloroform-d) δ9.13 (s, 1H), 7.41 (dd, J=7.1, 1.5Hz, 1H), 7.28 (dd, J=8.6, 2.0Hz, 1H), 7.22 (dd, J=8.6, 0.7 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 6.94 (s, 2H), 4.95-4.71 (m, 1H), 3.83 (s, 3H), 2.15 (d, J = 1.5Hz, 3H), 2.08 (d, J = 1.1Hz, 3H).

[0074] Example 4, Preparation method of intermediate 4:

[0075]

[0076] 1) Add 8 mL of trifluoroacetic acid, 1.5 g (0.55 mmol) of intermediate 2, and 1.4 g (0.44 mmol) of 3-acetaminophthalic anhydride to a reaction flask, stir well, and heat to 80 °C. After 6 hours of reaction, stop the reaction, evaporate the solvent, dissolve the residue in 10 mL of ethyl acetate, wash with saturated sodium carbonate aqueous solution (5 mL × 2), wash with 5 mL of brine, remove the solvent again, add 5 mL of n-heptane for slurry treatment, filter after 30 min, wash the filter cake with 10 mL of anhydrous ethanol, dry to obtain 2.17 g of intermediate 4, yield 86%. 1 H NMR (500MHz, DMSO-d6) δ7.69 (s, 1H), 7.55 (s, 1H), 7.37 (d, J = 1.6Hz, 1H), 7.28 (dd, J = 7.9, 1.5Hz, 1H), 7.15 (d, J = 7.8Hz, 1H) , 6.90-6.55 (m, 2H), 5.38 (s, 1H), 4.01 (dq, J=7.2, 3.2Hz, 2H), 3.82 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 1.05 (t, J=7.0Hz, 3H).

[0077]

[0078] 2) Add 8 mL of trifluoroacetic acid, 1.5 g (0.55 mmol) of intermediate 2, and 1.4 g (0.44 mmol) of 3-acetaminophthalic anhydride to a reaction flask, stir well, and heat to 80 °C. After 6 hours of reaction, stop the reaction, evaporate the solvent, dissolve the residue in 10 mL of ethyl acetate, wash with saturated sodium carbonate aqueous solution (5 mL × 2), wash with 5 mL of brine, remove the solvent again, add 5 mL of n-heptane for slurry treatment, filter after 30 min, wash the filter cake with 10 mL of anhydrous ethanol, dry to obtain 2.17 g of intermediate 4, yield 86%. 1 H NMR (500MHz, DMSO-d6) δ7.69 (s, 1H), 7.55 (s, 1H), 7.37 (d, J = 1.6Hz, 1H), 7.28 (dd, J = 7.9, 1.5Hz, 1H), 7.15 (d, J = 7.8Hz, 1H) , 6.90-6.55 (m, 2H), 5.38 (s, 1H), 4.01 (dq, J=7.2, 3.2Hz, 2H), 3.82 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 1.05 (t, J=7.0Hz, 3H).

[0079] Example 5, Preparation method of Aprestin:

[0080]

[0081] Under nitrogen protection, 0.38 g of TaCl5 and 50 mL of anhydrous acetonitrile were added to a reaction vessel. The mixture was cooled to 0°C in an ice bath and stirred for 10 min until a pale yellow suspension formed. Intermediate 4 (10.0 g) was added and stirred to dissolve. 30% H2O2 (5.1 mL) was slowly added dropwise at 0°C. The reaction was maintained at 0°C for 2 h, then increased to room temperature for 3 h, and the reaction was monitored by TLC until completion. The mixture was cooled to 0°C in an ice bath and 50 mL of saturated Na2SO3 was added dropwise until no bubbles were observed. Water was added, and a solid precipitated. The solid was filtered. The filter cake was washed with cold acetonitrile / water (1:1, 20 mL) and dried under vacuum (40°C). The crude product was dissolved in hot ethanol (30 mL), and silica gel (5 g) was added and stirred for 30 min. The mixture was hot-filtered and the filtrate was evaporated to dryness to obtain white crystalline apremilast. Yield: 93%. 1 H NMR (500MHz, DMSO-d6) δ7.69 (s, 1H), 7.55 (s, 1H), 7.37 (d, J = 1.6Hz, 1H), 7.28 (dd, J = 7.9, 1.5Hz, 1H), 7.15 (d, J = 7.8Hz, 1H) , 6.90-6.55 (m, 2H), 5.38 (s, 1H), 4.01 (dq, J = 7.2, 3.2Hz, 2H), 3.82 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 1.05 (t, J = 7.0Hz, 3H).

Claims

1. A method for preparing apremilast, characterized in that: Includes the following steps: Step 1: Starting with 3-ethoxy-4-methoxystyrene, the olefin is aziridineized to obtain intermediate 1 as shown below: Step 2: Intermediate 1 undergoes nucleophilic ring-opening with a methanethiol salt to obtain intermediate 2: Step 3: Intermediate 2 undergoes a salt-forming and alkali-treating reaction with a tartaric acid resolving agent to obtain chiral intermediate 3. Step 4: Intermediate 3 undergoes a condensation reaction with 3-acetamidophthalic anhydride to obtain intermediate 4. Step 5: Intermediate 4 is oxidized to obtain Apster: 。 2. The method for preparing apremilast according to claim 1, characterized in that, In step one: the solvent used to prepare Apre intermediate 1 is acetonitrile, N,N-dimethylformamide, tetrahydrofuran or acetone; the catalyst used is MgO or K2CO3.

3. The method for preparing apremilast according to claim 1, characterized in that, In step two: the solvent used to prepare Apre intermediate 2 is anhydrous DMF, anhydrous acetonitrile, anhydrous tetrahydrofuran or acetone; the nucleophile used is methanethiol salt.

4. The method for preparing apremilast according to claim 1, characterized in that, In step three, when preparing Apre intermediate 3, the solvent used is one or more of dichloromethane, methanol, methyl isobutyl ketone, ethyl acetate, and acetone; the tartaric acid resolving agent used is one or more of L-di-p-methoxybenzoyl tartaric acid, L-dibenzoyl tartaric acid, L-di-p-methylbenzoyl tartaric acid, L-di-p-chlorobenzoyl tartaric acid, L-di-p-bromobenzoyl tartaric acid, L-di-p-nitrobenzoyl tartaric acid, or L-di-p-cyanobenzoyl tartaric acid.

5. According to the method for preparing intermediate 3 as described in claim 1, after the reaction in step three is completed, an alkali treatment is performed. The alkali treatment solvent is water or an aqueous solution of an organic solvent, including ethanol or methanol, and the alkali includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.

6. The method for preparing intermediate 4 according to claim 1, characterized in that, In step four, when preparing intermediate 4, the solvent used is trifluoroacetic acid, glacial acetic acid, formic acid, or propionic acid.

7. The Apster method according to claim 1, characterized in that, After the reaction in step four is completed, the product is washed with an alkaline saturated aqueous solution and then pulped to obtain intermediate 4; wherein, the alkaline saturated aqueous solution is saturated sodium carbonate, saturated potassium carbonate, saturated sodium bicarbonate or saturated potassium bicarbonate.

8. The Apster method according to claim 1, characterized in that, In step five, the solvent used to prepare Apres is methanol, acetonitrile, tetrahydrofuran, or acetone; the catalyst used is TaCl5 or NbCl5.

Images