Preparation method for deuterated methoxyindole compound and intermediate thereof

Abstract

A preparation method for a deuterated methoxyindole compound, specifically relating to a preparation method for a compound represented by formula (I) and an intermediate thereof. The preparation method is convenient to operate, safe and controllable, has a high yield, and is suitable for industrial scaled-up production.

Description

A method for preparing deuterated methoxyindole compounds and their intermediates Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a method for preparing a deuterated methoxyindole compound, specifically to a method for preparing the compound of formula (I) and its intermediates. Background Technology

[0002] Complement Factor B (CFB) acts on the alternative pathway (AP). Inhibiting Factor B activity can prevent API pathway activation without interfering with the CP (classical pathway) and LP (lectin pathway), thus avoiding increased infection risk due to complement system inhibition.

[0003] WO2024169896 patent describes compound 1, which has good complement factor B (CFB) inhibitory activity.

[0004] The synthetic route of compound 1 described in the aforementioned patent is as follows:

[0005] In the above preparation method, the first step uses Ir(CO)₂acac / H₂ as the reaction reagent to obtain compound B, with a yield of 60%. The second step uses solid potassium carbonate and lithium hydroxide monohydrate as alkaline reagents to hydrolyze B, followed by liquid-phase preparation to obtain trifluoroacetate of compound 1. The trifluoroacetate of compound 1 is then treated with a saturated Na₂CO₃ solution to obtain compound 1 again, with a yield of 38%. Finally, compound 1 reacts with succinic acid to form succinate. This route uses reagents that are inconvenient to operate and pose safety hazards, such as H₂, and reagents that are costly and environmentally unfriendly, such as Ir(CO)₂acac. Furthermore, the products of each step require purification by silica gel column chromatography or liquid-phase preparation. The reaction time is long, the overall yield is low, and the cost is high, making it unsuitable for industrial-scale production. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing compound of formula (I), which is convenient to operate, safe and controllable, has a high yield, and is suitable for industrial-scale production.

[0007] In one aspect, the present invention provides a method for preparing a compound of formula (I), wherein a compound of formula (II) is prepared from a compound of formula (I) via step a;

[0008] Step a includes two steps, namely step a-1 and step a-2. Step a-1 contains an alkaline reagent, and step a-2 contains succinic acid.

[0009] In some embodiments, the alkaline reagent in step a-1 is selected from one or more of potassium trimethylsilanolate, sodium trimethylsilanolate, and potassium triethylsilanolate, preferably potassium trimethylsilanolate;

[0010] In some embodiments, the molar ratio of compound (II) to potassium trimethylsilanolate in step a-1 is 1:(2.0 to 6.0), preferably 1:(3.0 to 4.0), and more preferably 1:3.3;

[0011] In some embodiments, step a-1 further includes a solvent, which is selected from one or more of ethanol, methanol, and isopropanol, preferably ethanol;

[0012] In some embodiments, the mass ratio of compound II to ethanol in step a-1 is 1:(2-4), preferably 1:3.2;

[0013] In some embodiments, the reaction temperature in step a-1 is 40–80°C, preferably 60–70°C;

[0014] In some implementation schemes, the reaction time in step a-1 is 6 to 8 hours;

[0015] In some embodiments, the molar ratio of compound (II) to succinic acid in step a-2 is 1:(3.0 to 7.0), preferably 1:(4.0 to 5.0), and more preferably 1:4.5;

[0016] In some embodiments, step a-2 includes an aqueous solution of succinic acid, wherein the mass percentage of succinic acid is 5% to 20%, preferably 8% to 12%, and more preferably 11%.

[0017] In some embodiments, the reaction temperature in step a-2 is 30–60°C, preferably 40–45°C;

[0018] In some implementation schemes, the reaction time in step a-2 is 0.5 to 2.5 hours, preferably 1 hour;

[0019] In some embodiments, the crystallization temperature in step a-2 is 10–25°C, preferably 20–25°C;

[0020] In some implementations, the crystallization time in step a-2 is 3 to 5 hours, preferably 4 hours;

[0021] In some implementations, after step a-1, the reaction solution is directly added to the solid succinic acid or the aqueous solution containing succinic acid in step a-2;

[0022] In some embodiments, the compound of formula (II) is prepared by step a without column chromatography or preparative column separation and purification.

[0023] The present invention also provides a method for preparing a compound of formula (II), wherein a compound of formula (II) is obtained from a compound of formula (III) and a compound of formula (IV) by step b;

[0024] Step b includes a reducing agent, which is selected from one or more of sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, and potassium borohydride, preferably sodium triacetoxyborohydride;

[0025] In some embodiments, the reducing agent in step b is selected from sodium triacetoxyborohydride, and the molar ratio of the compound of formula (IV) and formula (III) to sodium triacetoxyborohydride is 1:(0.9-1.5):(2.0-4.5), preferably 1:(1.0-1.4):(2.5-3.5), and more preferably 1:1.1:3;

[0026] In some embodiments, the solvent in step b is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, and ethanol, preferably N,N-dimethylacetamide;

[0027] In some embodiments, the solvent in step b is selected from N,N-dimethylacetamide, and the mass ratio of N,N-dimethylacetamide to compound IV is 1:(4-6), preferably 1:5;

[0028] In some embodiments, the reaction temperature in step b is 20–50°C, preferably 40°C;

[0029] In some embodiments, step b includes a refining step (preferably recrystallization or pulping), wherein the refining solvent is one or more of isopropanol, methanol, ethanol, propanol, and water, preferably isopropanol, methanol, and water;

[0030] In some embodiments, the purification in step b involves adding crude product of formula (II) compound to isopropanol, heating (preferably 50-80°C) and stirring until dissolved, cooling to 5°C-35°C (preferably 20°C), adding methanol and stirring (preferably stirring for about 2 hours), finally adding water, stirring at 0°C-20°C (preferably 5°C-10°C) (preferably stirring for about 2 hours), filtering, and optionally washing the filter cake with an aqueous methanol solution. The resulting solid is high-purity (preferably, purity ≥95%, more preferably, purity ≥98%) formula (II) compound.

[0031] In some embodiments, in the purification process of step b, the mass ratio of isopropanol:methanol:water is 1:(0.8-1.5):(0.5-1.5), preferably 1:1:1.

[0032] In some implementations, step b does not involve column chromatography or preparative column separation and purification.

[0033] This invention provides a method for preparing compound (I), which is obtained through the following reaction formula.

[0034] The reaction conditions for step (a) are the same as those for any of the compounds involved in formula (I) mentioned above;

[0035] The reaction conditions for step (b) are the same as those for any of the compounds involved in formula (II) mentioned above.

[0036] Technical effects of the present invention:

[0037] 1. In the process route of the synthetic formula (I) of the present invention, the reaction conditions of each step are mild, safe and controllable, simple to operate, and have high yield. The product has high purity and chiral purity, and the post-processing is convenient. It is suitable for industrial production. In particular, the succinate is obtained directly in one pot in step (a), which is simple to operate and highly efficient.

[0038] 2. The process of this invention has simple operation steps, and the entire synthesis process does not use silica gel column chromatography or other preparative chromatographic methods. The intermediates have good stability, high purity, and high yield, making them suitable for large-scale industrial production. Detailed Implementation

[0039] The present invention will be further described in detail below with reference to embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art in accordance with the disclosure of the present invention shall fall within the protection scope of the present invention.

[0040] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0041] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0042] HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph with a Zorbax SB-C18 column (100×4.6 mm, 3.5 μm).

[0043] Thin-layer chromatography (TLC) analysis used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates with a diameter of 0.15mm-0.20mm, while thin-layer chromatography separation and purification used plates with a diameter of 0.4mm-0.5mm.

[0044] Example 1: Preparation of Compound II

[0045] Add 250g N,N-dimethylacetamide, 50g compound IV, and 62g compound III to the reaction vessel, maintain the internal temperature at 25°C, and stir for approximately 1.0 hour. Add 123g sodium triacetoxyborohydride, and after the addition is complete, adjust the internal temperature to 45°C and react for approximately 4 hours. After the reaction is complete, cool to 20°C, add 80g methanol, and stir for approximately 0.5 hours.

[0046] Add 100g of water to the crystallization vessel, slowly add the quenched reaction solution to the crystallization vessel, adjust the pH to about 7-8 with 50% potassium phosphate aqueous solution, filter, and collect filter cake I.

[0047] Add 280g isopropanol and filter cake I to the reactor, heat to 75℃, and stir to dissolve; add 280g methanol, cool to 20℃, and stir for about 2 hours; add 150g water, cool to 10℃, and stir for about 2 hours. Filter, wash the filter cake with 150g of 50% methanol aqueous solution (mass ratio 1:1, the same below), and collect filter cake II.

[0048] Filter cake II was dried under reduced pressure to obtain compound II (92.6 g).

[0049] Yield: 90%, HPLC purity: 99.50%.

[0050] Example 2: Preparation of Compound II

[0051] Add 250g N,N-dimethylacetamide, 50g compound IV, and 75g compound III to the reaction vessel, maintain the internal temperature at 25℃, and stir for approximately 1.0 hour. Add 123g sodium triacetoxyborohydride, and after the addition is complete, adjust the internal temperature to 40℃ and react for approximately 4 hours. After the reaction is complete, cool to 20℃, add 80g methanol, and stir for approximately 0.5 hours.

[0052] Add 100g of water to the crystallization vessel, then slowly add the quenched reaction solution to the crystallization vessel, and adjust the pH to about 7-8 with a 50% potassium phosphate aqueous solution.

[0053] Filter and collect filter cake I.

[0054] 280 g of isopropanol and filter cake I were added to a reaction vessel, heated to 75 °C, and stirred to dissolve. 280 g of methanol was added, and the mixture was cooled to 20 °C and stirred for approximately 2 hours. 150 g of water was added, and the mixture was cooled to 10 °C and stirred for approximately 2 hours. The mixture was filtered, and the filter cake was washed with 150 g of 50% methanol aqueous solution. Filter cake II was collected. Filter cake II was dried under reduced pressure to obtain compound II (90.6 g).

[0055] Yield 88%, HPLC purity 99.76%.

[0056] Example 3: Preparation of Compound II

[0057] Add 500g N,N-dimethylacetamide, 100g compound IV, and 101g compound III to the reactor. Maintain the internal temperature at 25°C and stir for approximately 1.0 hour. Add 123g sodium triacetoxyborohydride. After the addition is complete, adjust the internal temperature to 45°C and react for approximately 4 hours. After the reaction is complete, cool to 20°C, add 160g methanol, and stir for approximately 0.5 hours.

[0058] Add 100g of water to the crystallization vessel, then slowly add the quenched reaction solution to the crystallization vessel, and adjust the pH to about 7-8 with a 50% potassium phosphate aqueous solution.

[0059] Filter and collect filter cake I.

[0060] 560 g of isopropanol and filter cake I were added to a reaction vessel, heated to 75 °C, and stirred to dissolve. 560 g of methanol was added, the temperature was lowered to 20 °C, and the mixture was stirred for approximately 2 hours. 560 g of water was added, the temperature was lowered to 10 °C, and the mixture was stirred for approximately 2 hours. The mixture was filtered, and the filter cake was washed with 150 g of 50% methanol aqueous solution. Filter cake II was collected. Filter cake II was dried under reduced pressure to obtain compound II (144 g).

[0061] Yield: 78%, HPLC purity: 98.39%.

[0062] Example 4: Preparation of Compound I

[0063] Add 320g of ethanol, 100g of compound II, and 79g of potassium trimethylsilanolate to the reaction vessel and react at 65°C for about 8 hours.

[0064] After the reaction is complete, cool to 45°C, add 899g of succinic acid aqueous solution (99g of succinic acid dissolved in 800g of water), stir at 40°C for 1 hour; cool to 20°C, and stir for about 4 hours.

[0065] The mixture was filtered, the filter cake was collected, and dried under reduced pressure to obtain compound I, 82.8 g, yield: 87%, purity: 99.6%, chiral purity: 99.9%.

[0066] Example 5: Preparation of Compound I

[0067] Add 320g of ethanol, 100g of compound II, and 95g of potassium trimethylsilanolate to the reaction vessel and react at 65°C for about 6 hours.

[0068] After the reaction is complete, cool to 45°C, add 899g of succinic acid aqueous solution (99g of succinic acid dissolved in 800g of water), keep warm at 40°C and stir for 1 hour; cool to 20°C and stir for about 4 hours.

[0069] The mixture was filtered, the filter cake was collected, and dried under reduced pressure to obtain 87.6 g of compound I, with a yield of 92%, a purity of 99.7%, and a chiral purity of 100%.

[0070] Compound I: 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 8.02-8.04 (d, 2H), 7.67-7.69 (d, 2H), 7.29-7.30 (t, 1 H), 6.68(s, 1H), 6.48-6.49(t, 1H), 3.64-3.67(d, 1H), 3.26-3.30(t, 2H), 2.86-2.89(d, 1H), 2.46(s, 6H), 2.04-2.10(t, 1H), 1.76-1.78(d, 1H), 1.57-1.60(d, 1H), 1.40-1.49(m, 1H), 1. 19-1.28 (m, 1H), 0.69-0.77 (m, 1H), 0.45-0.49 (m, 1H), 0.27-0.30 (m, 2H), 0.03-0.04 (m, 2H).

Claims

1. A method for preparing a compound of formula (I), characterized in that, Compound of formula (I) is prepared from compound of formula (II) via step a; Step a includes two steps, namely step a-1 and step a-2. Step a-1 contains an alkaline reagent, which is selected from one or more of potassium trimethylsilanolate, sodium trimethylsilanolate, and potassium triethylsilanolate, preferably potassium trimethylsilanolate. Step a-2 contains succinic acid.

2. The preparation method according to claim 1, wherein the molar ratio of compound (II) to potassium trimethylsilanolate in step a-1 is 1:(2.0-6.0), preferably 1:(3.0-4.0).

3. The preparation method according to claim 2, wherein step a-1 further includes a solvent, wherein the solvent is selected from one or more of ethanol, methanol, and isopropanol, preferably ethanol.

4. The preparation method according to claim 1, wherein the molar ratio of compound (II) to succinic acid in step a-2 is 1:(3.0-7.0), preferably 1:(4.0-5.0).

5. The preparation method according to claim 4, wherein step a-2 comprises an aqueous solution of succinic acid, wherein the mass percentage of succinic acid is 5% to 20%, preferably 8% to 12%.

6. A method for preparing a compound of formula (II), characterized in that, Compound (II) was prepared from compound (III) and compound (IV) by step b; Step b includes a reducing agent, which is selected from one or more of sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, and potassium borohydride, preferably sodium triacetoxyborohydride; The reaction solvent is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, and ethanol, with N,N-dimethylacetamide being preferred.

7. The preparation method according to claim 6, wherein the reducing agent in step b is selected from sodium triacetoxyborohydride, and the molar ratio of the compound of formula (IV) and formula (III) to sodium triacetoxyborohydride is 1:(0.9-1.5):(2.0-4.5), preferably 1:(1.0-1.2):(2.5-3.5).

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