Process for the preparation of an iron catalyst and intermediates for remegapride

Abstract

The application is a method for preparing a remegapam intermediate, comprising a catalyst and a preparation method of the catalyst, which is used for preparing a remegapam intermediate through chiral asymmetric reduction, avoids using a traditional noble metal catalyst, reduces the preparation cost, and can be used for industrial production; wherein Fe 2+ / EDTA is used as a catalyst, and d-camphorsulfonic acid is used as an inducing agent, so that the key intermediate of remegapam can be efficiently prepared; by adopting the scheme, the key intermediate is obtained, the chiral purity is high, the operation is simple, and the industrial production of the product in the later stage can be realized.

Description

Technical Field

[0001] This invention relates to a method for preparing an iron catalyst and a rimexam intermediate, comprising a one-step asymmetric reduction method and an asymmetric reduction ammoniation method. Background Technology

[0002] Rimegepant, developed by Biohaven Pharmaceutical, is an oral CGRP receptor antagonist that promises to treat migraines through this recently popular pathway. Studies have shown that patients experience improvement in headache symptoms within 8 hours of treatment. Topline results from a Class III clinical trial indicate that a single oral dose of Rimegepant provides a rapid and effective treatment for migraines. It can resolve headaches and other bothersome symptoms without the need for repeated doses.

[0003] Migraine is one of the most common neurological disorders in medical practice, affecting nearly 16% of the U.S. population. It can be a serious and debilitating condition, with over 43% of migraine sufferers reporting moderate to severe disability. The 2019 Global Burden of Disease survey ranked migraine as the second leading cause of disability, and the leading cause of disability among women aged 15 to 49. The direct healthcare costs per person per year for migraine sufferers in the U.S. are estimated at $22,364, with total indirect costs estimated at over $19 billion. This comprehensive socioeconomic impact warrants further efforts to broaden our understanding of the pathophysiology of migraine and support the development of new treatments. Compared to Eli Lilly's 5HT1F receptor agonist Lasmiditan (Reyvow), which was launched in October 2019, and AbbVie's Ubrelvy (Ubrogepant), which targets the same receptor and was approved in December 2019, nearly 50% of physicians prefer to recommend Biohaven's Nurtec (Rimegepant).

[0004] In the synthesis process of Remigra, the intermediate compounds of formula 3 and formula 8 are key intermediates. The configuration of the two chiral centers in the drug molecule is mainly formed in these two steps. In the patent published by the original manufacturer (WO2009126530), there are two main methods for synthesizing the formula 3 compound. One is the reductase catalytic method, which uses a reductase to asymmetricly reduce the formula 1 compound to the formula 2 compound under enzymatic conditions and then protect it to obtain the formula 3 compound. The other method is to use metal rhodium as a catalyst to prepare the compound by asymmetric hydrogenation.

[0005] Enzymatic methods are currently one of the more popular ways to perform asymmetric reduction, but they also have problems. Enzymes are difficult to obtain, and it is difficult to preserve their activity and catalytic ability. Most enzyme-catalyzed reactions are single-use, and reuse is difficult, resulting in high costs. Using rhodium as a catalyst for asymmetric hydrogenation is also problematic. The catalyst preparation is difficult, the required hydrogenation is not safe, and the processing is complicated. Furthermore, rhodium is a precious metal and is expensive, so it should not be prepared on a large scale for industrial production. Summary of the Invention

[0006] To overcome the shortcomings of the above routes, this invention develops an iron catalyst for the asymmetric synthesis of the two key intermediates. In the preparation of compound 3, the newly developed iron catalyst is used (the preparation process is as follows). Figure 4 ), which can effectively catalyze the reaction, and the optical purity (ee value) of compound 3 was determined. Secondly, Fe was used. 2+ EDTA is used as a reducing agent for ammoniation, and the preparation cost of iron catalysts is relatively low, making it more suitable for industrial production.

[0007] The technical solution of this invention is a method for preparing a rimex intermediate and an iron catalyst, the specific steps of which are as follows:

[0008] The preparation of the iron catalyst compound of formula 13 includes the following steps:

[0009] (1) L-valine was heated to 90-100℃ under formic acid conditions to prepare compound 10;

[0010] (2) Compound 10 was reacted with phenyl dichlorophosphate under n-butyl conditions to prepare compound 12;

[0011] (3) Compound 12 was used to prepare compound 13, an iron catalyst, under the condition of ferrous chloride tetrahydrate.

[0012] The preparation process for compounds of formula 3 and formula 8 using an iron catalyst includes the following steps:

[0013] (1) Compound of Formula 1 is asymmetrically reduced to compound under the conditions of compound of Formula 13 with iron catalyst and potassium tert-butoxide.

[0014] (2) Compound 2 was then reacted with triisopropylchlorosilane under alkaline conditions to protect the hydroxyl groups and prepare compound 3.

[0015] (3) Compound of Formula 3 was reacted with compound of Formula 4 under palladium acetate conditions to prepare compound of Formula 5;

[0016] (4) Compound of formula 5 in Fe 2+The sulfonate of compound formula 7 was prepared by asymmetric reductive ammoniation using EDTA, dextrorotatory camphor sulfonic acid, ammonia and hydrogen.

[0017] (5) Compound 7 was dissociated under ammonia conditions to prepare compound 8.

[0018] In a preferred embodiment, the present invention provides an iron catalyst, characterized in that the iron catalyst comprises a compound of formula 13, wherein the compound of formula 13 is:

[0019]

[0020] In a preferred embodiment, the present invention further provides a method for preparing a compound of formula 13, characterized in that the method comprises the following steps:

[0021] 1a) Prepare compound 10 by heating L-valine to 90-100°C under formic acid conditions, wherein compound 10 is:

[0022]

[0023] 1b) Compound of Formula 10 is prepared by reacting it with phenyl dichlorophosphate under n-butyl conditions, wherein compound of Formula 12 is:

[0024]

[0025] 1c) Prepare compound 13 by subjecting compound 12 to ferrous chloride tetrahydrate.

[0026] In another preferred embodiment, in step 1a), the mass ratio of L-valine to acetic acid is 1:2 to 1:8, and the heating temperature is 70-100°C.

[0027] In another preferred embodiment, in step 1b), the base includes n-butyllithium, diisopropylaminolithium, methyllithium or diisopropylaminolithium; the reaction temperature is -60℃ to -80℃; and the equivalence ratio of phenylphosphonic dichloride to the compound of formula 10 is 1:1.1-1.2.

[0028] In another preferred embodiment, in step 1c), the ferrous compound reacting with the compound of formula 12 includes ferrous chloride tetrahydrate, ferrous sulfate heptahydrate, ferrous nitrate, and ferrous phosphate, and the equivalence ratio of phenylphosphonic dichloride to the compound of formula 10 is 1:1.1-1.2.

[0029] In a preferred embodiment, the present invention further provides a method for preparing compounds of formula 3 and formula 8, characterized in that the method comprises the following steps:

[0030] 2a) The compound of formula 1 is asymmetrically reduced to formula 2 under the conditions of the compound of formula 13 and potassium tert-butoxide, wherein the compound of formula 1 is:

[0031]

[0032] The compound of formula 2 is:

[0033]

[0034] 2b) After reacting Formula 2 with triisopropylchlorosilane under alkaline conditions, a compound of Formula 3 is prepared, wherein the compound of Formula 3 is:

[0035]

[0036] 2c) Reacting compound 3 with compound 4 under palladium acetate conditions to prepare compound 5, wherein compound 4 is:

[0037]

[0038] The compound of formula 5 is:

[0039]

[0040] 2d) Make compound 5 in Fe 2+ The sulfonate of compound 7 was prepared by reacting EDTA, dextrorotatory camphor sulfonic acid, alkali, and hydrogen gas. Compound 7 is:

[0041]

[0042] 2e) The compound of formula 7 is dissociated under alkaline conditions to prepare the compound of formula 8, wherein the compound of formula 8 is:

[0043]

[0044] In another preferred embodiment, in steps 2a) and 2b), the molar percentage concentration ratio of compound 13 to compound 1 is 1%mol-5%mol; the molar ratio of potassium tert-butoxide to compound 1 is 1:0.1-1:1; the reagents for applying the triisopropylsilyl protecting group after chiral reduction include triisopropylchlorosilane and triisopropylsilyltrifluoromethanesulfonate.

[0045] In another preferred embodiment, in step 2c), the reagent used for chiral salt formation includes dextrorotatory camphor sulfonic acid, L-tartaric acid, D-malic acid, or L-mandelic acid.

[0046] In another preferred embodiment, in step 2d), the catalyst used for reductive ammoniation includes Fe. 2+ / EDTA, sodium borohydride, sodium cyanoborohydride or borane; the molar percentage concentration of the catalyst is 5%mol-15%mol; the hydrogen pressure is 0.5-1MPa.

[0047] In another preferred embodiment, in steps 2d) and 2e), the alkaline conditions include ammonia, triethylamine, or diisopropylethylamine, and the pH is adjusted to 6-9.

[0048] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0049] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of the present invention more apparent and understandable, preferred embodiments are described below in detail with reference to the accompanying drawings. Attached Figure Description

[0050] Figure 1 This is a schematic diagram of the iron catalyst (compound of formula 13) of the present invention;

[0051] Figure 2 This is a schematic diagram of the structure of the intermediate (compound of formula 3) of the present invention;

[0052] Figure 3 This is a schematic diagram of the structure of the intermediate of the remigelpam (compound of formula 8) of the present invention;

[0053] Figure 4 This is a schematic diagram of the preparation steps of the iron catalyst (compound of formula 13) of the present invention;

[0054] Figure 5 This is a schematic diagram illustrating the preparation steps of the intermediates (compounds 3 and 8) of Remepiride using an iron catalyst (compound of formula 13) according to the present invention. Detailed Implementation

[0055] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0056] The preparation of compound of formula 13 for asymmetric reduction of iron catalysts includes the following steps:

[0057] Example 1: Preparation of (S)4-isopropyl-4,5-dihydrooxazole (compound of formula 10) (as in reaction formula 1):

[0058]

[0059] In a 1000ml three-necked flask, add 50g of L-valine and 250ml of formic acid, and heat to 90-100℃. React at this temperature for 10 hours. After the reaction is complete, concentrate the formic acid to 100ml, add 1200ml of water to the system and stir for 30 minutes. A solid precipitates out. Filter out the solid and dry it in a vacuum oven for 6 hours (55-60℃) to obtain 45.2g of white solid.

[0060] Example 2: Preparation of phosphine ligands (compound of formula 12) (as in reaction formula 2):

[0061]

[0062] In a 1000ml three-necked flask under nitrogen protection, 40g (0.354mol) of compound 10 and 300ml of tetrahydrofuran were added and stirred until dissolved. The system was then cooled to -70℃, and 195ml of LDA (2M diisopropylaminolithium) was added dropwise while maintaining the temperature below -65℃. After the addition was complete, the reaction was carried out at this temperature for 1 hour. Then, 75.93g (0.354mol) of phenylphosphonic dichloride was added, and the mixture was stirred at -70℃ for 30 minutes before being slowly raised to -20℃. 200ml of saturated ammonium chloride solution was added, and the mixture was allowed to stand and separate. The resulting organic phase, containing anhydrous sodium sulfate, was used directly in the next reaction step.

[0063] Example 3: Preparation of iron-catalyzed compound (Formula 13) (as in reaction formula 3):

[0064]

[0065] 77.50 g (0.389 mol) of ferrous chloride tetrahydrate was dissolved in 280 ml of methanol, and then added to the reaction solution obtained in the previous step. The mixture was stirred at room temperature for 10 hours, and the reaction solution was concentrated to 150 ml. 300 ml of purified water was added and stirred for 1 hour. A solid precipitated out. The solid was filtered out to obtain a green solid. The solid was placed in a vacuum oven and dried for 6 hours (50 °C, -0.09 MPa) to obtain 53.2 g of a light green solid.

[0066] A synthetic method for preparing the intermediate of retinoic acid includes the following steps:

[0067] Example 4: Preparation of intermediate compound of formula 3 of rimexam (e.g., reaction formula 4):

[0068]

[0069] In a 1000 mL three-necked flask, 60 g (0.343 mol) of compound 1 was dissolved in 300 mL of tetrahydrofuran. 7.52 g (2.5 mol%) of iron catalyst (compound 13), 10 mL of tert-butanol, and 7.6 g (0.068 mol) of potassium tert-butoxide were added. The mixture was kept at 25 ± 5 °C for 5 h. After confirming the complete reaction of compound 1 by thin-layer chromatography (TLC), the temperature was controlled at 10 ± 5 °C. Then, 80 mL of saturated ammonium chloride aqueous solution was added to the reaction mixture. After stirring for 10 minutes, the mixture was allowed to stand and separate into layers. The organic phase was separated, dried with anhydrous sodium sulfate, and filtered to obtain anhydrous sodium sulfate. The solution was concentrated to a brown oily substance and directly added to the next reaction step.

[0070] In a 1000 mL three-necked flask, the above-mentioned brown liquid (approximately 50 g, 0.291 mol) and triethylamine (44.2 g, 0.437 mol) were dissolved in ethyl acetate (300 mL). At 10 °C, triisopropylsilyltrifluoromethanesulfonate (89.3 g, 0.291 mol) was added, and the mixture was stirred for 30 minutes. Then, a saturated ammonium chloride solution (560 mL) was added, and the layers were separated. The organic layer was washed successively with water (200 mL) and a saturated sodium chloride solution (200 mL), and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain a light brown oil, which was dissolved in n-hexane (200 mL). The n-heptane solution was cooled to 0 °C and maintained for 30 minutes. A solid precipitated out; this solid was filtered off and dried under vacuum at 30 °C to obtain compound 3 (52 g, chiral HPLC > 98%).

[0071] Example 5: Preparation of intermediate compound 5 of rimexam (e.g., reaction formula 5):

[0072]

[0073]

[0074] In a 500 mL round-bottom flask, compound 3 (30 g, 90 mmol), tri-tert-butylphosphine tetrafluoroboric acid (2.6 g, 9.0 mmol), palladium acetate (1 g, 4.5 mmol), sodium tert-butoxide (13 g, 134.8 mmol), and toluene (1800 mL) were added sequentially for dissolution. Then, 1-bromo-2,3-difluorobenzene (21.2 g, 110 mmol) was added. The reaction mixture was heated at 95 °C for 3 hours. Thin-layer chromatography (TLC) showed that the starting material had essentially disappeared. The reaction solution was cooled to 25 °C, and 120 mL of ethyl acetate was added. The mixture was washed twice with saturated ammonium chloride solution (75 mL × 2). Insoluble flocculent matter was removed by filtration, and the organic layer was separated and concentrated under vacuum. The resulting dark solution was adsorbed onto a silica gel (150 g) packed bed and eluted with dichloromethane / petroleum ether (1:1) (or toluene) to remove a large amount of pigment. The solution was concentrated under vacuum to give 32 g of a yellow oil (80% yield).

[0075] 15 g of the above-mentioned yellow oily substance was dissolved in a water / n-butanol (1:4, 190 mL) solution, and then 0.6 mL of triethylamine was added. The mixture was stirred at 20 °C for 12 h, and a large amount of white solid precipitated out. The mixture was filtered, and the filter cake was washed with a water / isopropanol (4:1, 10 mL) solution. The solution was then dried under vacuum at 50 °C to obtain a white solid (36.8 g, chiral HPLC > 98%).

[0076] Example 6: Preparation of Remepiride intermediate compound of formula 7 (as in reaction formula 6):

[0077]

[0078] In a 2L hydrogenation reactor, 300.00g of purified water and 13.00g (5.6mmol) of dextrorotatory camphor sulfonic acid compound 6 were added and stirred until dissolved. Then, 32.00g (0.070mol) of compound 5 and Fe were added. 2+ / EDTA complex catalyst (24.3g, 0.07mol). Heat to 80-85℃, slowly introduce 0.6MPa hydrogen gas into the hydrogenation reactor, and maintain this pressure for approximately 10 hours. After the reaction is complete, cool to 20-25℃ and filter. The filter cake is compound 7 (salt form of dextrorotatory camphor sulfonic acid, wet weight 35.7g), a white crystalline solid. This product directly proceeds to the next reaction (dissociation into free base).

[0079] Example 7: Preparation of Remepiride intermediate compound of formula 8 (e.g., reaction formula 7):

[0080]

[0081] In a 1L three-necked flask, the aforementioned wet filter cake (compound of formula 7) and 350.00g of purified water were added. The mixture was then heated to 80°C and stirred until dissolved. The pH of the reaction system was adjusted to 7-8 with ammonia. The mixture was stirred and cooled to below 25°C. After filtration, the filter cake was a white, flaky solid, which was the target product, compound of formula 8. After drying, it weighed 23.3g and had a chiral HPLC purity greater than 98.0%.

[0082] The above description is only a specific embodiment of the present invention. The scope of protection of the method for preparing an iron catalyst and a rimex intermediate of the present invention includes, but is not limited to, these embodiments. In the appended claims of the present invention, the specific embodiments shown in the present invention can be replaced and modified, and such replacements and modifications should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing compounds of formula 3 and formula 8, characterized in that, The method includes the following steps: 2a) The compound of formula 1 is asymmetrically reduced to the compound of formula 2 under the conditions of the compound of formula 13 and potassium tert-butoxide, wherein the compound of formula 13 is: The compound of formula 1 is: The compound of formula 2 is: 2b) Reacting compound 2 with triisopropylsilyltrifluoromethanesulfonate under alkaline conditions to prepare compound 3, wherein compound 3 is: 2c) Reacting compound 3 with compound 4 under palladium acetate conditions to prepare compound 5, wherein compound 4 is: The compound of formula 5 is: 2d) Make compound 5 in Fe 2+ Compound of Formula 7 was prepared by reacting EDTA, dextrorotatory camphor sulfonic acid, ammonia, and hydrogen under the conditions of EDTA, dextrorotatory camphor sulfonic acid, ammonia, and hydrogen. Compound of Formula 7 is: 2e) The compound of formula 7 is dissociated under alkaline conditions to prepare the compound of formula 8, wherein the compound of formula 8 is: Step 2a) includes: In a 1000 mL three-necked flask, 0.343 mol of compound 1 was dissolved in 300 mL of tetrahydrofuran. 2.5 mol% of compound 13, 10 mL of tert-butanol, and 0.068 mol of potassium tert-butoxide were added. The mixture was kept at 25 ± 5 °C for 5 h. After thin-layer chromatography confirmed that compound 1 had reacted completely, the temperature was controlled at 10 ± 5 °C. 80 mL of saturated ammonium chloride aqueous solution was added to the reaction mixture. After stirring for 10 minutes, the mixture was allowed to stand and separate into layers. The organic phase was separated and dried with anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered out and concentrated to a brown oily substance, which was then used directly in the next reaction. Step 2b) includes: In a 1000 mL three-necked flask, 0.291 mol of the brown oil and 0.437 mol of triethylamine were dissolved in 300 mL of ethyl acetate. At 10 °C, 0.291 mol of triisopropylsilyltrifluoromethanesulfonate was added, and the mixture was stirred for 30 minutes. Then, 560 mL of saturated ammonium chloride solution was added, and the layers were separated. The organic layer was washed successively with 200 mL of water and 200 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain a light brown oil, which was dissolved in 200 mL of n-hexane. The n-hexane solution was cooled to 0 °C and maintained for 30 minutes, resulting in the precipitation of a solid. The solid was filtered off and dried under vacuum at 30 °C to obtain 52 g of the compound of formula 3, with a chiral HPLC efficiency >98%.

2. The method according to claim 1, characterized in that, In step 2d), the catalyst used for reductive ammoniation includes Fe. 2 + / EDTA; the molar ratio of catalyst to substrate is 1:1 to 1:1.5, and the hydrogen pressure is 0.5-1 MPa.

3. The method according to claim 1, characterized in that, In step 2e), the alkaline conditions include ammonia, triethylamine, or diisopropylethylamine, adjusted to a pH of 7-8.

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