A method for synthesizing a chiral alcohol intermediate of Remigipam

Abstract

The present application provides a method for synthesizing a chiral alcohol intermediate of remegipam, the method comprising: reacting an in-situ formed Rh catalyst and compound 6 under heating conditions in a solvent under a hydrogen atmosphere, and post-treating the reaction mixture to obtain a chiral alcohol intermediate of remegipam (i.e., compound 5), wherein the Rh catalyst is obtained by reacting a Rh catalyst precursor and a ligand; the ligand is selected from at least one of (1S, 1'S, 2R, 2'R, 3aS, 3'aS, 7aS, 7'aS)-ZhangPhos, (S)-BINAP, (R,R)-DIOP, (S)-SEGPhos, and (S,S)-QuinoxP*. The invention uses Rh reagent for efficient asymmetric catalysis to prepare the remigipam chiral alcohol intermediate, the conversion rate reaches 99%, and the ee value reaches more than 99%, the amount of catalyst used is small, the efficiency of converting the ketone into the chiral alcohol is high, high regioselectivity and high enantioselectivity are achieved, the reaction process is stable and controllable, side reactions are not likely to occur, and after the reaction is completed, simple column chromatography separation and purification are required, which is simple and efficient and conducive to industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of hydrogenation catalysis and relates to a method for synthesizing a remegipam chiral alcohol intermediate. Background Art

[0002] Rimegepant, with the CAS number of 1289023-67-1, is a calcitonin gene-related peptide (CGRP) receptor antagonist developed by Biohaven and first approved by the FDA on February 27, 2020. It is a calcitonin gene-related peptide (CGRP) receptor antagonist that can be used to treat adult migraine (affecting about 15% of the world's population). The migraine market size in 2024 could exceed $11 billion. Studies have shown that within 8 hours of treatment, patients' headache symptoms improved. The top-line results of the Phase III clinical trial showed that a single oral dose of rimegepan is a rapid and effective treatment for migraine. It can solve headaches and other disturbing symptoms without repeated medication. In its preparation process, the synthesis of the key intermediate ketone compound 5 is particularly important for cost control. How to easily obtain a single-configuration compound 1 has an important impact on the preparation process of Rimegepant. The structural inversion process of the preparation process of rimegepan is shown in the following formula:

[0003] WO2009126530 does not disclose specific reaction conditions, nor does it disclose the ratio of (9S)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptan[b]pyridine-5-one to the compound of formula II in the product. Due to the reaction conversion rate, the product may include multiple compounds, which is a complex mixture and it is difficult to obtain a single target product. However, according to the method disclosed in the invention for converting (9S)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptan[b]pyridine-5-one into the compound of formula II, it can be inferred that the ratio of (9S)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptan[b]pyridine-5-one is low, which means that the selectivity of the enzymatic reduction to obtain the compound of formula II is not high. The specific method is shown in the following formula:

[0004] The journal article (Organic Letters, 2012, 14 (18), 4938-4941) reported two asymmetric reduction methods for the compound of formula II: using the ketoreductase catalyst ESKRED-119 and the metal catalyst Rh-(R-Binapine)(COD)BF 4 , the ee values ​​of the obtained reaction products are above 98% and 99.9%, respectively, and the reaction formula is as follows:

[0005] Ketoreductase catalyst ESKRED-119 is available in few suppliers on the market and is expensive. Metal catalyst Rh-(R-Binapine)(COD)BF 4 Not available on the market, synthetic Rh-(R-Binapine)(COD)BF 4 The ligand R-Binapine used is also difficult to prepare. The reaction conditions of its preparation method are very harsh (for example, a hydrogen pressure of up to 100 psi is required), and the dangerous reagent hexachlorodisilane is used, see Angew. Chem. Int. Ed. 2003, 42, 3509.

[0006] CN113717103B conducts a selective reduction reaction of a raw material diketone compound in the presence of a catalyst, and then performs post-treatment to obtain a target compound, but the yield of the preparation is too low and the cost is high.

[0007]

[0008] According to the existing methods, it is difficult to obtain the target compound 5. Therefore, it is difficult and necessary to develop a simple, high-yield and high-purity preparation method for compound 5. Summary of the invention

[0009] In order to overcome the shortcomings of the prior art, the present application provides a method for synthesizing a chiral alcohol intermediate of Remigipam, which is prepared by catalytic hydrogenation. In the preparation of compound 5, Rh reagent is used for efficient asymmetric catalysis, and the conversion rate reaches 99%, and the ee value reaches more than 99%. The amount of catalyst used is small, and the catalyst turnover number (TON) can reach 10,000. The efficiency of converting this type of ketone into chiral alcohol is high, high regioselectivity and high enantioselectivity are achieved, and the reaction conditions are mild and environmentally friendly.

[0010] In one aspect, the present invention provides a method for synthesizing a chiral alcohol intermediate of Remigipam, the steps comprising:

[0011] In a hydrogen atmosphere, the in-situ formed Rh catalyst and compound 6 are reacted in a first solvent under heating conditions, and the reaction mixture is post-treated to obtain a remegipam chiral alcohol intermediate (ie, compound 5).

[0012] Furthermore, the preparation process of the Rh catalyst is as follows: under an inert atmosphere, a Rh catalyst precursor and a ligand are reacted in a second solvent at room temperature to obtain the catalyst.

[0013] Furthermore, the inert gas is argon or nitrogen.

[0014] Furthermore, the Rh catalyst precursor is selected from Rh(COD) 2 BF 4 、Rh(NBD) 2 BF 4 At least one of .

[0015] Further, the ligand is selected from at least one of (1S, 1'S, 2R, 2'R, 3aS, 3'aS, 7aS, 7'aS)-ZhangPhos, (S)-BINAP, (R,R)-DIOP, (R,Sp)-JosiPhos, (Sc,Rp)-DuanPhos, (S,S)-Ph-BPE, (S,S)-QuinoxP*, (S)-SEGPhos. Further, the ligand is selected from at least one of (1S, 1'S, 2R, 2'R, 3aS, 3'aS, 7aS, 7'aS)-ZhangPhos, (S)-BINAP, (R,R)-DIOP, (S)--SEGPhos, (S,S)-QuinoxP*.

[0016] Furthermore, the molar ratio of the Rh catalyst precursor to the ligand is 1:1 to 1.5, preferably 1, 1.1, 1.2, 1.3, 1.4 or 1.5.

[0017] Furthermore, the first solvent and the second solvent are each independently selected from at least one of ethanol, isopropanol, dioxane, toluene, acetonitrile, ethyl acetate and dichloromethane.

[0018] Furthermore, the room temperature refers to a temperature of 10-40°C, preferably 15-30°C.

[0019] Furthermore, the molar ratio of the Rh catalyst to compound 6 is 1:100-10000, preferably 1:5000 or 1:10000.

[0020] Furthermore, the heating temperature is 20-60°C, preferably 30, 40, 50 or 60°C.

[0021] Furthermore, the pressure of the hydrogen atmosphere is 5 to 50 bar, preferably 5, 10, 20, 30, 40 or 50 bar.

[0022] Furthermore, after the reaction mixture was dried under reduced pressure to dry the reaction solvent, compound 5 was separated by column chromatography.

[0023] Compared with the prior art, the present invention has the following beneficial effects: The present application uses Rh catalyst for one-step catalytic hydrogenation to prepare remigipan chiral alcohol intermediate, and the conversion rate reaches more than 99%, and the ee reaches more than 99%. The reaction steps are few, the post-treatment is simple, the reaction conditions are mild, and no extremely cold or hot conditions are required. While effectively simplifying the preparation process, the production efficiency and yield are greatly improved, which is environmentally friendly and meets the requirements of green environmental protection.

[0024] Compared with the prior art, the preparation process is simple and the cost is lower. The ee value of the obtained product is high. The reaction process is stable and controllable, and side reactions are not likely to occur. After the reaction is completed, it can be separated and purified by simple column chromatography, which is simple and efficient and conducive to industrial production. Furthermore, the preferred ligand is easy to obtain, has good selectivity, and has low use cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the hydrogen spectrum of the product obtained in entry 8 in Table 1 of Example 1 of the present invention; Figure 2 This is the carbon spectrum of the product obtained in entry 8 in Table 1 of Example 1 of the present invention. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0027] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0028] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0029] (1S,1'S,2R,2'R,3aS,3'aS,7aS,7'aS)-ZhangPhos is abbreviated as zhangphos.

[0030] Example 1 Screening of ligands In an argon-filled glove box, Rh(COD) 2 BF 4 The precursor (0.003 mmol) and the ligand shown in Table 1 (0.0033 mmol) were placed in a 1.5 mL vial equipped with a stirrer, and ultra-dry (DCM) solvent (0.3 mL) was added to dissolve the mixture. After stirring for 2 h in a glove box at room temperature, a reddish brown solution was obtained, which was the in situ formed Rh catalyst.

[0031] In a glove box filled with argon, the in-situ formed Rh catalyst (0.1 mol%, 100 μL), substrate (0.1 mmol), and ultra-dry DCM (2 mL) from which oxygen was removed were added to a 2 mL hydrogenation vial equipped with a magnetic rod. The hydrogenation vial was then transferred to a high-pressure reactor in the glove box, the gas valve was closed, the bottle was tightened, the gas in the autoclave was replaced 3 times, and 10 bar of hydrogen was filled in. The autoclave was placed in a 50 °C oil bath prepared in advance and reacted for about 48 h.

[0032] After the reaction was completed, the vent switch of the autoclave was opened, the hydrogen was slowly released, and then the autoclave was opened, the solvent was drained under reduced pressure, and the adsorbed metal was separated by column chromatography to obtain the product compound 5, and then the conversion rate was confirmed by nuclear magnetic resonance hydrogen spectrum, and the ee value was confirmed by high performance liquid chromatography (HPLC), as shown in Table 1.

[0033]

[0034] Table 1 Entry Ligand Conversion Rate % 6 / 5 / 7（%） ee(%) 1 (S)-BINAP >99 0 / 100 / 0 73 2 (R,R)-DIOP >99 0 / 69 / 31 33 3 (R,Sp)-JosiPhos >99 0 / 94 / 6 29 4 (Sc,Rp)-DuanPhos >99 0 / 52 / 48 94 5 (S,S)-Ph-BPE >99 0 / 100 / 0 35 6 (S,S)-QuinoxP* >99 0 / 96 / 4 97 7 (S)-SEGPhos >99 0 / 97 / 3 77 8 ZhangPhos >99 0 / 100 / 0 99 From the data in Table 1, it can be seen that under the same experimental conditions, in Entry 3, (R,Sp)-JosiPhos is used as a ligand, and the ee value is low; in Entry 4, (Sc,Rp)-DuanPhos is used as a ligand, and the peak area of ​​compound 5 accounts for only 52%; in Entry 5, (S,S)-Ph-BPE is used as a ligand, and the ee value is low; in Entry 6, (S,S)-QuinoxP* is used as a ligand, the ee value reaches 97%, the peak area of ​​compound 5 accounts for 96%, and the peak area of ​​over-reduction product 7 accounts for 4%, and the subsequent purification will cause a slight decrease in yield; As shown in Table 1, in Entry 8, ZhangPhos is used as a ligand, the conversion rate is greater than 99%, the ee value reaches 99%, and the yield of compound 5 reaches 100%, the effect is the best, and the catalyst dosage is 1% of the substrate. The catalyst dosage S / C = 100 during this experiment. In summary, different ligands have a great influence on the catalytic effect (from the perspective of conversion rate, yield and ee value).

[0035] The structural formulas of each ligand are shown below:

[0036] Compound 5: 1H NMR (400 MHz, Chloroform-d) δ 8.6 (dd, J = 4.9, 1.7 Hz,1H), 8.1 (dd, J = 7.7, 1.7 Hz, 1H), 7.3 (dd, J = 7.7, 4.8 Hz, 1H), 5.4 (s,1H), 4.9 (dd, J = 10.4, 4.7 Hz, 1H), 2.8 – 2.7 (m, 2H), 2.5 – 2.4 (m, 1H), 2.1 – 1.9 (m, 1H), 1.8 – 1.7 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 202.8,159.9, 150.4, 137.4, 132.0, 123.0, 70.5, 41.5, 33.5, 19.1. Example 2 Solvent screening using ligand zhangphos In an argon-filled glove box, Rh(COD) 2 BF 4 The precursor (0.006 mmol) and the ligand (0.0066 mmol) were placed in a 1.5 mL vial equipped with a stirrer, and a deoxygenated ultra-dry (DCM) solvent (0.6 mL) was added to dissolve them. After stirring for 2 h in a glove box at room temperature, a reddish-brown solution was obtained, which was the in-situ formed Rh catalyst.

[0037] In a glove box filled with argon, the in-situ formed Rh catalyst (0.1 mol%, 50 μL), substrate (0.1 mmol), and ultra-dry solvent (2 mL) from which oxygen was removed were added to a 2 mL hydrogenation vial equipped with a magnetic rod. The hydrogenation vial was then transferred to a high-pressure reactor in the glove box, the gas valve was closed, the bottle was tightened, the gas in the autoclave was replaced 3 times, and 10 bar of hydrogen was filled in. The reaction was carried out at room temperature for about 24 h.

[0038] After the reaction is completed, the vent switch of the autoclave is opened, the hydrogen is slowly released, and then the autoclave is opened, the solvent is drained under reduced pressure, and the adsorbed metal is separated by column chromatography to obtain the product, and then the conversion rate is confirmed by nuclear magnetic resonance hydrogen spectrum, and the ee value is confirmed by high performance liquid chromatography (HPLC). The specific screening situation is shown in Table 2 below.

[0039]

[0040] Table 2 Entry Solvents Conversion Rate % ee(%) 1 Methanol messy -- 2 Ethanol >99 97.1 3 Isopropyl alcohol >99 98.8 4 THF >99 95.7 5 DCM >99 99.3 6 DCE trace -- 7 CF3CH2OH >99 99.2 8 Dioxane >99 98.3 9 Toluene >99 98.1 10 EA >99 97.5 Combining the data in Table 1 and Table 2, it can be seen that the conversion rate using dichloromethane as the solvent is over 99%, and the ee value is 99.3%.

[0041] Example 3 High TON Experiment to Evaluate Catalyst Performance In an argon-filled glove box, Rh(COD) 2 BF 4 The precursor (0.003 mmol) and zhangphos (0.0033 mmol) were placed in a 1.5 mL vial equipped with a stirrer, and oxygen-free ultra-dry (DCM) solvent (0.3 mL) was added to dissolve. After stirring for 2 h in a glove box at room temperature, a red-brown solution was obtained, and Rh catalyst was formed in situ.

[0042] In a glove box filled with argon, the in-situ formed Rh catalyst (the amount used corresponds to S / C in Table 3), substrate (5 mmol), and ultra-dry DCM (2 mL) from which oxygen was removed were added to a 5 mL hydrogenation vial equipped with a magnetic rod, and then the hydrogenation vial was transferred to a high-pressure reactor in the glove box, the gas valve was closed, the bottle was tightened, the gas in the autoclave was replaced 3 times, and 10 bar of hydrogen was filled in. The autoclave was placed in a pre-prepared heating oil bath and reacted for about 48 hours.

[0043] After the reaction is completed, the vent switch of the autoclave is opened, the hydrogen is slowly released, and then the autoclave is opened, the solvent is drained under reduced pressure, and the adsorbed metal is separated by column chromatography to obtain the product, and then the conversion rate is confirmed by nuclear magnetic resonance hydrogen spectrum, and the ee value is confirmed by high performance liquid chromatography (HPLC). As shown in Table 3:

[0044] Table 3 Entry[a] S / C Conversion Rate % ee(%) 1 2000 99 97 2 5000 99 95 3[b] 5000 99 95 4[c] 5000 99 97 5[d] 10000 99 96 Note: [a] Reaction conditions: Compound 1a (5 mmol), H 2 (10 bar), 2.5 M, 48 h, 50 °C, unless otherwise stated. [b] 40 °C. [c] 30°C. [d] Compound 1a (10 mmol).

[0045] From the results in Table 3, it can be seen that under the corresponding temperature, pressure, reactant ratio and reaction degree, the turnover number (TON) of the catalytic reaction can reach up to 10,000, indicating that the in situ prepared Rh catalyst is of great significance to the production efficiency and product quality improvement of the chiral alcohol intermediate of Remigipam, and can ensure excellent corresponding selectivity and extremely high conversion rate.

[0046] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a chiral alcohol intermediate of Remigipam, characterized in that: The steps of the method include: ； In a hydrogen atmosphere, the in-situ formed Rh catalyst and compound 6 are reacted in a first solvent under heating conditions, and the reaction mixture is post-treated to obtain compound 5, wherein the Rh catalyst is obtained by reacting a Rh catalyst precursor and a ligand; The ligand is selected from at least one of (1S, 1'S, 2R, 2'R, 3aS, 3'aS, 7aS, 7'aS)-ZhangPhos, (S)-BINAP, (R,R)-DIOP, (S)--SEGPhos, and (S,S)-QuinoxP*.

2. The synthesis method according to claim 1, characterized in that: The preparation process of the Rh catalyst is as follows: under an inert atmosphere, a Rh catalyst precursor and a ligand are reacted in a second solvent at room temperature to obtain the catalyst.

3. The synthesis method according to claim 1 or 2, characterized in that: The inert gas is argon or nitrogen; the Rh catalyst precursor is selected from at least one of Rh(COD)2BF4 and Rh(NBD)2BF4.

4. The synthesis method according to claim 2, characterized in that: The molar ratio of the Rh catalyst precursor to the ligand is 1:1-1.

5.

5. The synthesis method according to claim 1 or 2, characterized in that: The first solvent and the second solvent are each independently selected from at least one of ethanol, isopropanol, dioxane, toluene, acetonitrile, ethyl acetate and dichloromethane.

6. The synthesis method according to claim 1, characterized in that: The molar ratio of the Rh catalyst to the compound 6 is 1:100-10000, preferably 1:5000 or 1:10000.

7. The synthesis method according to claim 1, characterized in that: The heating temperature is 20-60°C, preferably 30, 40, 50 or 60°C.

8. The synthesis method according to claim 1, characterized in that: The pressure of the hydrogen atmosphere is 5 to 50 bar, preferably 5, 10, 20, 30, 40 or 50 bar.

9. The synthesis method according to claim 1, characterized in that: The reaction mixture was decompressed to remove the reaction solvent, and then separated by column chromatography to obtain compound 5.

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