A process for the preparation of a remegapant intermediate

Abstract

This invention provides a method for preparing an intermediate of retinoic acid, belonging to the field of compound preparation technology. The preparation method includes the following steps: (1) compound M6 and R (1) The tert-butylsulfinamide reaction yields compound M6A; (2) Compound M6A undergoes a reduction reaction under the action of a reducing agent to yield (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptane[b]pyridine-5-amine. The preparation method of the present invention avoids the use of high-pressure hydrogenation and ammonia, resulting in less environmental pollution and a higher yield, which facilitates subsequent industrial production.

Description

Technical Field

[0001] This invention belongs to the field of compound preparation technology, specifically relating to a method for preparing a remigelpa intermediate, namely, a method for preparing (5S,6S,9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cycloheptane[b]pyridine-5-amine. Background Technology

[0002] NURTEC TM ODT (Rimegepant) is a potent, selective, competitive, orally active calcitonin gene-related peptide (CGRP) antagonist used for the acute treatment of migraine in adults. As a CGRP-targeting drug, Rimegepant inhibits acute migraine attacks by blocking the binding of CGRP to its receptor, thereby reducing the activity of the trigeminal vascular system. It is the first CGRP-targeting drug to be proven effective in both the acute treatment and prevention of migraine. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on February 27, 2020. Its structural formula is as follows: .

[0003] CN102656159A discloses two methods for synthesizing retinoic acid, with process routes shown as Route 1 and Route 2, respectively: Route 1 uses highly toxic and explosive sodium azide, and the resulting azide intermediate is also dangerous and unstable, making it unsuitable for industrial production. Route 2 provides an improved synthetic scheme for remedrapam, in which (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptano[b]pyridine-5-amine (M7) is the core molecular skeleton of remedrapam and a key intermediate in the synthetic route. There are two main methods for its synthesis: A. Transaminase-catalyzed method: This method involves the asymmetric synthesis of the amination product intermediate M7 using transaminase under ammonia source conditions. Enzyme-catalyzed asymmetric preparation offers significant advantages such as high conversion rates, good stereoselectivity, mild reaction conditions, and environmental friendliness. However, this method suffers from drawbacks including difficulty in enzyme acquisition, inconsistent enzyme activity and catalytic capacity, the fact that most enzyme-catalyzed reactions are single-use and difficult to reuse, resulting in high costs, demanding equipment requirements, and cumbersome operation.

[0004] B. Amination-reduction method: This method involves amination of isopropyl titanate under ammonia pressure of 100 Psi, followed by Pd / Al catalysis and hydrogenation at 100 Psi to obtain intermediate M7. The amination-reduction method for both amination and asymmetric hydrogenation requires ammonia, causing significant environmental pollution, necessitating stringent personnel safety and equipment requirements, and facing difficulties in obtaining approval. High-pressure hydrogenation methods have low safety, hindering large-scale preparation and industrial production. Using a metal / acid system results in substantial pollution and difficulties in heavy metal treatment. While CN119707808B uses hydroxylamine to eliminate ammonia pollution, the subsequent hydrogenation still requires high-pressure equipment. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing the intermediate of remexazol that avoids the use of high-pressure ammoniation hydrogenation, is simple to operate, has low environmental pollution, and has a high yield. Specifically, it provides a method for preparing (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptane[b]pyridine-5-amine (M7).

[0006] To achieve this objective, the present invention adopts the following technical solution: On one hand, the present invention provides a method for preparing (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptano[b]pyridine-5-amine, the method comprising the following steps: (1) Compound M6 and R The reaction of tert-butylsulfinamide yields compound M6A; (2) Compound M6A undergoes a reduction reaction under the action of a reducing agent to give compound M7, namely (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptane[b]pyridine-5-amine; the reaction route is as follows: ; R is a silicon protecting group with high steric hindrance.

[0007] Preferably, R is a TIPS group (triisopropylsilyl group).

[0008] Preferably, the compound M6 in step (1) and R The molar ratio of tert-butylsulfinamide is 1.0:1.0-6.0, for example 1.0:1.0, 1.0:1.5, 1.0:1.8, 1.0:2.0, 1.0:2.5, 1.0:3.0, 1.0:3.5, 1.0:3.5, 1.0:4.0, 1.0:4.5, 1.0:5.0, 1.0:5.5 or 1.0:6.0, more preferably 1.0:2.0 to 4.0, and even more preferably 1.0:3.0.

[0009] Preferably, the reaction in step (1) is carried out in the presence of a dehydrating agent.

[0010] Preferably, the dehydrating agent is tetraisopropyl titanate (Ti(OiPr)4) and / or tetraethyl titanate (Ti(OEt)4), and more preferably tetraisopropyl titanate.

[0011] Preferably, the molar ratio of compound M6 to dehydrating agent in step (1) is 1.0:1.5~2.0, for example 1.0:1.5, 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9 or 1.0:2.0, and more preferably 1.0:1.5.

[0012] Preferably, the reaction in step (1) is carried out in solvent 1, which is any one or a combination of at least two of tetrahydrofuran, dioxane or cyclopentyl methyl ether, and more preferably dioxane (i.e., 1,4-dioxane).

[0013] Preferably, in step (1), the amount of solvent 1 used relative to 1 gram of compound M6 is 4-10 mL (e.g., 4 mL, 5 mL, 6 mL, 6.4 mL, 7.2 mL, 8 mL, 8.8 mL, 9.6 mL or 10 mL, etc.), or it can be expressed as the amount of solvent 1 used is 4V-10V, preferably 4-6 mL, and more preferably 4 mL.

[0014] The reaction in step (1) does not require pressure. Preferably, the temperature of the reaction is 80℃~100℃ (e.g., 80℃, 82℃, 84℃, 86℃, 88℃, 90℃, 92℃, 94℃, 96℃ or 100℃, etc.), and the reaction time is 10h~16h (e.g., 10h, 11.5h, 13h, 14.5h or 16h, etc.).

[0015] Preferably, the reduction reaction in step (2) is carried out in solvent 2, which is selected from tetrahydrofuran and / or dioxane, and more preferably tetrahydrofuran.

[0016] When solvent 2 is tetrahydrofuran, the reducing agent in step (2) is preferably any one or a combination of at least two of lithium sec-butylborohydride, sodium borohydride or potassium borohydride; when solvent 2 is dioxane, the reducing agent is preferably any one or a combination of two of sodium borohydride or potassium borohydride.

[0017] Preferably, the molar ratio of compound M6A to reducing agent in step (2) is 1.0:3.0-4.0, for example 1.0:3.0, 1.0:3.2, 1.0:3.5, 1.0:3.8 or 1.0:4.0.

[0018] When solvent 2 is tetrahydrofuran and the reducing agent is sodium borohydride or potassium borohydride, the reaction temperature of the reduction reaction in step (2) is preferably 0~15℃ (e.g., 0℃, 2℃, 4℃, 6℃, 8℃, 10℃, 12℃ or 15℃, etc.), and more preferably 0~5℃; when solvent 2 is tetrahydrofuran and the reducing agent is sec-butyllithium borohydride, the reaction temperature of the reduction reaction in step (2) is preferably -20~-10℃ (e.g., -20℃, -19℃, -18℃, -17℃, -16℃, -15℃, -14℃, -13℃ or -10℃, etc.); when solvent 2 is dioxane and the reducing agent is sodium borohydride or potassium borohydride, since dioxane will solidify below 10℃, the reaction temperature of the reduction reaction in step (2) is preferably 10~15℃ (e.g., 10℃, 11℃, 12℃, 13℃ or 15℃, etc.). The reaction time of the reduction reaction in step (2) above is 3h~24h (e.g. 3h, 5h, 7h, 9h, 11h, 13h, 15h, 17h, 18h, 20h or 24h, etc.), more preferably 3h~12h, and even more preferably 3h~5h.

[0019] Preferably, in step (2), the amount of solvent 2 used relative to 1 gram of compound M6A is 10-15 mL (e.g., 10 mL, 10.5 mL, 11 mL, 12 mL, 13 mL, 14 mL or 15 mL, etc.), or it can be expressed as the amount of solvent 2 used in step (2) is 10V-15V.

[0020] In this invention, the preparation method of the (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptane[b]pyridine-5-amine specifically includes the following steps: (1) Compound M6 was dissolved in solvent 1, and then R-tert-butylsulfinamide and a dehydrating agent were added to the reaction solution. The mixture was heated to carry out the reaction to obtain crude compound M6A. The compound M6 and R The molar ratio of tert-butylsulfinamide is 1.0:1.0-6.0, the dehydrating agent is tetraisopropyl titanate and / or tetraethyl titanate, and the solvent 1 is any one or a combination of at least two of tetrahydrofuran, dioxane or cyclopentyl methyl ether. (2) Compound M6A is dissolved in solvent 2 and reduced by a reducing agent to obtain (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptane[b]pyridine-5-amine. Solvent 2 is tetrahydrofuran or dioxane. When solvent 2 is tetrahydrofuran, the reducing agent is any one or a combination of at least two of lithium sec-butylborohydride, sodium borohydride or potassium borohydride. When solvent 2 is dioxane, the reducing agent is any one or a combination of two of sodium borohydride or potassium borohydride.

[0021] Compared with the prior art, the present invention has the following beneficial effects: In this invention, the compound M7 can be prepared in high yield by the preparation method described above. The product yield of each step can reach more than 80%, and the total yield is more than 65%. Moreover, the method of this invention avoids the use of high-pressure hydrogenation and ammonia, which can realize industrial production in the later stage. Attached Figure Description

[0022] Figure 1 This is the LC-MS chromatogram of compound M7. Detailed Implementation

[0023] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0024] The synthetic routes involved in the following embodiments are as follows: Example 1-1 Synthesis of compound M6A: Weigh 4.5 g M6 (1.0 eq.), add THF (40 mL, 9V), start stirring, and add 1.2 g R - tert-butylsulfinamide (1.0 eq.) was added to Ti(OEt)4 (tetraethyl titanate) (4.5 g, 2.0 eq.), the mixture was heated to 80 °C, and stirred for 16 h until the reaction was complete. The reaction solution was cooled to room temperature, separated, and backwashed twice with saturated sodium chloride aqueous solution. The organic phase was concentrated to obtain 5.3 g of crude M6A.

[0025] Examples 1-2 Synthesis of compound M6A: Weigh 9.0 g M6 (1.0 eq.), add dioxane (36 mL, 4V), start stirring, and add 7.2 g R -tert-butylsulfinamide (3.0 eq.), added Ti(O) i Pr)4 (tetraisopropyl titanate) (9.0 g, 1.5 eq.), heated to 80 °C and stirred for 10 h until the reaction was complete. The reaction solution was cooled to room temperature, 90 mL of water was added, and the mixture was filtered. The filtrate was extracted three times with 90 mL of ethyl acetate, and the organic phase was concentrated to give 12.2 g of crude M6A.

[0026] Examples 1-3 Synthesis of compound M6A: Weigh 9.0 g of M6 (1.0 eq.), add cyclopentyl methyl ether (90 mL, 10V), start stirring, and add 12.1 g of [unspecified ingredient]. R -tert-butylsulfinamide (5.0 eq.), added Ti(O)i Pr)4 (9.0 g, 1.5 eq.) was heated to 80 °C and stirred for 10 h until the reaction was complete. The reaction solution was cooled to room temperature, 90 mL of water was added, and the mixture was filtered. The filtrate was extracted three times with 90 mL of ethyl acetate, and the organic phase was concentrated to give 11.4 g of crude M6A.

[0027] Examples 1-4 Synthesis of compound M6A: Weigh 9.0 g of M6 (1.0 eq.), add dioxane (90 mL, 10V), start stirring, and add 14.5 g of [unspecified ingredient]. R - tert-butyl sulfinamide (6.0 eq.), added Ti(O) i Pr)4 (9.0 g, 1.5 eq.) was heated to 80 °C and stirred for 10 h until the reaction was complete. The reaction solution was cooled to room temperature, 90 mL of water was added, and the mixture was filtered. The filtrate was extracted three times with 90 mL of ethyl acetate. The organic phase was concentrated to give 11.6 g of crude M6A.

[0028] Example 2-1 Synthesis of compound M7: The crude compound M6A obtained in Example 1-1 (5.0 g, 1.0 eq.) was dissolved in THF (50 mL, 10 V). Sodium borohydride (4.0 eq.) was then slowly added to the solution while maintaining the temperature at 0–5 °C. After the addition was complete, 0.5 mL of concentrated sulfuric acid was added dropwise, and the reaction was maintained at this temperature for 3 h. After the reaction was complete, water was added to quench the reaction mixture, and the temperature was maintained at 0–5 °C. The mixture was separated, the organic phase was concentrated, and 30 mL of isopropanol was added to dissolve the oily crude product. While stirring, 30 mL of 2.8 N isopropanol hydrochloride solution was slowly added, and the mixture was stirred for 2 h. The temperature was then slowly lowered to 0–10 °C, filtered, and the filter cake was dried under vacuum at 45 °C. 3.4 g of product M7 was obtained, with a purity of 99.50% and a two-step yield of 67%.

[0029] Example 2-2 Synthesis of compound M7: The crude compound M6A (10.0 g, 1.0 eq.) obtained in Examples 1-2 was dissolved in dioxane (100 mL, 10V). Potassium borohydride (4.0 eq.) was then slowly added to the solution while maintaining the temperature at 0-5°C. After the addition was complete, 0.5 mL of concentrated sulfuric acid was added dropwise, and the reaction was maintained at this temperature for 3 h. After the reaction was complete, water was added to quench the reaction mixture, and the temperature was maintained at 0-5°C. The mixture was separated, the organic phase was concentrated, and 50 mL of isopropanol was added to dissolve the oily crude product. While stirring, 30 mL of 2.8 N isopropanol hydrochloride solution was slowly added. After stirring for 2 h, the temperature was slowly lowered to 0-10°C, and the mixture was filtered. The filter cake was dried under vacuum at 45°C. 6.5 g of product M7 was obtained, with a purity of 99.70% and a two-step yield of 76%.

[0030] Example 2-3 Synthesis of compound M7: The crude compound M6A (10.0 g, 1.0 eq.) obtained in Examples 1-4 was dissolved in THF (150 mL, 15 V) and cooled to -20°C. A 1 mol / L lithium sec-butylborohydride / THF solution (3.0 eq.) was slowly added to the solution, maintaining the temperature no higher than -10°C, and the reaction was maintained at this temperature for 3 h. After the reaction was complete, 100 mL of 15% sodium chloride aqueous solution was added to quench the reaction, maintaining the temperature no higher than 0°C. The mixture was separated, the organic phase was concentrated, and 50 mL of isopropanol was added to dissolve the oily crude product. While stirring, 30 mL of 2.8 N isopropanol hydrochloride solution was slowly added, and the mixture was stirred for 2 h. The temperature was then slowly lowered to 0-10°C, filtered, and the filter cake was dried under vacuum at 45°C. 7.2 g of product M7 was obtained, with a purity of 99.70% and a two-step yield of 81%.

[0031] To facilitate data comparison and save space in the specification, the applicant has compiled the product results obtained by controlling different reaction conditions in this invention into Table 1 (Table 1 lists the reaction of step 1, i.e. the synthesis of compound M6A, in which the amount of raw material M6 used in step 1 is 1.0 eq.) and Table 2 (Table 2 lists the reaction of step 2, i.e. the synthesis of compound M7, in which the amount of M6A used in step 2 is 1.0 eq.).

[0032] Table 1 Table 2 Other conditions not listed in the table can be referred to the embodiments listed in the specification or adjusted by those skilled in the art based on experimental common sense.

[0033] The LCMS chromatogram of compound M7 prepared in this invention (testing instrument purchased from Agilent, model: 1060+6160) is shown below. Figure 1 As shown in the figure, the [M+H] molecular weight of compound M7 with a molecular mass of 447 is displayed. + .

[0034] The applicant declares that the present invention is illustrated by the above embodiments, but the present invention is not limited to the above process steps, that is, it does not mean that the present invention must rely on the above process steps to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptane[b]pyridine-5-amine, characterized in that, The preparation method includes the following steps: (1) Compound M6 and R The reaction of tert-butylsulfinamide yields compound M6A; (2) Compound M6A undergoes a reduction reaction under the action of a reducing agent to give compound M7, namely (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptane[b]pyridine-5-amine; the reaction route is as follows: ； R is a silicon protecting group with high steric hindrance.

2. The preparation method according to claim 1, characterized in that, R stands for triisopropylsilyl group.

3. The preparation method according to claim 1, characterized in that, In step (1), compound M6 and R The molar ratio of tert-butylsulfinamide is 1.0:1.0-6.

0.

4. The preparation method according to claim 3, characterized in that, In step (1), compound M6 and R The molar ratio of tert-butylsulfinamide is 1.0:2.0~4.

0.

5. The preparation method according to claim 1, characterized in that, The reaction in step (1) is carried out in the presence of a dehydrating agent, which is tetraisopropyl titanate and / or tetraethyl titanate; Preferably, the molar ratio of compound M6 to dehydrating agent in step (1) is 1.0:1.5~2.

0.

6. The preparation method according to claim 1, characterized in that, The reaction in step (1) is carried out in solvent 1, which is any one or a combination of at least two of tetrahydrofuran, dioxane or cyclopentyl methyl ether; Preferably, in step (1), the amount of solvent 1 used is 4-10 mL relative to 1 gram of compound M6; Preferably, the temperature of the reaction in step (1) is 80℃~100℃, and the reaction time is 10h~16h.

7. The preparation method according to claim 1, characterized in that, The reaction in step (2) is carried out in solvent 2, which is tetrahydrofuran or dioxane. When solvent 2 is tetrahydrofuran, the reducing agent is any one or a combination of at least two of lithium sec-butylborohydride, sodium borohydride or potassium borohydride. When solvent 2 is dioxane, the reducing agent is any one or a combination of two of sodium borohydride or potassium borohydride.

8. The preparation method according to claim 1, characterized in that, The molar ratio of compound M6A to reducing agent in step (2) is 1.0:3.0-4.

0.

9. The preparation method according to claim 7, characterized in that, When solvent 2 is tetrahydrofuran and reducing agent is sodium borohydride or potassium borohydride, the reaction temperature of the reduction reaction is 0~15℃ and the reaction time is 3h~24h. Preferably, when solvent 2 is tetrahydrofuran and reducing agent is sec-butylborohydride, the reaction temperature of the reduction reaction is -20~-10℃ and the reaction time is 3h~24h. Preferably, when solvent 2 is dioxane and reducing agent is sodium borohydride or potassium borohydride, the reaction temperature of the reduction reaction is 10~15℃ and the reaction time is 3h~24h. Preferably, in step (2), the amount of solvent 2 used is 10-15 mL relative to 1 gram of compound M6A.

10. The preparation method according to any one of claims 1-9, characterized in that, The preparation method of the (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptane[b]pyridine-5-amine specifically includes the following steps: (1) Compound M6 was dissolved in solvent 1, and then R-tert-butylsulfinamide and a dehydrating agent were added to the reaction solution. The mixture was heated to carry out the reaction to obtain crude compound M6A. The compound M6 and R The molar ratio of tert-butylsulfinamide is 1.0:1.0-6.0, the dehydrating agent is tetraisopropyl titanate and / or tetraethyl titanate, and the solvent 1 is any one or a combination of at least two of tetrahydrofuran, dioxane or cyclopentyl methyl ether. (2) Compound M6A is dissolved in solvent 2 and reduced by a reducing agent to obtain (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptane[b]pyridine-5-amine. Solvent 2 is tetrahydrofuran or dioxane. When solvent 2 is tetrahydrofuran, the reducing agent is any one or a combination of at least two of lithium sec-butylborohydride, sodium borohydride or potassium borohydride. When solvent 2 is dioxane, the reducing agent is any one or a combination of two of sodium borohydride or potassium borohydride.

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