A preparation method of (R)-benzopyran-4-ol compounds

Abstract

The present invention discloses a method for preparing a (R)-benzopyran-4-ol compound. The method comprises the following steps: in the presence of a catalyst 8, subjecting a compound represented by Formula II and a hydrogen donor to a reduction reaction as shown below to obtain a compound represented by Formula I. The method has high chiral purity and high yield, and provides a new method for synthesizing a key chiral intermediate of ticlopidine.

Description

Technical Field

[0001] The present invention relates to a preparation method of (R)-benzopyran-4-ol compounds. Background Art

[0002] In the field of medicine, (R)-5,7-difluorobenzopyran-4-ol This is a very important pharmacophore and a key chiral intermediate in the preparation of ticagrelor. The preparation of (R)-5,7-difluorobenzopyran-4-ol with high chiral purity can lay the foundation for the subsequent synthesis of ticagrelor API.

[0003] Patent CN107849003A discloses a method for preparing (R)-5,7-difluorobenzopyran-4-ol. Using 5,7-difluorobenzopyran-4-one (7) as a raw material, triethylamine and formic acid as hydrogen donors, and RuCl(p-isopropyltoluene) [(R,R)-Ts-DPEN] as a catalyst, (R)-5,7-difluorobenzopyran-4-ol with high chiral purity is obtained in a yield of 91.0%. However, large-scale production is still a long way off. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the limited defects of the existing preparation methods of (R)-chromen-4-ol compounds, and provide a preparation method of (R)-chromen-4-ol compounds. The product obtained by this preparation method has high chiral purity and high yield, and does not use hazardous reagents; furthermore, the method can also be reacted in the presence of a solvent-free medium, which is a green and environmentally friendly process that can be prepared on a large scale. The application provides a new method for synthesizing the key chiral intermediate of ticagrelor.

[0005] The present invention provides a method for preparing a (R)-chromen-4-ol compound, comprising the following steps: in the presence of a catalyst 8, subjecting a compound represented by Formula II and a hydrogen donor to a reduction reaction as shown below to obtain a compound represented by Formula I;

[0006]

[0007] wherein R1 and R2 are independently halogen.

[0008] Those skilled in the art should understand that the hydrogen donor is a reagent that can provide a hydrogen source and is applicable to the reduction reaction.

[0009] In some embodiments, R1 and R2 are independently fluoro, chloro, bromo, or iodo, preferably fluoro.

[0010] In some embodiments, the reduction reaction is carried out in a protective gas atmosphere, preferably nitrogen and / or argon.

[0011] In some embodiments, the reduction reaction is carried out in the presence of a solvent medium or in the absence of a solvent medium. The solvent medium is preferably an ether solvent, an alcohol solvent, a halogenated hydrocarbon solvent, or an ester solvent. The ether solvent may be tetrahydrofuran. The halogenated hydrocarbon solvent may be dichloromethane. The alcohol solvent may be methanol. The ester solvent may be ethyl acetate.

[0012] In some embodiments, the amount of the solvent medium used is the conventional amount used in the art for such hydrolysis reactions. The volume-to-mass ratio of the solvent medium to the compound of Formula II is preferably 1-5 mL / g, for example 1.1 mL / g.

[0013] In some embodiments, the molar ratio of the catalyst 8 to the compound of formula II is (0.0005-0.02):1, preferably (0.005-0.01):1, for example 0.0006:1.

[0014] In some embodiments, the hydrogen donor is formic acid, ammonium formate, or a mixture of formic acid and an organic amine, preferably a mixture of formic acid and an organic amine. The organic amine may be triethylamine or diisopropylethylamine, preferably triethylamine. In the mixture of formic acid and an organic amine, the molar ratio of formic acid to the organic amine is preferably 1:(0.5-11), for example 1:(1-5).

[0015] In some embodiments, the hydrogen donor is a mixture of formic acid and triethylamine in a molar ratio of 1:(0.5-11) or a mixture of formic acid and diisopropylethylamine in a molar ratio of 1:(0.5-11).

[0016] In some embodiments, the hydrogen donor is a mixture of formic acid and triethylamine in a molar ratio of 1:(1-5) or a mixture of formic acid and diisopropylethylamine in a molar ratio of 1:(1-5).

[0017] In some embodiments, when the hydrogen donor is a mixture of formic acid and an organic amine, the molar ratio of the formic acid to the compound of Formula II is preferably (2-22):1, for example (4-20):1, or even 6:1. The molar ratio of the organic amine to the compound of Formula II is preferably (1-22):1, for example (3-20):1.

[0018] In some embodiments, when the hydrogen donor is a mixture of formic acid and an organic amine, the reduction reaction can be carried out in the absence of a solvent medium. Preferably, the raw materials for the reduction reaction consist of catalyst 8, the compound represented by formula II, and the hydrogen donor.

[0019] In some embodiments, the reaction temperature of the reduction reaction is 20°C-75°C, preferably 35°C.

[0020] In some embodiments, the progress of the reduction reaction can be monitored using conventional assay methods in the art (e.g., TLC, HPLC, GC, or NMR), with the reaction endpoint generally being the point at which the compound of Formula II ceases to react. The reaction time for the reduction reaction can be 1-12 hours, preferably 40 minutes.

[0021] In some embodiments, when the hydrogen donor is a mixture of formic acid and an organic amine, the reduction reaction further comprises the following steps: dissolving the compound of Formula II and catalyst 8 in the solvent medium, adding the organic amine, and adding formic acid dropwise in the protective gas atmosphere under ice bath conditions (e.g., 0°C); after the addition is completed, heating to 35°C for reaction.

[0022] In some embodiments, when the hydrogen donor is a mixture of formic acid and an organic amine, the reduction reaction further comprises the following steps: mixing the compound of Formula II and catalyst 8, adding an organic amine, and dropwise adding formic acid in an ice bath (e.g., 0° C.) in the protective gas atmosphere; after the dropwise addition, heating the mixture to 35° C. for reaction.

[0023] In some embodiments, the reduction reaction may further include post-treatment, which includes the following steps: after the reduction reaction is completed, ethyl acetate and water are added to the reaction solution, the organic phase is washed with a saturated sodium carbonate aqueous solution (for example, once) and a saturated salt water solution (for example, once), the organic phase is concentrated, and the compound shown in Formula I is purified by silica gel column.

[0024] In some embodiments, R1 and R2 are independently fluorine; the reduction reaction is carried out in a protective gas atmosphere; the reduction reaction is carried out in the presence of a solvent medium; the volume mass ratio of the solvent medium to the compound shown in Formula II is 1.1 mL / g; the molar ratio of the catalyst 8 to the compound shown in Formula II is (0.005-0.01):1; the hydrogen donor is a mixture of formic acid and an organic amine; the molar ratio of the formic acid to the compound shown in Formula II is (4-20):1; the molar ratio of the organic amine to the compound shown in Formula II is 20:1; The reaction temperature of the original reaction is 35°C; the reduction reaction comprises the following steps: dissolving the compound represented by Formula II and the catalyst 8 in the solvent medium, adding the organic amine, and adding formic acid dropwise in the protective gas atmosphere under ice bath conditions; after the addition, heating to 35°C for reaction; the reduction reaction also includes post-treatment, which comprises the following steps: after the reduction reaction is completed, adding ethyl acetate and water to the reaction solution, washing the organic phase with a saturated sodium carbonate aqueous solution (for example, once) and a saturated salt water solution (for example, once), concentrating the organic phase, and purifying with a silica gel column to obtain the compound represented by Formula I.

[0025] In some embodiments, R1 and R2 are independently fluorine; the reduction reaction is carried out in a protective gas atmosphere; the reduction reaction is carried out in the presence of a solvent-free medium; the molar ratio of the catalyst 8 to the compound of Formula II is 0.0006:1; the hydrogen donor is a mixture of formic acid and an organic amine; the molar ratio of formic acid to the compound of Formula II is 6:1; the molar ratio of the organic amine to the compound of Formula II is 3:1; the reaction temperature of the reduction reaction is 35°C; the reduction reaction comprises the following steps: mixing the compound of Formula II and the catalyst 8, adding the organic amine, and adding formic acid dropwise in the protective gas atmosphere under ice bath conditions; after the dropwise addition, heating to 35°C for reaction; the reduction reaction also includes post-treatment, which comprises the following steps: after the reduction reaction is completed, adding ethyl acetate and water to the reaction solution, washing the organic phase with a saturated sodium carbonate aqueous solution and a saturated brine in sequence, concentrating the organic phase, and purifying it with a silica gel column to obtain the compound of Formula I.

[0026] The present invention also provides a catalyst composition for use as a reagent for converting pyrone compounds into pyranol compounds. The catalyst composition consists of the catalyst 8 and the hydrogen donor described above.

[0027] In some embodiments, the pyrone compound is a compound represented by Formula II as described above.

[0028] In some embodiments, the method for converting pyrone compounds into pyranol compounds is the same as the method for preparing (R)-benzopyran-4-ol compounds described above.

[0029] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0030] The reagents and raw materials used in the present invention are commercially available.

[0031] The positive progress of the present invention is that: the present invention provides a method for preparing (R)-benzopyran-4-ol compounds. After multiple experiments, it was found that the use of a new high-efficiency chiral reduction catalyst [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloride (mesitylene)ruthenium (II) (8) can produce a product with high chiral purity, an ee value greater than 99.9%, and a yield of up to 99.7%. In addition, the reaction conditions are mild and the operation is simple, which has the potential for large-scale production compared to the methods reported in the literature. Therefore, the technology of the present invention has more advantages and application value than the methods reported in the literature. DETAILED DESCRIPTION

[0032] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0033] Example 1:

[0034] Preparation of (R)-5,7-difluorobenzopyran-4-ol (1)

[0035]

[0036] Compounds 7 (3.69 g, 20.05 mmol) and 8 (60 mg, 0.1 mmol) were dissolved in 4 mL of tetrahydrofuran. 56 mL of triethylamine was added, and the mixture was stirred under nitrogen for 20 min. Then, 3 mL of formic acid was added dropwise at 0°C. After completion of the addition, the mixture was heated to 35°C and stirred for 40 min. 200 mL of ethyl acetate and 40 mL of water were added, and the layers were separated. The organic layer was washed once with saturated aqueous sodium carbonate (40 mL) and once with saturated brine. Concentration afforded 5.73 g of a yellow solid, which was then eluted through a silica gel column with n-hexane:ethyl acetate (5:1) to afford 3.72 g of a white needle-shaped solid. The yield was 99.7%, the purity was 99.9%, and the ee value was >99.9%.

[0037] APCI-MS m / z: 169.05 [M-H2O] +1 ; 1H NMR (600MHz, CDCl3) δ6.41 (td, J=8.7, 8.1, 2.3Hz, 2H), 5.00 (t, J=3.3Hz, 1H), 4.35-4.21 (m, 2H), 2.09-1.95 (m, 3H);

[0038] 13 C NMR (101MHz, CD3OD) δ164.74-160.58 (m), 156.78 (dd, J=15.1, 9.6Hz), 109.01 (dd, J=20.8, 3.9Hz), 99.23 (dd, J=24.8, 3.5Hz), 95.02 (t, J=26.6Hz), 61.47, 55.80 (d, J=4.0Hz), 29.90;

[0039] Example 2:

[0040] Compounds 7 (3.69 g, 20.05 mmol) and 8 (120 mg, 0.2 mmol) were dissolved in 4 mL of tetrahydrofuran. 56 mL of triethylamine was added, and the mixture was stirred under nitrogen for 20 min. 3 mL of formic acid was then added dropwise at 0°C. The mixture was heated to 35°C and stirred for 40 min. 200 mL of ethyl acetate and 40 mL of water were added, and the layers were separated. The organic layer was washed once with saturated sodium carbonate solution (40 mL) and once with saturated brine. The mixture was concentrated to yield 5.73 g of a yellow solid. The solid was then washed with n-hexane:ethyl acetate (5:1) on a silica gel column to yield 3.73 g of a white needle-shaped solid. The yield was 99.9%, the purity was 99.9%, and the ee value was >99.9%. The mass spectrum, H-spectrum, C-spectrum, and optical rotation data of the product were the same as those in Example 1.

[0041] Example 3

[0042] Compounds 7 (3.69 g, 20.05 mmol) and 8 (120 mg, 0.2 mmol) were dissolved in 4 mL of tetrahydrofuran and added to 56 mL of triethylamine under nitrogen. The mixture was stirred for 20 minutes. 15 mL of formic acid was then added dropwise at 0°C. The temperature was raised to 35°C and stirred for 40 minutes. 200 mL of ethyl acetate and 40 mL of water were added, and the mixture was separated. The organic layer was washed once with saturated sodium carbonate solution (40 mL) and once with saturated brine. The mixture was concentrated to yield 5.73 g of a yellow solid. The solid was then washed with n-hexane:ethyl acetate (5:1) on a silica gel column to afford 3.62 g of a white needle-shaped solid. The yield was 97.0%, the purity was 99.9%, and the ee value was >99.9%. The mass spectrum, H-spectrum, C-spectrum, and optical rotation data of the product were the same as those in Example 1.

[0043] Example 4

[0044] Investigating the effect of asymmetric catalysts on reduction reactions

[0045]

[0046] i: Using catalyst (S)-Me-CBS (CAS: 112022-81-8)

[0047] At 0°C, (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,2,3]oxazolidinone (3 g) was dissolved in 10 mL of tetrahydrofuran. A mixture of 80 mL of tetrahydrofuran and 59.6 mL of a 2M borane-methyl sulfide solution in tetrahydrofuran was added, and the mixture was stirred for 20 minutes. A solution of 5 (20 g, 108.61 mmol) in tetrahydrofuran (100 mL) was added dropwise at 0°C. The mixture was stirred for 4 hours. The reaction was quenched by the slow addition of 100 mL of methanol. The reaction solution was concentrated to obtain an off-white solid, which was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 19.63 g of a white solid with a purity of 99.35% and an ee value of 81.4%. It was recrystallized from 100 mL of hexane to obtain 13.74 g of a white solid with an HPLC purity of 99.3%, a yield of 67.7%, and an ee value of 93.1%. 1 H NMR (600MHz, CDCl3) δ6.41 (td, J=8.7, 8.1, 2.3Hz, 2H), 5.00 (t, J=3.3Hz, 1H), 4.35-4.21 (m, 2H), 2.09-1.95 (m, 3H).

[0048] ii: Using catalyst A

[0049] Compound 7 (0.50 g, 2.72 mmol) and catalyst A (1 mg, 0.0016 mmol) were dissolved in 1.5 mL of tetrahydrofuran, and 0.56 mL of triethylamine was added. Under nitrogen protection, the mixture was stirred for 20 min. 0.3 mL of formic acid was then added dropwise at 0°C. After completion of the addition, the temperature was raised to 35°C and stirred for 48 h. 2 mL of water was added, and the mixture was extracted with ethyl acetate. The reaction solution was concentrated to obtain 0.37 g of an off-white solid. HPLC analysis showed that the reaction was not complete, resulting in a yield of 73.2%, a HPLC purity of 95.7%, and an ee value of 99.9%.

[0050] iii: Using catalyst B

[0051] Compound 7 (0.50 g, 2.72 mmol) and catalyst B (1 mg, 0.0011 mmol) were dissolved in 6.5 mL of methanol, H2 was introduced, the pressure was increased to 30 Bar, and the mixture was stirred at 35°C for 24 h. TLC showed that the raw material did not react.

[0052] iv: Using catalyst 8

[0053] Compound 7 (0.50 g, 2.72 mmol) and catalyst 8 (1 mg, 0.0016 mmol) were dissolved in 1.13 mL of triethylamine under nitrogen protection and stirred for 20 min. 0.6 mL of formic acid was then added dropwise at 0°C. After completion of the addition, the mixture was heated to 35°C and stirred for 40 min. 2 mL of water was added and the mixture was extracted with ethyl acetate. The reaction solution was concentrated to obtain 0.60 g of a yellow-white solid, which was then eluted on a silica gel column with n-hexane:ethyl acetate (5:1) to obtain 0.50 g of a white solid. The yield was 99.7%, the HPLC purity was 99.9%, and the ee value was 99.9%.

[0054] According to the above experimental results, when catalyst 8 is used to prepare compound 1 in a solvent-free medium, the yield is 99.7%, the purity is 99.9%, and the ee value is 99.9%, indicating the best catalytic effect.

Claims

1. A method for preparing a (R)-benzopyran-4-ol compound, characterized in that: The method comprises the following steps: in the presence of catalyst 8, subjecting the compound represented by formula II and a hydrogen donor to a reduction reaction as shown below to obtain the compound represented by formula I; wherein R1 and R2 are independently halogen.

2. The method for preparing the (R)-chromen-4-ol compound according to claim 1, wherein The reduction reaction satisfies one or more of the following conditions: (1) R1 and R2 are independently fluorine, chlorine, bromine or iodine; (2) The reduction reaction is carried out in a protective gas atmosphere; (3) The reduction reaction is carried out in the presence of a solvent medium or in the absence of a solvent medium; (4) The molar ratio of the catalyst 8 to the compound represented by formula II is (0.0005-0.02):1; (5) The hydrogen donor is formic acid, ammonium formate, or a mixture of formic acid and an organic amine; (6) The reaction temperature of the reduction reaction is 20°C-75°C.

3. The method for preparing the (R)-chromen-4-ol compound according to claim 2, wherein: The reduction reaction satisfies one or more of the following conditions: (1) R1 and R2 are independently fluorine; (2) The protective gas is nitrogen and / or argon; (3) The solvent medium is an ether solvent, an alcohol solvent, a halogenated hydrocarbon solvent or an ester solvent; (4) The volume-to-mass ratio of the solvent medium to the compound of Formula II is 1-5 mL / g; (5) The molar ratio of the catalyst 8 to the compound represented by formula II is (0.005-0.01):1; (6) The hydrogen donor is a mixture of formic acid and an organic amine; (7) The reaction temperature of the reduction reaction is 35°C.

4. The method for preparing the (R)-chromen-4-ol compound according to claim 3, wherein: The reduction reaction satisfies one or more of the following conditions: (1) The ether solvent is tetrahydrofuran; (2) The halogenated hydrocarbon solvent is dichloromethane; (3) The alcohol solvent is methanol; (4) The ester solvent is ethyl acetate; (5) The volume mass ratio of the solvent medium to the compound represented by Formula II is 1.1 mL / g; (6) The molar ratio of the catalyst 8 to the compound represented by formula II is 0.0006:1; (7) In the mixture of formic acid and organic amine, the molar ratio of the formic acid to the organic amine is 1:(0.5-11); (8) The organic amine is triethylamine or diisopropylethylamine; (9) When the hydrogen donor is a mixture of formic acid and an organic amine, the molar ratio of the formic acid to the compound represented by Formula II is (2-22):1; (10) When the hydrogen donor is a mixture of formic acid and an organic amine, the molar ratio of the organic amine to the compound represented by Formula II is (1-22):1; (11) When the hydrogen donor is a mixture of formic acid and an organic amine, the reduction reaction can be carried out in the absence of a solvent medium.

5. The method for preparing the (R)-chromen-4-ol compound according to claim 1, wherein The raw materials for the reduction reaction consist of the catalyst 8, the compound represented by formula II and the hydrogen donor.

6. The method for preparing the (R)-chromen-4-ol compound according to claim 4, wherein: The reduction reaction satisfies one or more of the following conditions: (1) In the mixture of formic acid and organic amine, the molar ratio of the formic acid to the organic amine is 1:(1-5); (2) When the hydrogen donor is a mixture of formic acid and an organic amine, the molar ratio of the formic acid to the compound represented by Formula II is (4-20):1; (3) When the hydrogen donor is a mixture of formic acid and an organic amine, the molar ratio of the organic amine to the compound represented by Formula II is (3-20):

1.

7. The method for preparing the (R)-chromen-4-ol compound according to claim 6, wherein: When the hydrogen donor is a mixture of formic acid and an organic amine, the molar ratio of the formic acid to the compound represented by Formula II is 6:

1.

8. The method for preparing the (R)-chromen-4-ol compound according to claim 2, wherein: The hydrogen donor is a mixture of formic acid and triethylamine in a molar ratio of 1:(0.5-11) or a mixture of formic acid and diisopropylethylamine in a molar ratio of 1:(0.5-11).

9. The method for preparing the (R)-chromen-4-ol compound according to claim 8, wherein: The hydrogen donor is a mixture of formic acid and triethylamine in a molar ratio of 1:(1-5) or a mixture of formic acid and diisopropylethylamine in a molar ratio of 1:(1-5).

10. The method for preparing the (R)-chromen-4-ol compound according to claim 1, wherein: When the hydrogen donor is a mixture of formic acid and an organic amine, the reduction reaction further comprises the following steps: dissolving the compound represented by Formula II and the catalyst 8 in a solvent medium, adding the organic amine, and dropwise adding formic acid in an ice bath under a protective gas atmosphere; after the dropwise addition, heating the mixture to 35° C. to carry out the reaction; Alternatively, when the hydrogen donor is a mixture of formic acid and an organic amine, the reduction reaction further comprises the following steps: mixing the compound of Formula II and catalyst 8, adding the organic amine, and dropwise adding formic acid in an ice bath under a protective gas atmosphere; after the dropwise addition, heating the mixture to 35° C. to carry out the reaction.

11. The method for preparing the (R)-chromen-4-ol compound according to claim 1, wherein: It is either Option 1 or Option 2: Scheme 1: R1 and R2 are independently fluorine; the reduction reaction is carried out in a protective gas atmosphere; the reduction reaction is carried out in the presence of a solvent medium; the volume mass ratio of the solvent medium to the compound represented by Formula II is 1.1 mL / g; the molar ratio of the catalyst 8 to the compound represented by Formula II is (0.005-0.01):1; the hydrogen donor is a mixture of formic acid and an organic amine; the molar ratio of the formic acid to the compound represented by Formula II is (4-20):1; the molar ratio of the organic amine to the compound represented by Formula II is 20:1; the reaction temperature of the reduction reaction is 35°C; the reduction reaction comprises the following steps: dissolving the compound represented by Formula II and the catalyst 8 in the solvent medium, adding the organic amine, and dropwise adding formic acid in the protective gas atmosphere under ice bath conditions; after the dropwise addition, the temperature is raised to 35°C for reaction; Scheme 2: R1 and R2 are independently fluorine; the reduction reaction is carried out in a protective gas atmosphere; the reduction reaction is carried out in the presence of a solvent-free medium; the molar ratio of the catalyst 8 to the compound represented by Formula II is 0.0006:1; the hydrogen donor is a mixture of formic acid and an organic amine; the molar ratio of the formic acid to the compound represented by Formula II is 6:1; the molar ratio of the organic amine to the compound represented by Formula II is 3:1; the reaction temperature of the reduction reaction is 35°C; the reduction reaction comprises the following steps: mixing the compound represented by Formula II and the catalyst 8, adding the organic amine, and adding formic acid dropwise in the protective gas atmosphere under ice bath conditions; after the dropwise addition, the temperature is raised to 35°C for reaction.

12. Use of a catalyst composition as a reagent for converting a pyrone compound into a pyranol compound, the catalyst composition comprising the catalyst 8 and the hydrogen donor according to any one of claims 2 to 8.

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