Preparation method of vernakalant

Abstract

The invention relates to the field of chemical medicine synthesis, in particular to a preparation method of vernakalant, which comprises the following steps: reacting a compound Y with a cyclohexane derivative to convert into a compound A, converting the compound A into a chiral compound B through a first ketoreductase, introducing a branched chain into the compound B through a compound C to generate a compound D, and synthesizing the vernakalant. After the compound D is converted into a compound E, the compound E is converted into the vernakalant through second ketoreductase. According to the method, a chiral cyclohexanolamine derivative, namely a compound B, can be conveniently synthesized by controlling and catalyzing reduction of cyclohexanone through dynamic dynamics of ketoreductase, after a branched chain is introduced by keeping an original space structure, pyrrolidone, namely a compound E, is obtained by diester cyclization through a Dieckmann reaction, and finally, vernakalant is obtained by catalytic reduction through reductase. The whole reaction conditions are mild, the raw materials are easy to obtain, and the cost is low.

Description

Technical Field

[0001] The invention relates to the field of chemical drug synthesis, and in particular to a preparation method of Vernakalant. Background Art

[0002] Vernakalant is a new antiarrhythmic drug, and its synthesis method is of great significance in drug production.

[0003] Since Vernakallan has a chemical structure with three chiral centers, it is often necessary to use raw materials with specific spatial configurations for synthesis. For example, (R)-3-hydroxypyrrole can be used as the starting material, and the existing synthesis route is as follows:

[0004]

[0005] The above synthetic route solves the chirality problem of the product in the last step of the process by chiral preparative liquid phase separation. However, isomer 1' cannot be effectively recycled, resulting in a high overall cost of the process route.

[0006] Another existing synthetic route uses a chiral catalytic reagent to achieve a specific spatial configuration. The specific route is as follows:

[0007]

[0008] In this synthetic route, natural L-proline is used as a chiral catalyst to obtain compound 42, which is then further converted into compound 35. The carbonyl group of compound 35 is converted into a hydroxyl group through asymmetric reduction and undergoes a configuration flip to meet the spatial configuration requirements of the product Vernakalane. The optical purity of the product obtained by this method is highly uncertain.

[0009] The use of chromium ligands (salen) can easily form a chiral center chemical structure that meets the requirements, but salen is difficult to recycle, resulting in high costs. The specific synthesis route is as follows:

[0010]

[0011] Enzymatic synthesis can more reliably form the chemical structure of the chiral center that meets the requirements, such as the following synthetic route:

[0012]

[0013] The raw material cost of this process route is still relatively high. Summary of the invention

[0014] The object of the present invention is to provide a method for preparing Vernakallan with a relatively reliable product spatial structure and low cost.

[0015] In order to achieve the above object, the present invention provides the following technical solutions:

[0016] A method for preparing Vernakalant, characterized by comprising:

[0017] Releasing compound Y with a cyclohexane derivative to convert it into compound A;

[0018] Converting the compound A into a compound B having a specific spatial configuration by a first ketoreductase;

[0019] Reacting the compound B with the compound C to generate the compound D;

[0020] Converting the compound D into compound E;

[0021] converting the compound E into Vernakalant via a second ketoreductase;

[0022] The structural formulas of the above-mentioned compound A, compound B, compound C and compound E are as follows:

[0023]

[0024] Optionally, the converting of the compound A into a compound B having a specific spatial configuration by a first ketoreductase comprises:

[0025] Adding the compound A to a phosphate buffer, and then adding the first ketoreductase, the first coenzyme, glucose and glucose dehydrogenase, and reacting at a temperature between 20° C. and 35° C. to generate the compound B;

[0026] The pH value of the phosphate buffer is any value between 6.5 and 7.5, the first ketoreductase is EW-KRED-R116, the first coenzyme is nicotinamide adenine dinucleoside phosphate (NADP), and the mass ratio of the compound A to the first ketoreductase is any value between (19 and 21):1.

[0027] Optionally, the converting the compound E into Vernakalant by a second ketoreductase comprises:

[0028] Adding the compound E to a phosphate buffer, and then adding the second ketoreductase, the second coenzyme, glucose and glucose dehydrogenase, reacting at a temperature between 20° C. and 35° C. to obtain a reaction solution containing Vernakalant;

[0029] The pH value of the phosphate buffer is any value between 6.5 and 7.5, the second ketoreductase is EW-KRED-R116, the second coenzyme is nicotinamide adenine dinucleoside phosphate (NADP), and the mass ratio of the compound E to the second ketoreductase is any value between (20.7 and 22.8):4.

[0030] Optionally, the converting the compound E into Vernakalant by a second ketoreductase further comprises:

[0031] Toluene is added to extract the reaction solution, hydrochloric acid is added to the organic phase, and the crystals are separated by filtration to obtain the solid Vernakalant.

[0032] Optionally, the compound A is obtained by reacting a cyclohexane derivative with a compound Y, and the structural formula of the compound Y is

[0033] Optionally, the preparation method of compound A comprises:

[0034] Anhydrous potassium carbonate is added to the acetonitrile solution of the compound Y and 2-bromocyclohexanone is added dropwise to react to generate the compound A.

[0035] Optionally, the preparation method of compound A comprises:

[0036] The compound Y is reacted with cyclohexene oxide in an acetonitrile solvent under the catalysis of anhydrous potassium carbonate to generate a compound Z, wherein the structural formula of the compound Z is

[0037] A dichloromethane solution of dimethyl sulfoxide is added dropwise to a dichloromethane solution of oxalyl chloride at a temperature between -68°C and -75°C, and after completion of the reaction at a temperature between -55°C and -63°C, a dichloromethane solution of the compound Z is added dropwise, and after stirring the reaction, triethylamine is added dropwise at a temperature between -50°C and -65°C to generate the compound A.

[0038] Optionally, the preparation method of compound Y comprises:

[0039] Triethylamine is added to a methanol solution of glycine methyl ester hydrochloride, and methyl acrylate is added dropwise at a temperature between 20°C and 35°C. After the reaction is completed, extraction is performed with methyl tert-butyl ether, and hydrochloric acid is added to adjust the pH value to between 1 and 2 to generate the compound Y.

[0040] Optionally, reacting the compound B with the compound C to generate the compound D comprises:

[0041] Fluoroboric acid and a dichloromethane solution of the compound C are added dropwise to an aqueous solution of the compound B at a temperature between -4°C and 4°C, and reacted at a temperature between 20°C and 35°C to obtain the compound D dissolved in an organic phase.

[0042] Optionally, converting the compound D into compound E comprises:

[0043] Sodium hydrogen is added to toluene, and the toluene solution of the compound D is added dropwise at a temperature between 50° C. and 60° C. and the temperature is maintained until the reaction is completed, thereby generating the compound E.

[0044] Optionally, the preparation method of compound C comprises:

[0045] Sodium hydrogen is added to a solution of 3,4-dimethoxyphenylethanol in methyl tert-butyl ether, and trichloroacetonitrile is added at a temperature between 0° C. and 5° C. and the temperature is maintained until the reaction is completed, thereby generating the compound E.

[0046] The beneficial effects of the present invention are: the enzymatic reaction has high selectivity, and a specific spatial configuration is formed by the enzymatic reaction, which helps to improve the optical purity of the product and make the spatial structure of the product more reliable. The chiral cyclohexanolamine derivative, i.e., compound B, can be conveniently synthesized by using the dynamic kinetic control of ketoreductase to catalyze the reduction of cyclohexanone. After the original spatial structure is introduced into the side chain, the diester cyclization of the Dickmann reaction is used to obtain pyrrolone, i.e., compound E, and finally the reductase catalytic reduction is used to obtain Vernakallan. The overall reaction conditions are relatively mild, and the raw materials are relatively easy to obtain, and the cost is relatively low.

[0047] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The present invention is a flowchart of the method for preparing Vernakalant shown in Example 1. DETAILED DESCRIPTION

[0049] The technical solution of the present invention will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0050] In the description of the present invention, it should be noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., indicating the orientation or positional relationship, are based on the orientation or positional relationship shown in the drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as limiting the present invention. In addition, the terms "first", "second", and "third" are used for descriptive purposes only, and cannot be understood as indicating or implying relative importance.

[0051] In the description of the present invention, it should be noted that, unless otherwise clearly specified and limited, the terms "installed", "connected", and "connected" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection, or it can be indirectly connected through an intermediate medium, or it can be the internal communication of two components. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0052] In addition, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0053] See also Figure 1 The preparation method of Vernakalan claimed in the present invention comprises reacting compound Y with a cyclohexane derivative to convert it into compound A, and converting compound A into a chiral compound B through a first ketoreductase, introducing a branch chain into compound B through compound C to generate compound D, converting compound D into compound E, and then converting compound E into Vernakalan through a second ketoreductase. The structural formulas of compound A, compound B, compound C and compound E are shown below:

[0054]

[0055] In the present invention, the chiral cyclohexanolamine derivative, i.e., compound B, can be conveniently synthesized by using the dynamic kinetic control of ketoreductase to catalyze the reduction of cyclohexanone. After the original spatial structure is maintained and the branched chain is introduced, the diester cyclization by the Dickmann reaction is used to obtain pyrrolone, i.e., compound E. Finally, the reductase is used to catalyze the reduction to obtain vernakalan. The overall reaction conditions are relatively mild, the raw materials are relatively easy to obtain, and the cost is low.

[0056] In some embodiments, converting compound A into compound B having a specific spatial configuration by a first ketoreductase comprises:

[0057] Compound A is added to a phosphate buffer, and a first ketoreductase, a first coenzyme, glucose and glucose dehydrogenase are added, and the reaction is carried out at a temperature of any value between 20°C and 35°C to generate compound B. The reaction temperature can be, for example, any value of 20°C, 23°C, 26°C, 29°C, 32°C and 35°C;

[0058] The pH value of the phosphate buffer is any value between 6.5 and 7.5, for example, it can be any value between 6.5, 6.7, 6.9, 7.1, 7.3 and 7.5, the first ketoreductase is EW-KRED-R116, the first coenzyme is nicotinamide adenine dinucleoside phosphate, and the mass ratio of compound A to the first ketoreductase is any value between (19 and 21):1, for example, it can be any value between (19:1), (19.5:1), (20:1), (20.5:1) and (21:1).

[0059] In some embodiments, converting Compound E to Vernakalant via a second ketoreductase comprises:

[0060] Adding compound E to a phosphate buffer, and continuing to add a second ketoreductase, a second coenzyme, glucose and glucose dehydrogenase, reacting at a temperature of any value between 20°C and 35°C to obtain a reaction solution containing Vernakalan, wherein the reaction temperature can be, for example, any value of 20°C, 23°C, 26°C, 29°C, 32°C and 35°C;

[0061] The pH value of the phosphate buffer is any value in the range of 6.5 to 7.5, for example, any value in the range of 6.5, 6.7, 6.9, 7.1, 7.3 and 7.5, the second ketoreductase is EW-KRED-R116, the second coenzyme is nicotinamide adenine dinucleoside phosphate, and the mass ratio of compound E to the second ketoreductase is any value in the range of (20.7 to 22.8):4, for example, any value in the range of (20.7:4), (21.4:4), (22.1:4) and (22.8:4).

[0062] In some embodiments, converting Compound E to Vernakalant via a second ketoreductase further comprises:

[0063] Toluene is added to extract the reaction solution, hydrochloric acid is added to the organic phase, and the crystals are filtered and separated to obtain solid Vernakallan hydrochloride. Vernakallan can be separated from other components in the reaction solution by extracting Vernakallan with a non-polar solvent toluene, which helps to improve the purity of the product. Vernakallan hydrochloride obtained by combining hydrochloric acid with Vernakallan has a low solubility in toluene, so that crystals are precipitated, making it easy to obtain high-purity Vernakallan.

[0064] In some embodiments, compound A is obtained by reacting a cyclohexane derivative with compound Y, and the structural formula of compound Y is

[0065] Compound Y has low cost and is convenient for introducing the ester bond required for the Dickmann reaction into compound A, thereby facilitating the subsequent generation of the pyrrolone structure in compound E, thereby facilitating the formation of a chiral carbon connected to a hydroxyl group on the pyrrole ring to obtain the target product, vernakalan.

[0066] In some embodiments, the preparation method of compound A comprises:

[0067] Anhydrous potassium carbonate is added to an acetonitrile solution of compound Y and 2-bromocyclohexanone is added dropwise to react to generate compound A. Compound A is obtained by only one-step reaction, the process is simple and the reaction conditions are mild, which helps to reduce the difficulty of synthesis and simplify the synthesis route.

[0068] In some embodiments, the preparation method of compound A comprises:

[0069] Compound Y is reacted with cyclohexene oxide in acetonitrile solvent under the catalysis of anhydrous potassium carbonate to generate compound Z, the structural formula of compound Z is

[0070] To a dichloromethane solution of oxalyl chloride is added a dichloromethane solution of dimethyl sulfoxide at a temperature between -68°C and -75°C, wherein the temperature may be, for example, any of -68°C, -69°C, -71°C, -73°C and -75°C; after the reaction is completed at a temperature between -55°C and -63°C, a dichloromethane solution of compound Z is added dropwise, wherein the temperature may be, for example, any of -55°C, -57°C, -59°C, -61°C and -63°C; after stirring the reaction, triethylamine is added dropwise at a temperature between -50°C and -65°C, wherein the temperature may be, for example, any of -50°C, -55°C, -60°C and -65°C to generate compound A.

[0071] Cyclohexene oxide is easier to obtain and has a lower cost among cyclohexane derivatives. Introducing epoxy groups into compound A through cyclohexene oxide helps to reduce the cost of raw materials.

[0072] In some embodiments, the method for preparing compound Y comprises:

[0073] Triethylamine is added to a methanol solution of glycine methyl ester hydrochloride, and methyl acrylate is added dropwise at a temperature of any value between 20°C and 35°C, and the temperature can be, for example, any value between 20°C, 23°C, 26°C, 29°C, 32°C and 35°C. After the reaction is completed, extraction is performed with methyl tert-butyl ether, and hydrochloric acid is added to adjust the pH value to any value between 1 and 2, for example, any value between 1, 1.2, 1.4, 1.6, 1.8 and 2, to generate compound Y. Glycine methyl ester, methyl acrylate, solvent methanol and catalyst triethylamine are all low in cost and easy to obtain, which helps to reduce the synthesis cost.

[0074] In some embodiments, reacting compound B with compound C to form compound D comprises:

[0075] Fluoroboric acid and a dichloromethane solution of compound C are added dropwise to an aqueous solution of compound B at a temperature between -4°C and 4°C, for example, -4°C, -2°C, 0°C, 2°C and 4°C, and reacted at a temperature between 20°C and 35°C, for example, 20°C, 25°C, 30°C and 35°C, to obtain compound D dissolved in the organic phase.

[0076] In some embodiments, converting Compound D to Compound E comprises:

[0077] Sodium hydrogen is added to toluene, and a toluene solution of compound D is added dropwise at a temperature of any value between 50°C and 60°C and the temperature is maintained until the reaction is completed to generate compound E. The reaction temperature can be, for example, any value among 50°C, 52°C, 54°C, 56°C, 58°C and 60°C.

[0078] In some embodiments, the preparation method of compound C comprises:

[0079] Sodium hydrogen is added to a solution of 3,4-dimethoxyphenylethanol in methyl tert-butyl ether, and trichloroacetonitrile is added at a temperature of any value between 0°C and 5°C and the temperature is maintained until the reaction is completed to generate compound E. The reaction temperature can be, for example, any value between 0°C, 1°C, 2°C, 3°C, 4°C and 5°C.

[0080] Please refer to the following examples for details.

[0081] Embodiment 1:

[0082] See also Figure 1 The preparation method of Vernakalant shown in a preferred embodiment of the present application comprises:

[0083] S1. Converting compound A into compound B having a specific spatial configuration by a first ketoreductase.

[0084] S2. Compound B is reacted with compound C to generate compound D.

[0085] S3. Convert compound D into compound E.

[0086] S4. Converting compound E into Vernakalant by a second ketoreductase.

[0087] Among them, the structural formulas of compound A, compound B, compound C, compound E and Vernakallan are:

[0088]

[0089] Step S1 includes:

[0090] S110, synthesizing compound Y, the structural formula of compound Y is

[0091] S120, reacting compound Y with a cyclohexane derivative to generate compound A.

[0092] S130, converting compound A into compound B under the catalysis of a first ketoreductase.

[0093] Step S110 includes:

[0094] S111, add 0.15 mol triethylamine (Et3N) (15.2 g), 0.1 mol glycine methyl ester hydrochloride (12.6 g) and 80 ml methanol into a reaction bottle, add 0.11 mol methyl acrylate dropwise at 35°C, and continue the reaction for 6 hours after the addition is complete to generate 3-[(2-methoxy-2-oxo)]aminoalanine methyl ester. The reaction formula in step S111 is as follows:

[0095]

[0096] S112, 200 ml of methyl tert-butyl ether and 80 ml of water were added to the reaction solution, the mixture was allowed to stand for stratification and the water layer was removed, 10% hydrochloric acid was added to the organic layer to adjust the pH value of the solution to 1.7, part of the solvent was evaporated, a solid salt was precipitated, and the compound Y was obtained by filtration and drying. The calculated yield was 65%, and the purity was 95% as measured by high performance liquid chromatography (HPLC).

[0097] Step S120 includes:

[0098] S121, add 30 ml of acetonitrile, 25 mmol of compound Y, totaling 5.3 g, and 54 mmol of anhydrous potassium carbonate, totaling 7.5 g, to a reaction flask. Dissolve 20 mmol of 2-bromocyclohexanone, totaling 3.54 g, in 10 ml of acetonitrile, and dropwise add to the reaction flask at room temperature of 28°C. After the dropwise addition is complete, continue to react at room temperature for 3 hours to generate compound A. Evaporate the solvent under reduced pressure, leaving solid residue in the reaction flask. The reaction formula in step S121 is as follows:

[0099]

[0100] S122, add 50 ml of dichloromethane and 25 ml of water to the residue, add 10% hydrochloric acid dropwise to a pH value of 3.5 after sufficient dissolution. Continue stirring for 30 minutes and let stand to separate the layers, separate the organic layer and concentrate, dissolve the residue in 30 ml of 60% methanol, cool and crystallize, filter and dry to obtain 3.3 g of compound A. The calculated yield is 61%.

[0101] Step S130 includes:

[0102] In 100 ml of phosphate buffer with a concentration of 0.1 mol / L and a pH value of 6.8, add 25 mmol of compound A, a total of 6.8 grams, a first ketoreductase EW-KRED-R116, a total of 0.34 grams, a first coenzyme nicotinamide adenine dinucleoside phosphate (NADP), a total of 0.05 grams, 6.75 grams of glucose, and a total of 1 gram of glucose dehydrogenase. React at 25°C for 24 hours, at which time the conversion rate exceeds 99%, add 100 ml of ethyl acetate for extraction, extract twice, combine the organic phases, and dry them by rotary evaporation to obtain a total of 6.5 grams of compound B, with a calculated yield of 95%. The reaction formula in step S130 is as follows:

[0103]

[0104] Step S2 includes:

[0105] S210. Prepare compound C.

[0106] S220, reacting compound B with compound C to obtain compound D.

[0107] Step S210 includes:

[0108] Add 50mmol of 3,4-dimethoxyphenylethanol, totaling 9.1g, and 80ml of methyl tert-butyl ether to the reaction bottle, stir and dissolve, then slowly add 75mmol of 60% sodium hydrogen, totaling 3g. After cooling to 0°C, add 75mmol of trichloroacetonitrile (Cl3CCN), totaling 10.8g, and keep the temperature within the range of 0°C to 5°C to continue the reaction for one hour. After the reaction is completed, slowly add the reaction mixture to ice water, separate the organic phase, and extract the aqueous phase once with 50ml of methyl tert-butyl ether, combine the organic phases, add anhydrous sodium sulfate to dry, filter out the desiccant, and concentrate under reduced pressure to obtain a total of 15g of compound C, with a calculated yield of 92%. The purity measured by HPLC is 96%. The reaction formula in step S220 is as follows:

[0109]

[0110] Step S220 includes:

[0111] The 22 mmol of compound B extracted in step S130, a total of 6 grams, was redissolved in 120 ml of ethyl acetate, cooled to 0°C, and then fluoroboric acid was added dropwise until the pH value was 3.5, and 10 ml of a dichloromethane solution containing 22 mmol of compound C was continued to be added dropwise. After the addition was completed, the mixture was heated to room temperature for 3 hours, and a saturated sodium bicarbonate solution was added until the pH value was 6.5. After stirring for 30 minutes, the water layer was separated, and the organic layer was washed with water and dried, and concentrated to obtain a solid compound D. The mass of compound D was 8.7 grams, and the calculated yield was 90%. The reaction formula in step S220 is as follows:

[0112]

[0113] Step S3 includes:

[0114] 0.6 g of 60% sodium hydroxide was added to 100 ml of toluene, and 10 ml of a toluene solution of compound D was added dropwise at 55°C, wherein the toluene solution contained 18 mmol of compound D, totaling 7.9 g. After the addition was completed, the reaction was continued at 60°C for three hours, cooled to room temperature, 40 ml of water was added, and the pH value was adjusted to 4.8 with hydrochloric acid, the water layer was separated and the organic layer was concentrated to obtain a total of 5.2 g of compound E, with a calculated yield of 83%. The reaction formula in step S3 is as follows:

[0115]

[0116] Step S4 includes:

[0117] S410, 13 mmol of compound E (4.5 g), 3.51 g of glucose, 0.026 g of the second coenzyme NADP, 0.21 g of the second ketoreductase EW-KRED-R122 and 0.52 g of glucose dehydrogenase were added to 60 ml of phosphate buffer with a concentration of 0.1 mol / L and a pH value of 7.2, and the reaction was carried out at 30° C. for 24 hours, at which time the conversion rate was greater than 99%.

[0118] S420, extract the organic phase twice with two 50 ml portions of toluene, add 10% hydrochloric acid dropwise until no more crystals are precipitated, and obtain 4.6 g of the product after centrifugal freeze drying, with a calculated yield of 92%.

[0119] The reaction formula in step S4 is as follows:

[0120]

[0121] The product obtained in step S4 is Vernakalant hydrochloride, which can be obtained by adjusting the pH after redissolution and re-extracting and crystallizing.

[0122] The purity of Vernakalant was 99.5% as determined by HPLC, and the optical purity was 99.9%.

[0123] Vernakalan synthesized by the above method has high optical purity, low raw material cost, mild reaction steps and high practicality.

[0124] Embodiment 2:

[0125] The difference between this embodiment and the first embodiment is that step S120 in this embodiment includes:

[0126] S123. Dissolve 25 mmol of compound Y (5.3 g), 30 mmol of anhydrous potassium carbonate (4.2 g) and 25 mmol of cyclohexene oxide (2.45 g) in 30 ml of acetonitrile. After reacting at room temperature for 24 hours, filter out the generated inorganic salt, recover the solvent acetonitrile under reduced pressure, and redissolve the residue in 10 ml of dichloromethane to obtain a residual solution containing compound Z.

[0127] S124, 29mmol of oxalyl chloride (oxalyl dichloride) totaling 3.7 grams was dissolved in 60 ml of dichloromethane, cooled to -70 ° C, and then a DMSO-dichloromethane solution formed by 60mmol of dimethyl sulfoxide (DMSO) totaling 4.7 grams dissolved in 6ml of dichloromethane (CH2Cl2) was added dropwise. After the addition was complete, the temperature was adjusted to -60 ° C and maintained, and the residual solution obtained in step S123 was added dropwise after 5 minutes of reaction. After the addition was complete, the reaction was stirred for 15 minutes. Stop the heat preservation, continue to add 17 ml of triethylamine, and pay attention to the temperature not higher than -50 ° C during the addition. After the temperature returned to room temperature, the reaction mixture was poured into 70 ml of water, the organic layer was separated and concentrated, 30 ml of 60% methanol was added, and the cooling crystallization was filtered and dried to obtain a total of 5.4 grams of compound A, and the calculated yield was 79%.

[0128] The reaction formulas in step S123 and step S124 are as follows:

[0129]

[0130] The raw material cost of the method in step S120 in this embodiment is relatively low.

[0131] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0132] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing Vernakalant, characterized in that: include: Converting compound A into compound B having a specific spatial configuration by a first ketoreductase; Reacting the compound B with the compound C to generate the compound D; Converting the compound D into compound E; converting the compound E into Vernakalant via a second ketoreductase; The structural formulas of the above-mentioned compound A, compound B, compound C and compound E are as follows:

2. The preparation method according to claim 1, characterized in that The step of converting compound A into compound B having a specific spatial configuration by a first ketoreductase comprises: Adding the compound A to a phosphate buffer, and then adding the first ketoreductase, the first coenzyme, glucose and glucose dehydrogenase, and reacting at a temperature between 20° C. and 35° C. to generate the compound B; The pH value of the phosphate buffer is any value between 6.5 and 7.5, the first ketoreductase is EW-KRED-R116, the first coenzyme is nicotinamide adenine dinucleoside phosphate (NADP), and the mass ratio of the compound A to the first ketoreductase is any value between (19 and 21):

1.

3. The preparation method according to claim 1, characterized in that: The converting the compound E into Vernakalant via a second ketoreductase comprises: Adding the compound E to a phosphate buffer, and then adding the second ketoreductase, the second coenzyme, glucose and glucose dehydrogenase, reacting at a temperature between 20° C. and 35° C. to obtain a reaction solution containing Vernakalant; The pH value of the phosphate buffer is any value between 6.5 and 7.5, the second ketoreductase is EW-KRED-R116, the second coenzyme is nicotinamide adenine dinucleoside phosphate (NADP), and the mass ratio of the compound E to the second ketoreductase is any value between (20.7 and 22.8):

4.

4. The preparation method according to claim 1, characterized in that: The compound A is obtained by reacting a cyclohexane derivative with a compound Y, and the structural formula of the compound Y is 5. The preparation method according to claim 4, characterized in that: The preparation method of the compound A comprises: Anhydrous potassium carbonate is added to the acetonitrile solution of the compound Y and 2-bromocyclohexanone is added dropwise to react to generate the compound A.

6. The preparation method according to claim 4, characterized in that: The preparation method of the compound A comprises: The compound Y is reacted with cyclohexene oxide in an acetonitrile solvent under the catalysis of anhydrous potassium carbonate to generate a compound Z, wherein the structural formula of the compound Z is A dichloromethane solution of dimethyl sulfoxide is added dropwise to a dichloromethane solution of oxalyl chloride at a temperature between -68°C and -75°C, and after completion of the reaction at a temperature between -55°C and -63°C, a dichloromethane solution of the compound Z is added dropwise, and after stirring the reaction, triethylamine is added dropwise at a temperature between -50°C and -65°C to generate the compound A.

7. The preparation method according to claim 4, characterized in that: The preparation method of the compound Y comprises: Triethylamine is added to a methanol solution of glycine methyl ester hydrochloride, and methyl acrylate is added dropwise at a temperature between 20°C and 35°C. After the reaction is completed, extraction is performed with methyl tert-butyl ether, and hydrochloric acid is added to adjust the pH value to between 1 and 2 to generate the compound Y.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The reacting of the compound B with the compound C to generate the compound D comprises: Fluoroboric acid and a dichloromethane solution of the compound C are added dropwise to an aqueous solution of the compound B at a temperature between -4°C and 4°C, and reacted at a temperature between 20°C and 35°C to obtain the compound D dissolved in an organic phase.

9. The preparation method according to any one of claims 1 to 7, characterized in that: The converting of the compound D into the compound E comprises: Sodium hydrogen is added to toluene, and the toluene solution of the compound D is added dropwise at a temperature between 50° C. and 60° C. and the temperature is maintained until the reaction is completed, thereby generating the compound E.

10. The preparation method according to any one of claims 1 to 7, characterized in that: The preparation method of the compound C comprises: Sodium hydrogen is added to a solution of 3,4-dimethoxyphenylethanol in methyl tert-butyl ether, and trichloroacetonitrile is added at a temperature between 0° C. and 5° C. and the temperature is maintained until the reaction is completed, thereby generating the compound E.

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