WO2018024017A1

WO2018024017A1 - Preparation method for 6-fluoro-2-(epoxy-2-yl)chroman

Info

Publication number: WO2018024017A1
Application number: PCT/CN2017/084869
Authority: WO
Inventors: 杨汉荣; 李涛; 陶荣盛; 王博
Original assignee: 上海朴颐化学科技有限公司
Priority date: 2016-08-04
Filing date: 2017-05-18
Publication date: 2018-02-08
Also published as: CN107686480A

Abstract

The present invention relates to a preparation method for 6-fluoro-2-(epoxy-2-yl)chroman. The preparation method comprises the following steps: (1) if a compound as represented by formula (II) is in an R form, subjecting a compound as represented by formula (III) to a reduction reaction in water under the action of ammonium formate or glucose, an R-reductase, and a coenzyme with the condition that pH = 6.0-8.0, or if the compound as represented by formula (II) is in an S form, subjecting a compound as represented by formula (III) to a reduction reaction in water or an alcoholic solvent under the action of an R-reductase and a coenzyme with the condition that pH = 7.0-9.5; (2) subjecting the compound as represented by formula (II) that is in an R form or an S form to an epoxidation in an organic solvent in presence of alkali; and (3) performing chiral resolution on a compound as represented by formula (I') by means of column chromatography. The method of the present invention features ingenious design, a convenient and effective synthetic route, and simple and easy-to-conduct process procedures, and is environmentally friendly.

Description

Preparation method of 6-fluoro-2-(epoxy-2-yl) color full

The present application claims priority from Chinese Patent Application No. CN201610629486.4, filed on Aug. 4, 2016. This application cites the entire text of the above-mentioned Chinese patent application.

Technical field

The present invention relates to the technical field of nebivolol synthesis, and more particularly to the technical field of synthesis of 6-fluoro-2-(epoxy-2-yl) chroma, in particular to a 6-fluoro-2-(epoxy) -2-yl) A method of coloring a single isomer.

Background technique

Nebivolol hydrochloride is a drug developed by Johnson & Johnson Company of the United States for the treatment of essential hypertension. Its chemical name is α,α'-[imine bis(methylene) bis(6-fluoro- 3,4-Dihydro-2H-1-benzopyran-2-methanol)] hydrochloride, first marketed in Germany and the Netherlands in 1997, is a cardiac selective β-receptor block with vasodilating action. The stagnation agent has the advantages of protective effect on the heart, good antihypertensive effect, good tolerance and less adverse reactions, and low dose and good curative effect.

The nebivolol structure has four chiral carbon atoms with a total of 10 isomers, of which (R, R, R, S) have good receptor blocking properties, while another configuration (S, S, The isomers of S, R) have a good effect on controlling the release of NO although they have no pharmaceutically active activity. Therefore, among the current commercial drugs, Is a racemate, ie equivalent (S, S, S, R)-α, α'-[imine bis(methylene) bis(6-fluoro-3,4-dihydro-2H- 1-benzopyran-2-methanol)] and (R,R,R,S)-α,α'-[imine bis(methylene)bis(6-fluoro-3,4-dihydro- A mixture of 2H-1-benzopyran-2-methanol)].

It is known in the art to synthesize α,α'-[imine bis(methylene)bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol)] molecules The structure is a challenge for the technician. If 6-fluoro-2-(epoxy-2-yl)chroman (I) containing 4 isomers is used as a starting material to synthesize nebivolol, 4 asymmetric carbon atoms in nebivolol are produced. A mixture of 16 stereoisomers (in the case of asymmetric substitutions) or a mixture of 10 stereoisomers (in the case of symmetric substitutions).

Therefore, in the existing synthesis, a single isomer of 6-fluoro-2-(epoxy-2-yl)chroman (I) is first obtained, and R, R-(I) and S, R-(I) are The raw material is reacted to obtain isomers of nebivolol (R, R, R, S), and then S, S-(I) and R, S-(I) are used as raw materials to obtain nebivolol (S). Isomers of S, S, R) in order to avoid the formation of other isomers.

As shown in Formula 1, four single isomers of 6-fluoro-2-(epoxy-2-yl)chroman (I) are currently synthesized. The S-(IV)-6-fluorochroman-2-carboxylic acid S-(IV) is obtained by chemical resolution or enzymatic resolution of the mixed 6-fluorochroman-2-carboxylic acid (IV). And (R)-6-fluorochroman-2-carboxylic acid R-(IV), which are then converted to the corresponding chiral chloroketone intermediates S-(III) and R-(III). If the chiral chloroketone intermediate S-(III) is asymmetrically reduced or enzymatically reduced by two methods, two chiral chlorohydrin intermediates S, S-(II) and S, R-(II) are obtained, respectively. Then separate the rings to obtain two single configurations of 6-fluoro-2-(epoxy-2-yl)chroman S, S-(I) and S, R-(I); if the chiral chloroketone will be obtained The intermediate R-(III) is asymmetrically reduced or enzymatically reduced by two methods to obtain two chiral chlorohydrin intermediates R, S-(II) and R, R-(II), respectively. The other two single configurations of 6-fluoro-2-(epoxy-2-yl)chromes are R, S-(I) and R, R-(I).

Although this method yields four single configurations of 6-fluoro-2-(epoxy-2-yl)chroman (I), there are several problems:

1. The cost of splitting 6-fluorochroman-2-carboxylic acid (IV) is relatively high. Whether chemical separation or enzymatic resolution is cumbersome, the resolution is not high; and two isomers are obtained at the same time, so a single (S)-6-fluorochroman-2-carboxylic acid S The price of -(IV) or (R)-6-fluorochroman-2-carboxylic acid R-(IV) is much higher than that of the mixed 6-fluorochroman-2-carboxylic acid (IV).

2. After the resolution of 6-fluorochroman-2-carboxylic acid (IV), to synthesize the chiral chloroketone intermediates S-(III) and R-(III), two reactions must be carried out in parallel, while chiral chlorine The ketone intermediates S-(III) and R-(III) to the last four 6-fluoro-2-(epoxy-2-yl)chroman (I) must be in parallel with four reactions, which is complicated and unsuitable Industrial production.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the defects in the prior art that the steps of synthesizing the four isomers of 6-fluoro-2-(epoxy-2-yl)chroman (I) are complicated and the process is cumbersome. The invention provides a preparation method of 6-fluoro-2-(epoxy-2-yl) color. The method is cleverly designed, the synthesis route is simple and efficient, the process flow is simple and easy, and the environment is green, which provides a new choice for the industrial preparation of nebivolol epoxide. Moreover, the present invention has a high overall yield of color (I) obtained from the preparation of chloroketone to obtain a single configuration.

The invention provides a preparation method of 6-fluoro-2-(epoxy-2-yl) chroma, which comprises the following steps:

(1) According to the formula (II), the compound of the formula (II) is prepared by the following method:

If the compound of formula (II) is R form, it comprises the following steps: under the action of ammonium formate or glucose, R-reductase and coenzyme in water, pH=6.0-8.0 (preferably 7.5-7.8), III) a compound is subjected to a reduction reaction to obtain a compound of the formula (II); wherein the coenzyme is a nicotinamide adenine dinucleotide;

If the compound of formula (II) is S-type, it comprises the following steps: in water, in an alcohol solvent, under the action of S-type reductase and coenzyme, pH=7.0-9.5 (preferably 7.8-8.0), III) a compound is subjected to a reduction reaction to obtain a compound of the formula (II); wherein the coenzyme is nicotinamide adenine dinucleotide and/or nicotinamide adenine dinucleoside phosphate;

(2) epoxidizing the R-form or S-form compound of the formula (II) obtained in the step (1) in an organic solvent in the presence of a base to obtain a compound of the formula (I') in a corresponding configuration;

(3) chiral resolution of the compound of the formula (I') obtained in the step (2) by column chromatography to obtain a compound of the formula (I) in a single stereo configuration;

Wherein, the carbon marked by * indicates chiral carbon, which includes S type and R type;

It is indicated that the chemical bond does not have a specific stereo configuration, and the chiral carbon to which the bond is attached includes an S-type, an R-form, and a stereoisomer mixture.

In the preparation method, in the step (1), if the compound of the formula (II) is R type and ammonium formate is used as a hydrogen source, the preparation method preferably comprises: mixing the compound of the formula (III), water and ammonium formate, Further, R-type reductase and coenzyme are added, and the pH is adjusted to 7.5 to 7.8 to carry out a reaction.

In the preparation method, in the step (1), if the compound of the formula (II) is R type and ammonium formate is used as the hydrogen source, the preparation method preferably comprises: buffer solution, ammonium formate, formula (at 20 ° C) III) The compound, the R-type reductase and the coenzyme are mixed, and the pH of the system is adjusted to 7.8 to carry out the reaction.

In the preparation method, in the step (1), if the compound of the formula (II) is of the R type and glucose is used as the hydrogen source, the preparation method preferably comprises: mixing the compound of the formula (III), glucose and the R-reductase. The pH of the system was adjusted to 7.5, followed by the addition of coenzyme and maintaining the pH = 7.5 for the reaction.

In the preparation method, in the step (1), if the compound of the formula (II) is of the R type and glucose is used as the hydrogen source, the preparation method preferably comprises: mixing the compound of the formula (III), glucose and the R-reductase. The pH of the system was adjusted to 7.5 with an aqueous solution of sodium carbonate, followed by the addition of coenzyme and maintaining the pH = 7.5 for the reaction.

In the preparation method, in the step (1), if the compound of the formula (II) is S-type, the preparation method comprises the steps of: mixing the compound of the formula (III), water and an alcohol solvent, and further adding the S-type reductase and the coenzyme. The pH was adjusted to 7.8 to 8.0 to carry out the reaction.

In the preparation method, in the step (1), if the compound of the formula (II) is S-type, the preparation method preferably comprises: mixing the compound of the formula (III), a buffer solution and an alcohol solvent, and then adding the S-type reductase. The reaction was carried out with a coenzyme and pH adjustment to 7.8.

In the preparation method, in the step (1), if the compound of the formula (II) is of the S type, the preparation method preferably comprises: reducing the buffer solution, the alcohol solvent, the compound of the formula (III), and the S type at 20 ° C. The enzyme was mixed with the coenzyme, and the pH of the system was adjusted to 7.8 to carry out the reaction.

In the preparation method, in the step (1), if the compound of the formula (II) is S-type, the preparation method preferably comprises: mixing the S-type reductase, the alcohol solvent, water and the coenzyme at 15 to 25 ° C, The pH of the diluted ammonia was adjusted to 8.0, and the compound of the formula (III) was further added thereto, and the reaction was carried out at 25 to 30 °C.

In the preparation method, in the step (1), a buffer solution may be added in the preparation method of the compound of the formula (II) of the R type or the S type, and it is preferred to add a buffer solution to the preparation method of the compound of the formula R (II). In the preparation method of the R type (II) compound, the buffer solution may be It is a buffer solution of potassium dihydrogen phosphate. In the preparation method of the S type (II) compound, the buffer solution may be a buffer solution of potassium dihydrogen phosphate. When the buffer solution is further included in the reaction system, the timing of addition of the buffer solution is preferably the same as the timing of addition of water. The buffer solution is preferably a buffer solution of potassium dihydrogen phosphate. The preparation method of the potassium dihydrogen phosphate buffer solution preferably comprises mixing potassium dihydrogen phosphate with water (preferably distilled water) and adjusting the pH to 6.8-7.5, preferably 7.0-7.2 with a base. The base is preferably one or more of sodium hydroxide, aqueous ammonia, sodium carbonate, and potassium hydroxide. The concentration of the solution formed by mixing the potassium dihydrogen phosphate with distilled water is preferably 0.8 to 1.2 mol/L, preferably 0.1 mol/L. The base preferably adjusts the pH of the buffer solution in the form of a solution of 1.5 to 2.5 mol/L, more preferably 2.0 mol/L.

In the preparation method, in the preparation method of the compound of the formula (II) of the S type in the step (1), the alcohol solvent preferably contains an alcohol having 1 to 4 carbon atoms, more preferably isopropanol. The volume-to-mass ratio of the alcohol solvent to the compound of the formula (III) is preferably (10 to 20 mL): 1 g, more preferably 16 mL: 1 g.

In the preparation method, in the step (1), the reductase may include an R-type reductase and a S-type reductase.

The S-type reductase is preferably a carbonyl reductase 1184 of Huzhou Yuhui Biotechnology Co., Ltd. The R-type reductase is preferably a carbonyl reductase 740 of Huzhou Yuhui Biotechnology Co., Ltd. The S-type or R-type reductase is preferably 0.2 to 2.0 times the mass of the compound of the formula (III) depending on the enzyme activity.

In the step (1), the chirality of the hydroxy-substituted carbon atom in the compound of the product formula (II) depends on the reductase used, and if the compound of the formula (II) obtained by using the R-reductase is the R-type, if the S-type reduction is employed The compound of the formula (II) obtained by the enzyme is in the S form.

In the preparation method, in the preparation method of the compound of the formula R (II) in the step (1), the coenzyme is nicotinamide adenine dinucleotide (coenzyme I, NAD+). In the preparation method of the S-form (II) compound, the coenzyme is nicotinamide adenine dinucleotide (coenzyme I, NAD+) and/or nicotinamide adenine dinucleoside phosphate (coenzyme II, NADP+). Whether R or S (II) In the preparation method of the compound, the coenzyme is preferably used in an amount of 0.01 g to 0.20 g/L, which is a ratio of the coenzyme mass to the total volume of the system before adjusting the pH. When the S-type reductase is used in combination with NADP+, in the case where isopropanol is a hydrogen source, the reduction reaction may not add a buffer solution.

In the preparation method, in the preparation method of the compound of the formula (1), whether in the R type or the S type (II), the pH of the system is preferably one or more of sodium hydroxide, ammonia water, sodium carbonate and potassium hydroxide. For the adjustment, a sodium hydroxide aqueous solution having a concentration of 1.5-2.5 mol/L, a sodium carbonate aqueous solution having a mass concentration of 15 to 25%, or a dilute aqueous ammonia having a mass concentration of 28%, more preferably a 20% aqueous sodium carbonate solution or 2.0 mol. /L aqueous sodium hydroxide solution.

In the preparation method, in the preparation method of the compound of the formula (1), whether in the R type or the S type (II), the temperature of the reduction reaction is preferably room temperature (0 to 40 ° C), more preferably 20 to 40. °C, most preferably 25 to 30 °C.

In the preparation method, in the preparation method of the compound of the formula (1), whether in the R type or the S type (II), the progress of the reduction reaction can be monitored by a conventional means in the art (for example, HPLC or TLC). In general, when the compound of the formula (III) disappears, the reaction end point is preferably 5 to 28 hours, more preferably 10 to 18 hours.

In the preparation method, in the preparation method of the compound of the formula (II) of the S type in the step (1), after the reduction reaction is completed, the product can be further purified by a post-treatment step. The post-treatment step preferably comprises mixing the reaction system with diatomaceous earth, filtering, washing with an organic solvent, layering, extracting the aqueous phase with an organic solvent, drying the organic phase, and filtering. In the post-treatment step, the organic solvent is preferably ethyl acetate, dichloromethane or chloroform.

In the preparation method, in the preparation method of the R type (II) compound using the ammonium formate as the hydrogen source in the step (1), after the reduction reaction is completed, the product can be further purified by the post-treatment step. The post-treatment step preferably comprises mixing the reaction system with diatomaceous earth, filtering, washing with an organic solvent, layering, extracting the aqueous phase with an organic solvent, drying the organic phase, and filtering. In the post-treatment step, the organic solvent is preferably ethyl acetate, dichloromethane or chloroform.

In the preparation method, in the preparation method of the R-form (II) compound using glucose as a hydrogen source in the step (1), after the reduction reaction is completed, the product can be further purified by a post-treatment step. The post-treatment step preferably comprises mixing the system with diatomaceous earth, suction filtration, washing the filter cake with toluene, and drying the organic phase with anhydrous sodium sulfate.

In the above preparation method, the step (2) preferably comprises mixing the compound of the formula (II) with an organic solvent, cooling to 0 ° C or lower, and adding a base to carry out an epoxidation reaction.

In the preparation method, the step (2) preferably comprises dissolving the compound of the formula (II) in an organic solvent, cooling to below 0 ° C, adding a base, followed by epoxidation at 15 to 25 ° C.

In the preparation method, in the step (2), the organic solvent may be an organic solvent commonly used in such reactions in the art, preferably toluene, acetone or an alcohol having 1 to 4 carbon atoms. The alcohol having 1 to 4 carbon atoms is preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or sec-butanol. The amount of the organic solvent generally does not affect the progress of the reaction, and is preferably 4 to 8 mL/g of the compound of the formula II, more preferably 4.6 mL/g of the compound of the formula II to 5.1 mL/g of the compound of the formula II.

In the preparation method, in the step (2), the base is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The molar ratio of the base to the compound of the formula (II) is preferably from 1:1 to 4.1:1, more preferably from 2:1 to 2.4:1.

In the preparation method, in the step (2), the temperature of the epoxidation reaction is preferably 0 to 40 ° C, more preferably 10 to 30 ° C, and most preferably 15 to 25 ° C, and the temperature referred to herein means The reaction temperature after the addition of the base. In the preparation method, in the step (2), the temperature of the reaction system is preferably controlled to be 0 ° C or less when a base is added.

In the preparation method, in the step (2), the progress of the reaction can be monitored by conventional means in the art (for example, TLC or HPLC), and the present invention is generally used as a reaction end point when the compound of the formula (II) disappears. It is preferably 5 to 20 hours, more preferably 16 hours.

In the preparation method, in the step (2), after the epoxidation reaction is completed, the product can be further purified by post-treatment. The post-treatment preferably comprises: cooling in an ice water bath, adding vinegar to the system Acid, filter, wash the residue with an organic solvent, wash the organic phase with water, brine, and dry. The molar ratio of the acetic acid to the compound of the formula (II) is preferably from 0.5:1 to 1:1. The organic solvent is preferably ethyl acetate or toluene.

In the preparation method, in the step (3), the column chromatography may be a conventional column chromatography in the art, which means that the achiral column is used to separate the hand by adjusting the silica fineness and the eluent polarity. A product of a chirality in a single stereo configuration. The column chromatography is preferably carried out using 200 to 400 mesh, more preferably 200 to 300 mesh silica gel. The column chromatography is preferably carried out by wet loading. The eluent used in the column chromatography is preferably a mixed solvent of dichloromethane and methanol, or a mixed solvent of ethyl acetate and n-heptane. When the compound of the formula (I') is in the R form, the eluent used is preferably dichloromethane:methanol = 45:1 or ethyl acetate: n-heptane = 1:15, which is a volume ratio. When the compound of the formula (I') is in the S form, the eluent used is preferably dichloromethane:methanol = 40:1 or ethyl acetate: n-heptane = 1:15, which is a volume ratio.

According to the above method, if the reduction is carried out by R-type reductase, the compounds of the formula (I) obtained by column chromatography are respectively R, R-(I) and S, R-(I); if catalyzed by S-type reductase Upon reduction, the compounds of formula (I) isolated by column chromatography are S, S-(I) and R, S-(I), respectively.

The positive effects of the present invention are:

1. Directly using 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one (III) as a raw material, eliminating the 6-fluorochroman-2-carboxylic acid ( Resolution of IV), and subsequent synthesis of two chiral compounds of formula (III) (2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one), which reduce the cost of raw materials, It simplifies the process operation and improves the convenience of industrial production.

2. The selective rotation of the compound of formula (III) (2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one) by reductase is carried out to obtain a specific chiral hydroxyl group. a compound of formula (II) (chlorohydrin), which is then used separately The R type and the S type (II) compound are reacted to obtain two compounds of the formula (I') (epoxide); only two parallel reactions are required to obtain four chiral specific 6-fluoro-2- (rings). Oxy-2-yl) is full. Compared with the four parallel reactions of the original process, the workload is reduced by half and the efficiency is doubled.

3. The present invention prepares a chiral specific compound of the formula (I) by column chromatography, and ensures the ee value and the de value of each single isomer (I), thereby avoiding the resolution and reaction level in the prior art. problem.

detailed description

For a better understanding of the contents of the present invention, further description will be made below in conjunction with the specific embodiments. It is to be understood that the following specific examples are merely illustrative of the invention and are not intended to be limiting.

In the following examples, the S-type reductase was purchased from the carbonyl reductase 1184 of Huzhou Yuhui Biotechnology Co., Ltd. R-type reductase was purchased from carbonyl reductase 740 of Huzhou Yuhui Biotechnology Co., Ltd.

Example 1:

1. Preparation of (1S)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol (S-(II))

14.3 g (0.1 mol) of potassium dihydrogen phosphate was dissolved in 1080 mL of distilled water to prepare a 0.1 mol/L solution, and the pH was adjusted to 7.5 with 2.0 mol/L sodium hydroxide to prepare a buffer solution.

At 20 ° C, 720 mL of isopropanol was added to the above buffer solution, and 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one (III) 45.0 g (0.2 mol) was added, and S type was added. Reductase 90.0 g and NAD + 0.18 g were adjusted to 7.8 with 2.0 mol/L sodium hydroxide and reacted at 15 to 25 ° C for 18 hours. After the reaction was completed, 90 g of diatomaceous earth was added and stirred uniformly, then filtered, washed twice with 1000 mL of ethyl acetate, and allowed to stand for separation. The first batch of organic phase was separated, and the aqueous phase was extracted with 1000 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated tolujjjjjjjjjjjjjjjjjjjjjjj - (II), yield 77.1%.

2. Preparation of 6-fluoro-2-((R)-epoxy-2-yl)chroman (R-(I))

35.0 g (0.15 mol) of (1S)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol S-(II) was dissolved in 180 mL of toluene, and the system was cooled to below 0 °C. Thereafter, 14.6 g (0.365 mol) of sodium hydroxide solid was slowly added, followed by stirring at 15 to 25 ° C for 16 hours, and TLC showed the reaction was completed. After cooling in an ice water bath, 11 mL of acetic acid was added dropwise, and the salt was precipitated. The mixture was filtered and washed three times with 150 mL of ethyl acetate. The combined organic phases were washed once with 400 mL of water and 300 mL of brine, dried over anhydrous sodium sulfate, filtered and Dry to give 30.7 g of a yellow oil, 6-fluoro-2-((R)-epoxy-2-yl)-chrome, R-(I), yield 98.0%.

3, (S)-6-fluoro-2-((R)-epoxy-2-yl)chroman (S,R-(I)) and (R)-6-fluoro-2-((R) Preparation of -epoxy-2-yl)chroman (R,R-(I))

The column was packed in 300 g of 300-400 mesh silica gel and rinsed with dichloromethane; 30.7 g of the yellow oil 6-fluoro-2-((R)-epoxy-2-yl) obtained in the above step was filled with R-( I) Dissolved in 50 mL of dichloromethane, wet-loaded, and then eluted as a mobile phase with a mixed solution of dichloromethane:methanol=45:1 to obtain 13.8 g of (S)-6-fluoro-2-( (R)-Epoxy-2-yl) color saturating S, R-(I), chiral purity 99.91%, chemical purity 99.19%; and 13.6 g (R)-6-fluoro-2-((R)- Epoxy-2-yl) color full R, R-(I), chiral purity 99.89%, chemical purity 99.83%, total yield (total yield S, R-(I) yield and R, R The sum of the yields of -(I), i.e., the total amount of the two products obtained, divided by the amount of the above mixture, was 89.3%, and the intersection was not counted.

Example 2:

1. Preparation of (1R)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol (R-(II))

15.4 g (0.11 mol) of potassium dihydrogen phosphate was dissolved in 1128 mL of distilled water to prepare a 0.1 mol/L solution, and the pH was adjusted to 7.0 with 2.0 mol/L sodium hydroxide to prepare a buffer solution.

94.0 g (1.5 mol) of ammonium formate and 47.0 g (0.2 mol) of 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one (III) were added to the above buffer solution at 20 °C. R type reductase 94.0 g and NAD + 0.19 g were further adjusted to 7.8 with 2.0 mol/L sodium hydroxide and reacted at 15 to 25 ° C for 28 hours. After the reaction was completed, 94 g of diatomaceous earth was added and stirred uniformly, then filtered, washed twice with 1000 mL of ethyl acetate, and allowed to stand for separation. The first batch of organic phase was separated, and the aqueous phase was extracted with 1000 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj - (II), yield 66.4%.

2. Preparation of 6-fluoro-2-((S)-epoxy-2-yl)chroman (S-(I))

35.0 g (0.15 mol) of (1R)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol S-(II) was dissolved in 160 mL of toluene, and the system was cooled to below 0 °C. Thereafter, 24.6 g (0.615 mol) of sodium hydroxide solid was slowly added, followed by stirring at 15 to 25 ° C for 16 hours, and TLC showed the reaction was completed. After cooling in an ice water bath, 14 mL of acetic acid was added dropwise, and the salt was precipitated. The salt was filtered and washed three times with 200 mL of ethyl acetate. The combined organic phases were washed once with 250 mL of water and 200 mL of brine, dried over anhydrous sodium sulfate, filtered and Dry to give 20.6 g of a yellow oil, 6-fluoro-2-((S)-epoxy-2-yl), sat.

3, (S)-6-fluoro-2-((S)-epoxy-2-yl)chroman (S,S-(I)) and (R)-6-fluoro-2-((S) Preparation of -epoxy-2-yl)chroman (R,S-(I))

The column was packed in 300 g of 300-400 mesh silica gel and rinsed with dichloromethane; 20.6 g of the yellow oil 6-fluoro-2-((R)-epoxy-2-yl) obtained in the above step was colored with S-( I) dissolved in 40 mL of dichloromethane, wet-loaded, and then eluted as a mobile phase with a mixed solution of dichloromethane:methanol=40:1 to obtain 8.5 g of (S)-6-fluoro-2-( (S)-epoxy-2-yl) color saturating S, S-(I), chiral purity 99.50%, chemical purity 99.50%; and 8.1 g(R)-6-fluoro-2-((S)- Epoxy-2-yl) color full R, S-(I), chiral purity 99.8%, chemical purity 99.5%, total yield (calculated as in Example 1) was 80.4%, and the intersection was not counted.

Example 3:

1. Preparation of (1S)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol (S-(II))

Add 154.3 g of S-type reductase, 16.0 mL of isopropanol, 250 mL of water and NADP+0.01 g to a 500 mL enamel kettle at 15 to 25 ° C. Adjust the pH to 8.0 with dilute ammonia (28%), then add 2-chloro 15.0 g of 1-(6-fluorochroman-2-yl)ethan-1-one (III) was reacted at 25-30 ° C for 5 hours, and the reaction was complete by TLC. After adding 25 g of diatomaceous earth, the mixture was stirred and filtered, and the cake was beaten with 125 mL to 200 mL of toluene, dried over anhydrous sodium sulfate, and concentrated to give 24.5 g of pale yellow oily product (1S)-2-chloro-1-(6-fluorochroman-2- Ethyl-1-alcohol S-(II), yield 97.1%.

2. Preparation of 6-fluoro-2-((R)-epoxy-2-yl)chroman (R-(I))

24.5 g of (1S)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol S-(II) was dissolved in 180 mL of toluene, and the system was cooled to below 0 ° C, and then slowly 7.5 g of sodium hydroxide solid was added, followed by stirring at 15 to 25 ° C for 16 hours, and TLC showed the reaction was completed. Under ice cooling, 8.5 mL of acetic acid was added dropwise, and the salt was precipitated. The mixture was filtered, and the salt was washed three times with 50 mL of toluene. The combined organic phases were washed once with 30 mL of brine, dried over anhydrous sodium sulfate, filtered and dried. 23.0 g of a yellow oily 6-fluoro-2-((R)-epoxy-2-yl)chrome R-(I), yield 98.9%.

The column was packed in 200 g of 200-300 mesh silica gel and rinsed with n-heptane; 23.0 g of the yellow oil 6-fluoro-2-((R)-epoxy-2-yl) obtained in the above step was filled with R-( I) Wet loading, and then eluting with a mixed solution of ethyl acetate: n-heptane = 1:15 as mobile phase to obtain 9.7 g of (S)-6-fluoro-2-((R)-epoxy, respectively. -2-yl) color full S, R-(I), chiral purity 99.93%, chemical purity 99.15%; and 6.7 g (R)-6-fluoro-2-((R)-epoxy-2-yl ) color full R, R-(I), chiral purity 99.85%, chemical purity 99.87%, total yield (total yield S, R-(I) yield and R, R-(I) The sum of the rates, i.e., the total amount of the two products obtained, divided by the amount of the above mixture, was 71.3%, and the cross portion of 3.5 g was not counted.

Example 4:

1. Preparation of (1R)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol (R-(II))

2-5.0-fluoro-1-(6-fluorochroman-2-yl)ethan-1-one (III) 25.0 g (0.1 mol), glucose 23.7 g, R were sequentially added to a 500 mL reaction flask at 15 to 25 °C. - Reductase 50.0g, dissolved in 20% sodium carbonate The pH was adjusted to 7.5, and the reaction was carried out by adding NAD + 0.25 g, and the pH was maintained at 7.5 during the reaction. After 10 hours of reaction, the TLC dot plate showed that the reaction was completed. After adding 250 g of diatomaceous earth and suction filtration, the filter cake was rinsed with 1500 mL of toluene, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 24.0 g of pale yellow oily product (1R)-2-chloro-1-(6- Fluorin-2-yl)ethan-1-ol R-(II) in a yield of 95.0%.

2. Preparation of 6-fluoro-2-((S)-epoxy-2-yl)chroman (S-(I))

24.0 g of (1R)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol S-(II) was dissolved in 120 mL of toluene, and the system was cooled to below 0 ° C. 7.5 g of sodium hydroxide solid was added, followed by stirring at 15 to 25 ° C for 16 hours, and TLC showed the reaction was completed. After cooling in an ice water bath, 7.8 mL of acetic acid was added dropwise, and the salt was precipitated. The mixture was filtered, and the salt was washed three times with 50 mL of toluene. The combined organic phases were washed once with 230 mL of water and 90 mL of brine, dried over anhydrous sodium sulfate and filtered. Drying, 22.0 g of a yellow oily 6-fluoro-2-((S)-epoxy-2-yl)-supplemented S-(I) was obtained in a yield of 99.9%.

Take 200-300 mesh silica gel 220g column and rinse with n-heptane; 22.0g of yellow oil 6-fluoro-2-((R)-epoxy-2-yl) obtained in the above step is color-filled with S-( I) Wet loading, and then eluting with a mixed solution of ethyl acetate: n-heptane = 1:15 as mobile phase, respectively, to obtain 8.7 g of (S)-6-fluoro-2-((S)-epoxy -2-yl) color full S, S-(I), chiral purity 99.55%, chemical purity 99.53%; and 4.9 g (R)-6-fluoro-2-((S)-epoxy-2-yl The color is full of R, S-(I), the chiral purity is 99.8%, the chemical purity is 99.5%, the total yield (calculation method is the same as in Example 1) is 61.8%, and the cross portion is 10.1 g.

Claims

A 6-fluoro-2-(epoxy-2-yl) color full preparation method comprising the following steps:

(1) According to the formula (II), the compound of the formula (II) is prepared by the following method:

If the compound of formula (II) is R form, it comprises the steps of: reducing the compound of formula (III) under the action of ammonium formate or glucose, R-reductase and coenzyme in water, pH=6.0-8.0; a compound of formula (II); wherein the coenzyme is nicotinamide adenine dinucleotide;

If the compound of formula (II) is S-type, it comprises the steps of: reducing the compound of formula (III) in water, in an alcohol solvent, under the action of S-type reductase and coenzyme, and at a pH of 7.0 to 9.5. a compound of formula (II); wherein the coenzyme is nicotinamide adenine dinucleotide and/or nicotinamide adenine dinucleoside phosphate;

(2) epoxidizing the R-form or S-form compound of the formula (II) obtained in the step (1) in an organic solvent in the presence of a base to obtain a compound of the formula (I') in a corresponding configuration;

(3) chiral resolution of the compound of the formula (I') obtained in the step (2) by column chromatography to obtain a compound of the formula (I) in a single stereo configuration;

Wherein, the carbon marked by * indicates chiral carbon, which includes S type and R type;
It is indicated that the chemical bond does not have a specific stereo configuration, and the chiral carbon to which the bond is attached includes an S-type, an R-form, and a stereoisomer mixture.
The preparation method according to claim 1, wherein:

In the step (1), if the compound of the formula (II) is in the R form and ammonium formate is used as the hydrogen source, The preparation method comprises the steps of: mixing a compound of the formula (III), water and ammonium formate, adding an R-reductase and a coenzyme, and adjusting the pH to 7.5-7.8;

Alternatively, in the step (1), if the compound of the formula (II) is R type and ammonium formate is used as a hydrogen source, the preparation method comprises the following steps: at 20 ° C, a buffer solution, ammonium formate, a compound of the formula (III), and an R type. The reductase and the coenzyme are mixed, and the pH of the system is adjusted to 7.5-7.8 to carry out the reaction;

Alternatively, in the step (1), if the compound of the formula (II) is R-type and glucose is used as a hydrogen source, the preparation method comprises the steps of: mixing the compound of the formula (III), glucose and R-reductase, and adjusting the pH of the system to 7.5, followed by the addition of coenzyme and maintaining the pH = 7.5 for the reaction;

Alternatively, in the step (1), if the compound of the formula (II) is R-type and glucose is used as a hydrogen source, the preparation method comprises the steps of: mixing a compound of the formula (III), glucose and an R-reductase, and further using an aqueous solution of sodium carbonate. Adjusting the pH of the system to 7.5, then adding the coenzyme and maintaining the pH = 7.5 to carry out the reaction;

Alternatively, in the step (1), if the compound of the formula (II) is S-type, the preparation method comprises the steps of: mixing the compound of the formula (III), water and an alcohol solvent, adding a S-type reductase and a coenzyme, and adjusting the pH to 7.8. ～8.0 to carry out the reaction;

Alternatively, in the step (1), if the compound of the formula (II) is S-type, the preparation method comprises the steps of: mixing a buffer solution, an alcohol solvent, a compound of the formula (III), a S-type reductase and a coenzyme at 20 ° C, and then Adjusting the pH of the system to 7.8-8.0 to carry out the reaction;

Alternatively, in the step (1), if the compound of the formula (II) is S-type, the preparation method comprises the steps of: mixing the S-type reductase, the alcohol solvent, the water and the coenzyme at 15 to 25 ° C, and adjusting the pH to 8.0 with dilute ammonia water. Further adding a compound of the formula (III), and conducting the reaction at 25 to 30 ° C;

Alternatively, in the step (1), if the compound of the formula (II) is S-type, the preparation method comprises the steps of: mixing the compound of the formula (III), a buffer solution and an alcohol solvent, adding a S-type reductase and a coenzyme, and adjusting the pH to The reaction was carried out at 7.8 to 8.0.
The preparation method according to claim 1, wherein in the preparation method of the compound of the formula (1) of the R type or the S type, a buffer solution is further added to the system in the step (1); The buffer solution is preferably a buffer solution of potassium dihydrogen phosphate; the preparation method of the potassium dihydrogen phosphate buffer solution preferably comprises: mixing potassium dihydrogen phosphate with distilled water, and adjusting the pH to 6.8-7.5, preferably 7.0- with a base. 7.2; the base is preferably one or more of sodium hydroxide, ammonia water, sodium carbonate and potassium hydroxide; the concentration of the solution formed by mixing the potassium dihydrogen phosphate with distilled water is preferably 0.8-1.2 mol/L. Preferably, 0.1 mol/L; the base preferably adjusts the pH of the buffer solution in the form of a solution of 1.5 to 2.5 mol/L, more preferably 2.0 mol/L.
The preparation method according to claim 1, wherein in the step (1), the alcohol solvent contains an alcohol having 1 to 4 carbon atoms, preferably isopropanol; and the alcohol solvent is preferably a formula ( II) The volume-to-mass ratio of the compound is (10 to 20 mL): 1 g, preferably 16 mL: 1 g.
The preparation method according to claim 1, wherein in the step (1), the reductase comprises an R-type reductase and a S-type reductase; and the S-type reductase is Huzhou Yuhui Biotechnology Co., Ltd. a carbonyl reductase 1184; the R-type reductase is a carbonyl reductase 740 of Huzhou Yuhui Biotechnology Co., Ltd.; the S-type or R-type reductase, according to different enzyme activities, the mass is the mass of the compound of formula (III) 0.2 to 2.0 times.
The preparation method according to claim 1, wherein in the step (1), the coenzyme is used in an amount of 0.01 g to 0.20 g/L, which is a ratio of the coenzyme mass to the total volume of the system.
The preparation method according to claim 1, wherein in the preparation method of the compound of the formula (1) of the R type or the S type, the pH of the system is sodium hydroxide, ammonia water, sodium carbonate and potassium hydroxide in the step (1). One or more adjustments; preferably a sodium hydroxide aqueous solution having a concentration of 1.5 to 2.5 mol/L, a 15 to 25% aqueous sodium carbonate solution or a dilute aqueous ammonia having a mass concentration of 28%, more preferably a mass concentration of 20%. A sodium carbonate aqueous solution or a 2.0 mol/L aqueous sodium hydroxide solution.
The preparation method according to claim 1, wherein in the step (1), the temperature of the reduction reaction is 0 to 40 ° C, preferably 20, in the preparation method of the R type or the S type compound of the formula (II). ～40 ° C, more preferably 25 to 30 ° C.
The preparation method according to claim 1, wherein the step (2) comprises: (II) the compound is mixed with an organic solvent, cooled to below 0 ° C, and a base is added to carry out an epoxidation reaction;

Alternatively, the step (2) comprises: dissolving the compound of the formula (II) in an organic solvent, cooling to below 0 ° C, adding a base, followed by epoxidation at 15 to 25 ° C.
The preparation method according to claim 1, wherein in the step (2), the organic solvent is toluene, acetone or an alcohol having 1 to 4 carbon atoms; the 1-4 carbon atoms; The alcohol is preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or sec-butanol; the mass ratio of the organic solvent to the compound of the formula II is preferably (4 to 8 mL): 1 g. More preferably 4.6 mL / g of the compound of formula II - 5.1 mL / g of the compound of formula II;

And/or, in the step (2), the base is an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; and the molar ratio of the base to the compound of the formula (II) is preferably 1:1 to 2 :1, more preferably 2:1 to 2.4:1;

And/or, in the step (2), the temperature of the epoxidation reaction is 0 to 40 ° C, preferably 10 to 30 ° C, more preferably 15 to 25 ° C, and the temperature referred to herein means the addition of the base. Reaction temperature; in the step (2), when the alkali is added, the temperature of the reaction system is preferably controlled below 0 ° C;

And/or, in step (3), the column chromatography is performed by using 200-400 mesh silica gel column, preferably 200-300 mesh silica gel column; the column chromatography is performed by wet method; the column is The eluent used in the chromatography is a mixed solvent of dichloromethane and methanol, or a mixed solvent of ethyl acetate and n-heptane; when the compound of the formula (I') is of the R type, the eluent used is preferably dichloromethane: Methanol = 45:1 or ethyl acetate: n-heptane = 1:15, the ratio is a volume ratio; when the compound of the formula (I') is S-type, the eluent used is preferably dichloromethane: methanol = 40: 1 or ethyl acetate: n-heptane = 1:15, the ratio is a volume ratio.