CN107686480A - A kind of method for preparing nebivolol epoxides individual isomer - Google Patents

Abstract

The invention provides a method for preparing nebivolol epoxide 6-fluoro-2-(epoxy-2-yl) chroman (I) single isomer. The method uses the mixed 2-chloro-1-(6-fluorochroman-2-yl) ethyl-1-ketone (III) as a raw material; it is selectively reduced by a reductase to obtain a chiral hydroxyl Chlorohydrins (II), then generate a mixture (R/S)-(I) of diastereomers of two epoxides in the presence of a base; then this mixture is prepared by separation of column chromatography to obtain two A single isomer (I) of an enantiopure epoxide. According to the above method, if the reduction is catalyzed by R-reductase, the single isomers obtained are R, R-(I) and S, R-(I); if the reduction is catalyzed by S-reductase, the single isomer obtained is The isomers are S,S‑(I) and R,S‑(I). The present invention is ingenious in design, the synthetic route is simple and efficient, the technological process is simple and easy, and is green and environmentally friendly, and is a single isocyanate (I) for the industrialized preparation of nebivolol epoxide 6-fluoro-2-(epoxy-2-based) chroman (I). Constructs provide a new approach.

Description

A kind of method for preparing single isomer of nebivolol epoxide

technical field

The present invention relates to the technical field of nebivolol synthesis, more specifically, to the technical field of synthesis of 6-fluoro-2-(epoxy-2-yl) chroman, in particular to a 6-fluoro-2-(cyclo Oxy-2-yl) chroman single isomer method.

Background technique

Nebivolol hydrochloride (Nebivolol) is a drug developed by Johnson & Johnson of the United States for the treatment of essential hypertension. Its chemical name is α, α'-[iminebis(methylene)bis(6-fluoro- 3,4-dihydro-2H-1-benzopyran-2-methanol)] hydrochloride, first listed in Germany and the Netherlands in 1997, is a cardioselective β-receptor blocker with vasodilator effect It has the advantages of protecting the heart, good antihypertensive effect, good tolerance, less adverse reactions, low dose and good curative effect.

The structural formula of Nebivolol has four chiral carbon atoms, and there are 10 isomers in total, among which (R, R, R, S) has good receptor blocking properties, while the other configuration (S, S, Although S, R) isomers have no pharmaceutical activity, they have a better effect on controlling the release of NO. Therefore, in the current commercially available drugs, it is still a racemate, that is, an equivalent amount of (S,S,S,R)-α,α'-[iminebis(methylene)bis(6-fluoro -3,4-dihydro-2H-1-benzopyran-2-methanol)] and (R,R,R,S)-α,α'-[iminobis(methylene)bis(6 -Fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol)].

It is known in the prior art to synthesize α,α'-[iminobis(methylene)bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol)] molecules Structures are a challenge for technicians. If the 6-fluoro-2-(epoxy-2-yl) chroman (I) containing 4 isomers is used to synthesize Nebivolol as a raw material, the 4 asymmetric carbon atoms in Nebivolol produce Mixture of 16 stereoisomers (in case of asymmetric substitution) or mixture of 10 stereoisomers (in case of symmetrical substitution). As is evident from the presence of symmetry in the structure of nebivolol, a total of 10 stereoisomers can be produced.

Therefore, the single isomer of 6-fluoro-2-(epoxy-2-yl) chroman (I) must be obtained earlier, with R, R-(I) and S, R-(I) as raw materials, the reaction is obtained Nebivolol (R, R, R, S) isomers, and then use S, S-(I) and R, S-(I) as raw materials to react to obtain Nebivolol (S, S, S ,R) isomers, so as to avoid the formation of other isomers.

At present, the single isomers of four 6-fluoro-2-(epoxy-2-yl) chroman (I) are generally synthesized with 6-fluorochroman-2-carboxylic acid (IV) as raw material, (S)-6-fluorochroman-2-carboxylic acid S-(IV) and (R)-6-fluorochroman-2-carboxylic acid R-(IV) were obtained respectively through chemical resolution or enzymatic resolution, They are then transformed into the corresponding chiral ketone intermediates S-(III) and R-(III). If the chiral ketone 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, Close the ring respectively to obtain two single configurations of 6-fluoro-2-(epoxy-2-yl) chroman S, S-(I) and S, R-(I); if the chiral ketone 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), and then ring-closing to obtain Two other single-configuration 6-fluoro-2-(epoxy-2-yl)chromans R,S-(I) and R,R-(I).

Though this method has obtained the 6-fluoro-2-(epoxy-2-base) chroman (I) of four single configurations, there are following problems:

1. The cost of splitting 6-fluorochroman-2-carboxylic acid (IV) is relatively high. Both chemical resolution and enzymatic resolution are cumbersome, and the resolution efficiency is not high; and two configurational isomers must be obtained at the same time, so a single ( S )-6-fluorochroman-2-carboxylic acid S -(IV) or ( R )-6-fluorochroman-2-carboxylic acid R-(IV) is much more expensive than vortexed 6-fluorochroman-2-carboxylic acid (IV).

2. After the resolution of 6-fluorochroman-2-carboxylic acid (IV), to synthesize chiral ketone intermediates S-(III) and R-(III), two reactions must be performed in parallel, and from chiral chlorine Ketone intermediates S-(III) and R-(III) to the last four 6-fluoro-2-(epoxy-2-yl) chroman (I) must have four reactions in parallel, which is complicated to operate and is not suitable for Industrial production.

Contents of the invention

Aiming at the problems and deficiencies in the above-mentioned synthesis of 6-fluoro-2-(epoxy-2-yl) chroman (I) four isomers, the present invention provides a method for preparing nebivolol epoxide 6- Fluoro-2-(epoxy-2-yl)chroman (I) single isomer method. The method is ingeniously designed, the synthetic route is simple and efficient, the process flow is simple and easy, and it is green and environmentally friendly. Constructs provide a new approach.

The method uses spun 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one (III) as raw material; it is selectively reduced by reductase to obtain chiral hydroxyl Chlorohydrins (II), and then generate a mixture (R/S)-(I) of diastereoisomers of two epoxides in the presence of a base; then this mixture is prepared by separation by column chromatography to obtain two A single isomer (I) of an enantiopure epoxide.

According to the above method, the reductase includes R-reductase and S-reductase. If the reduction is catalyzed by R-reductase, the single isomers obtained are R,R-(I) and S,R-(I); if the reduction is catalyzed by S-reductase, the single isomers obtained are S,S-(I) and R,S-(I).

Preferably, the enzyme reduction reaction is carried out in a mixed solution of C _1-4 alcohol or water and buffer solution, in the presence of reductase and coenzyme, the pH of the system is 7.0-8.0, and the reaction temperature is 0-30°C.

Preferably, the ring-closing reaction uses toluene, acetone or C _1-4 alcohol as solvent, alkali metal hydroxide as base, and the reaction temperature is 0~30 ^° C.

Preferably, in the separation method of column chromatography, silica gel is used as a filler, and a mixed solvent of dichloromethane and methanol is used as an eluent.

The beneficial effects of the present invention are specifically:

1. Directly adopting 2-chloro-1-(6-fluorochroman-2-yl) ethyl-1-ketone (III) of mixed rotation is a raw material, eliminating the need for 6-fluorochroman-2-carboxylic acid (IV ) resolution, and subsequent work on the synthesis of two chiral 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ones (III). The cost of raw materials is reduced, the process operation is simplified, and the convenience of industrial production is improved.

2. Using reductase to selectively reduce 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one (III) to obtain chlorohydrin (II) with chiral hydroxyl , then a mixture of diastereoisomers (R/S)-(I) of the two epoxides is generated in the presence of a base; only two parallel reactions are required to achieve four 6-fluoro-2- Synthesis of Single Isomers of (Epoxy-2-yl)chromans (I). 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 obtains two enantiopure single isomers (I) of epoxides through the separation and preparation of column chromatography, thereby obtaining four 6-fluoro-2-(epoxy-2-yl) chromans The single isomer of (I), can guarantee the ee value and de value of each single isomer (I) like this. The problems of splitting and reaction level of products in the original scheme are avoided.

detailed description

In order to better understand the content of the present invention, the following will be further described in conjunction with specific examples. It should be understood that the following specific examples are only used to illustrate the present invention, rather than limit the present invention.

Example 1:

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

Take 14.3 g of potassium dihydrogen phosphate, dissolve it in 1080 mL of distilled water, and make a 0.1 mol/L solution, adjust the pH to 7.5 with 2.0 mol/L sodium hydroxide, and prepare a buffer solution for later use.

At room temperature (20 ^o C), add 720 mL of isopropanol to the above buffer solution, add 45.0 g of 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one (III), S- 90.0 g of reductase and 0.18 g of NAD+ were adjusted to 7.8 with 2.0 mol/L sodium hydroxide, and reacted at room temperature for 18 hours. After the detection reaction is complete, add 90g of diatomaceous earth and stir evenly, then filter, wash twice with 1000mL ethyl acetate, stand and separate the layers, separate the first batch of organic phase, and extract the water phase with 1000mL ethyl acetate for two Once, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 35.0 g of light yellow oily product ( 1S )-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-alcohol S-(II), yield 77.1%.

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

Dissolve 35.0g (1 S )-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol S-(II) in 180mL toluene, cool the system below 0 ^o C, Slowly add 14.6 g of solid sodium hydroxide, then stir at room temperature for 16 hours, TLC shows that the reaction is complete. Under cooling in an ice-water bath, add 11 mL of acetic acid dropwise to precipitate salt, filter and wash the salt with 150 mL of ethyl acetate three times, wash the combined organic phase with 400 mL of water and 300 mL of saline, dry over anhydrous sodium sulfate, filter, and spin After drying, 30.7 g of yellow oily substance 6-fluoro-2-(( R )-epoxy-2-yl)chroman R-(I) was obtained with a yield of 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))

Take 800g of silica gel of 300~400 mesh and pack it into a column, and wash it with dichloromethane; 6-fluoro-2-(( R )-epoxy-2-yl)chroman R-( 1) be dissolved in 50mL dichloromethane, wet load sample, then use the mixed solution of dichloromethane:methanol=45:1 as mobile phase elution, obtain 13.8g ( S )-6-fluoro-2-( ( R )-epoxy-2-yl)chroman S,R-(I) and 13.6g ( R )-6-fluoro-2-(( R )-epoxy-2-yl)chroman R,R -(I), the total recovery is 89.3%, and the intersection part is not counted.

Example 2:

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

Take 15.4 g of potassium dihydrogen phosphate, dissolve it in 1128 mL of distilled water, and make a 0.1 mol/L solution, adjust the pH to 7.0 with 2.0 mol/L sodium hydroxide, and prepare a buffer solution for later use.

At room temperature (20 ^o C), add 0.22g of zinc chloride, 94.0g of ammonium formate, 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one (III) to the above buffer solution 47.0 g, 94.0 g of R-reductase and 0.19 g of NAD+, adjusted to 7.8 with 2.0 mol/L sodium hydroxide, and reacted at room temperature for 28 hours. After the detection reaction is complete, add 94g of diatomaceous earth and stir evenly, then filter, wash twice with 1000mL ethyl acetate, stand and separate the layers, separate the first batch of organic phase, and extract the water phase with 1000mL ethyl acetate for two Once, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 31.5 g of light yellow oily product ( 1R )-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-alcohol R-(II), yield 66.4%.

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

Dissolve 35.0g (1 R )-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol S-(II) in 160mL toluene, cool the system below 0 ^o C, Slowly add 24.6 g of solid sodium hydroxide, then stir at room temperature for 16 hours, TLC shows that the reaction is complete. Under cooling in an ice-water bath, add 14 mL of acetic acid dropwise to precipitate salt, filter and wash the salt with 200 mL of ethyl acetate three times, and wash the combined organic phase with 250 mL of water and 200 mL of saline respectively, dry over anhydrous sodium sulfate, filter, and spin After drying, 20.6g of yellow oily substance 6-fluoro-2-(( S )-epoxy-2-yl)chroman S-(I) was obtained with a yield of 77.9%.

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))

Take 300~400 mesh silica gel 600g to pack the column, and rinse with dichloromethane; 6-fluoro-2-(( R )-epoxy-2-yl)chroman R-( 1) be dissolved in 40mL dichloromethane, wet load sample, then use the mixed solution of dichloromethane:methanol=40:1 as mobile phase elution, obtain 8.5g ( S )-6-fluoro-2-( ( S )-epoxy-2-yl)chroman S,S-(I) and 8.1g ( R )-6-fluoro-2-(( S )-epoxy-2-yl)chroman R,S -(I), the total recovery is 80.4%, and the intersection part is not counted.

In this specification, the invention has been described with reference to specific embodiments thereof. However, it is obvious that various modifications and changes can be made without departing from the spirit and scope of the invention. Accordingly, the specification should be regarded as illustrative rather than restrictive.

Claims (8)

1. one kind prepares the method for the fluoro- 2- of nebivolol epoxides 6- (epoxy -2- bases) chroman (I) individual isomer, the party Method comprises the following steps that：

A) the chloro- 1- of the 2- of DL (6- fluorine chroman -2- bases) second -1- ketone (III) selective reduction is obtained by band using reductase There is the chloropharin (II) of chiral hydroxyl group, then generate the mixture of the diastereoisomer of two epoxides in the presence of base (R/S)-(I)；

B) said mixture is prepared to the individual isomer of two pure epoxides of mapping by the separation of column chromatography (I)

。

2. method according to claim 1, the individual isomer (I) of the epoxides is as shown in following structural formula：

。

3. method according to claim 1, it is characterised in that described reductase includes R- reductases and S- is reduced Enzyme.

4. method according to claim 1, using R- reductases, the individual isomer being prepared is R, R- (I) and S,R-(I)。

5. method according to claim 1, using S- reductases, the individual isomer being prepared is S, S- (I) and R,S-(I)。

6. method according to claim 1, it is characterised in that enzyme reduction reaction in C_1-4Alcohol or water and buffering it is molten In the mixed solution of liquid, reductase in the presence of coenzyme with carrying out, and system pH is 7.0 ~ 8.0, reaction temperature 0 ~ 30^oC。

7. method according to claim 1, it is characterised in that ring closure reaction is with toluene, acetone or C_1-4Alcohol to be molten Agent, using alkali metal hydroxide as alkali, reaction temperature 0 ~ 30^oC。

8. method according to claim 1, it is characterised in that using silica gel as filler in the separation method of column chromatography, Using the mixed solvent of dichloromethane and methanol as eluant, eluent.