CN103539710A

CN103539710A - Synthesis method of (R)-bicalutamide

Info

Publication number: CN103539710A
Application number: CN201210223260.6A
Authority: CN
Inventors: 不公告发明人
Original assignee: Sinopharm Yixin Pharmaceutical Co Ltd
Current assignee: Sinopharm Yixin Pharmaceutical Co Ltd
Priority date: 2012-07-02
Filing date: 2012-07-02
Publication date: 2014-01-29

Abstract

The invention provides a synthesis method route of (R)-bicalutamide. As a drug for treating a prostatic cancer, bicalutamide is racemoid in general, but the (R)-type activity is 60 times of (S)-type activity, so that chiral synthesis (R)-type bicalutamide is very important. The method disclosed by the invention comprises the following steps: by taking (R)-3-bromo-2-hydroxy-2-methyl propionic acid as a raw material, preparing a chiral intermediate by reaction of esterification, oxidization and the like, and finally preparing the (R)-bicalutamide from 4-cyan-3-( trifluoromethyl) phenylamine. The key point of the synthesis method is that the synthesis method is mild in reaction condition, high in yield, convenient to process, low in cost, and applicable to industrial production.

Description

A kind of synthetic method of (R)-bicalutamide

Technical field

The present invention relates to organic compound preparation process amelioration, more particularly about the improvement in synthesis of antitumor drug (R)-bicalutamide (R-Bicalutamide)

Background technology

At present, prostate cancer is the second largest lethality malignant tumour of the male sex, reduce the contents level of male hormone in body, it is the common method for the treatment of prostate cancer, wherein bicalutamide is the most widely used antiandrogen medicine in the whole world, there is optical siomerism in bicalutamide, wherein the activity of (R)-bicalutamide is 60 times of (S)-bicalutamide activity; Two enantiomorphs of bicalutamide are all at liver intracellular metabolite, (S)-bicalutamide is more faster at liver intracellular metabolite than (R)-bicalutamide, this burden that has just increased liver is the bad patient of liver especially, adopts the intake of single medicine to alleviate the burden of liver by being conducive to and has avoided some other side effect.

(R)-bicalutamide chemistry (2R)-N-[4-cyano group-3-trifluoromethyl by name]-3-[(4-fluorophenyl) alkylsulfonyl]-2-hydroxy-2-methyl propionyl, its structural formula is as follows:

Its reaction examination of the bibliographical information of racemization bicalutamide (Howard Tucker J.Med.Chem.1988,31,954-959, Howard Tucker USP463605) is as follows:

Figure DEST_PATH_403943DEST_PATH_IMAGE002

(R) bibliographical information of-bicalutamide mainly by (Leonid Kirkovsky.etal.J.Med.Chem.2000,43,581-590) D-PROLINE is that the starting raw material chirality of carrying out is synthetic, its reaction formula is as follows:

Figure DEST_PATH_175589DEST_PATH_IMAGE003

In the route of this synthetic (R)-bicalutamide, harsh at the preparation process conditional of compound 7 to 8, solvent must be used DMA, and side reaction is more, and aftertreatment difficulty, need to carry out purifying by column chromatography.

Also have some similarly as WO134563, WO0128990, WO9519770 etc. have also carried out pertinent literature report to (R)-bicalutamide.Based on above report, it is carried out to process modification and prepare (R)-bicalutamide.

Summary of the invention

The preparation technology who the object of the present invention is to provide a kind of antiprostate cancer (R)-bicalutamide, the method can reduce environmental pollution, simple to operate, and it is convenient to process, and the finished product impurity is few, is applicable to suitability for industrialized production.

Reaction formula of the present invention is as follows:

Technical scheme provided by the invention totally has following step:

(1) the bromo-2-hydroxy-2-methyl of (the R)-3-propionic acid of take obtains compound R 1:(R through esterification as raw material) the bromo-2-hydroxy-2-methyl of-3-ethyl propionate

(2) compound R 1 is with to fluoro thiophenol, condensation obtains R2

(3) R2 carries out oxydrolysis reaction and obtains R3

(4) again with 4-cyano group-3-(trifluoromethyl) aniline reaction forms acid amides and obtains R-bic

More than prepare the method for (R)-bicalutamide, operation steps is as follows:

1, the bromo-2-hydroxy-2-methyl of (R)-3-propionic acid is that raw material obtains compound R 1. through ethyl esterification

2, the R1 of equivalent is dissolved in anhydrous THF, is cooled to-5 ~ 0oC, keeps this temperature to add 2 times of amount Anhydrous potassium carbonates, slowly drips the THF solution to fluoro thiophenol of equivalent, finishes and rises to stirred overnight at room temperature, through aftertreatment, obtains oily compound R2.

3, R2 is dissolved in ethanol, adds catalyzer and hydrogen peroxide to be oxidized, and is oxidized completely directly to adding aqueous sodium hydroxide solution hydrolysis in solution, through aftertreatment, obtains white solid compound R 3.

4,4-cyano group-3-(trifluoromethyl of the R3 of equivalent and 0.95 equivalent) DMAP of aniline and catalytic amount is dissolved in THF, maintains the temperature at-10 ~-5 ℃, drips sulfur oxychloride, finishes room temperature reaction 16 ~ 18h.Aftertreatment, ethyl alcohol recrystallization obtains white solid (R)-bicalutamide.

Advantage of the present invention: simple to operate, aftertreatment is easy, does not have special and unmanageable reagent, and environmental pollution is less, and productive rate is higher is suitable for industrialized production.

accompanying drawing explanation:

Fig. 1 is the chemical equation figure of patent of invention; Fig. 2 is compound R 3 nucleus magnetic hydrogen spectrum figure; Fig. 3 is R-bic nucleus magnetic hydrogen spectrum figure.

embodiment:

First be the preparation of raw material:

1. (2R)-1-(2-methacryloyl) Pyrrolidine-2-carboxylic acid

D-PROLINE (30 g, 0.26mol), acetone 240 mL stir, add 6 mol/L NaOH solution 200 mL to be cooled to 0-5 ℃, slowly drip 2-methacrylic chloride (17.2 g, 0.4 mol), in dropping process, control PH more than 13, finish room temperature reaction 3 hours, removing acetone under reduced pressure adjusts PH ≈ 2. to add sodium-chlor to saturated with dilute sulphuric acid, by ethyl acetate (300mL*3 time), extract, anhydrous sodium sulfate drying, suction filtration, filtrate steams cooling crystallization after most of solvent, suction filtration, oven dry obtains white solid product 33 g, fusing point: 102-103oC, yield 67.1%.

2. (3R)-brooethyl-3-methyl Pyrrolidine is [2,1-c] [Isosorbide-5-Nitrae]-oxazines-Isosorbide-5-Nitrae-diketone also

Compound R 1(33g; 0.18mol) be dissolved in 130 mL DMF, under nitrogen protection, add NBS (47.0g, 0.26mol); finish room temperature reaction 5h; decompression steams DMF, adds 1L water, strong stirring 30min; obtain solid suction filtration; obtain white solid product (44.1g), fusing point: 150-152 ℃, yield 94.4%.

3. the bromo-2-hydroxy-2-methyl of (R)-3-propionic acid

(3R)-brooethyl-3-methyl Pyrrolidine also [2, 1-c] [1, 4]-oxazine-1, 4-diketone (44.1g, 0.17mol) adding concentration is 4mol/L hydrochloric acid 120 mL, at 60-70 ℃ of reaction 12h, by ethyl acetate (200mL*3 time), extract, organic layer is added to 1M NaOH 300mL, separate organic phase water intaking layer, with acid PH=3 ~ 4 of dilute hydrochloric acid furnishing, by ethyl acetate (200mL*3 time), extract, dry, suction filtration, evaporate to dryness, re-crystallizing in ethyl acetate obtains white needles compound (R)-3-bromo-2-hydroxy-2-methyl propionic acid (25.6g), ee:99.4%, fusing point: 106-108 ℃, yield 83.1%.

The preparation of R-bic:

1. the bromo-2-hydroxy-2-methyl of (R)-3-ethyl propionate (R1)

(R)-3-bromo-2-hydroxy-2-methyl propionic acid (25.6g, 0.14mol) is dissolved in 200 mL ethanol, adds 2.5g tosic acid, this reaction solution is heated to reflux state reaction to spend the night, decompression steams ethanol, adds 100mL water, is extracted with ethyl acetate, organic layer with saturated sodium bicarbonate washing once, dry, filter evaporate to dryness, obtain oily compound R1(29.2g), yield: 98.9%.

2. (3R)-methyl is to fluorobenzene thioether group-2-hydroxy-2-methyl ethyl propionate (R2)

Compound R 1(29.2g, 0.14mol) be dissolved in anhydrous THF, be cooled to-5 ~ 0 ℃, keep this temperature to add Anhydrous potassium carbonate (39.2g, 0.28mol), slowly drip the THF solution to fluoro thiophenol (17.8g, 0.14mol), finish and rise to stirred overnight at room temperature, suction filtration, filtrate decompression evaporate to dryness, obtains faint yellow oily compound R2(32.4g), directly put in next step reaction.Crude product yield 90.8%.

3.(3R)-methyl is to fluorobenzene sulfuryl-2-hydroxy-2-methyl propionic acid (R3)

Compound R 2(32.4g, 0.125mol) be dissolved in 100 mL ethanol, add sodium wolframate (0.32g), under stirring, slowly drip 30% hydrogen peroxide 32 mL, finish stirred overnight at room temperature, then in reaction solution, add 6mol/L sodium hydroxide solution 100mL, stirring reaction 6h, reactant decompression steams alcohol solvent, ethyl acetate for residuum (100mL*3 time) extraction, anhydrous sodium sulfate drying, suction filtration, filtrate steams cooling crystallization after most of solvent, suction filtration, oven dry obtains white solid compound (R3) 28.6 g, fusing point: 113-116 ℃, yield 86.9%.

4. R-bic

Compound R 3(28.6g, 0.11mol), 4-cyano group-3-(trifluoromethyl) aniline (19.3g, 0.10mol), and the DMAP of catalytic amount is dissolved in THF, maintains the temperature at-10 ~-5 ℃, slowly drip sulfur oxychloride (23.1g, 0.17mol), finish room temperature reaction 16 ~ 18h.In reaction solution, add 100 mL shrends to go out, decompression steams THF, and ethyl acetate (100mL*3 time) extraction is dry, suction filtration, and evaporate to dryness, adds 100mL dissolve with ethanol recrystallization, obtains R-bic (25.3g), ee:99.7%, yield 94.8%.Fusing point: 178-179 ℃, [a] D20-83.2o(c 1, MeOH), mass spectrometric detection m/z:430 (molecular ion peak).

Claims

1. a synthetic method for (R)-bicalutamide, is characterized in that, mainly comprises following step:

(1) the bromo-2-hydroxy-2-methyl of (the R)-3-propionic acid of take obtains compound R 1:(R through esterification as raw material) the bromo-2-hydroxy-2-methyl of-3-ethyl propionate;

(2) compound R 1 is with to fluoro thiophenol, condensation obtains R2 ;

(3)r2 carries out oxydrolysis reaction and obtains R3;

(4) again with 4-cyano group-3-(trifluoromethyl) aniline reaction forms acid amides and obtains R-bic.

2. according to patent, require 1 preparation method, it is characterized in that, in step (1), esterifying reagent is selected from methyl alcohol, ethanol, preferred alcohol.

3. according to patent, require 1 preparation method, it is characterized in that, in step (1), catalyzer is selected from FeCl3, sulfuric acid, hydrochloric acid, tosic acid, preferably tosic acid.

4. according to patent, require 1 preparation method, it is characterized in that, in step (2), alkali is selected from sodium hydride, salt of wormwood, and sodium methylate,

Preferred salt of wormwood.

5. according to patent, require 1 preparation method, it is characterized in that, in step (3), oxidising agent is selected hydrogen peroxide, and m-chloro-benzoic acid peroxide etc. is hydrogen peroxide preferably.

6. according to patent, require 1 preparation method, it is characterized in that, in step (3), the solvent of product recrystallization is selected from toluene, ethyl acetate, ethyl acetate.

7. according to patent, require 1 preparation method, it is characterized in that, in step (4), acylating reagent is selected sulfur oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, preferably sulfur oxychloride.

8. according to patent, require 1 preparation method, it is characterized in that, in step (4), add the temperature of acylating reagent need maintain-10 ~-5 ℃.