CN106748884B - Preparation method of bicalutamide intermediate - Google Patents

Preparation method of bicalutamide intermediate Download PDF

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CN106748884B
CN106748884B CN201611148101.9A CN201611148101A CN106748884B CN 106748884 B CN106748884 B CN 106748884B CN 201611148101 A CN201611148101 A CN 201611148101A CN 106748884 B CN106748884 B CN 106748884B
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cyano
trifluoromethylphenyl
methacrylamide
acid
solvent
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CN106748884A (en
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李建军
高志远
熊继业
余晓磊
梁波
乔玉峰
周红军
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BEIJING ZHENDONG GUANGMING PHARMACEUTICAL RESEARCH INSTITUTE Co.,Ltd.
SHANXI ZHENDONG PHARMACEUTICAL Co.,Ltd.
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Beijing Zhendong Guangming Pharmaceutical Research Institute Co ltd
Shanxi Zhendong Pharmaceutical Co ltd
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00Preparation of carboxylic acid nitriles
    • C07C253/30Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups

Abstract

The invention provides a preparation method of a bicalutamide intermediate, in particular to a method for preparing 3-chloro-N- (4-cyano-3-trifluoromethylphenyl) -2-hydroxy-2-methylpropanamide by using N- (4-cyano-3-trifluoromethylphenyl) methacrylamide: in a solvent, N- (4-cyano-3-trifluoromethylphenyl) methacrylamide is used as a raw material, acid is added, the mixture is cooled to 0-15 ℃, the mixture is stirred, sodium hypochlorite solution is dropwise added for oxidation, the temperature of a reaction system is kept at 0-15 ℃ after dropwise addition, the reaction is carried out for 0.5-1 hour, and the obtained solution is separated and purified to obtain high-purity 3-chloro-N- (4-cyano-3-trifluoromethylphenyl) -2-hydroxy-2-methylpropionamide.

Description

Preparation method of bicalutamide intermediate
Technical Field
The invention belongs to the field of biological medicine and chemical medicine synthesis, and particularly relates to a preparation method of an antiandrogen medicine bicalutamide intermediate.
Background
Bicalutamide (Bicalutamide), with the chemical name N- [4-cyano-3- (trifluoromethyl) phenyl ] -3- (4-fluorobenzothioyl) -2-methyl-2-hydroxypropionamide, and with the english name N- [4-cyano-3- (trifluoromethyl) phenyl ] -3- [ (4-fluorophenyl) sulfonyl ] -2-hydroxy-2-methyl-propanamide, has the following formula:
the tablet was first marketed in the United kingdom in 1995 under the trade name Casodex, and is approved for import in 1999 for bicalutamide tablets. The bicalutamide is a nonsteroidal antiandrogen drug which is collected in the 32 th edition of the United states pharmacopoeia, has definite curative effect, strong action specificity, effective oral administration, convenient administration, good tolerance and longer half-life, is the only drug for treating the prostatic cancer by oral administration (50 mg/tablet) at present, can be applied to the treatment of the advanced prostatic cancer by combining with LHRH, can reduce various toxic and side effects by 70 percent compared with the first generation antiandrogen flutamide, has higher effect than the flutamide, is the anti-tumor drug with the fastest increase of the sales at present, has good clinical application prospect, is developed autonomously at home, can reduce the drug price, reduces foreign exchange and meets the drug use requirements of people.
The synthesis method of bicalutamide reported in the literature is many, and the route with practical value is to condense 4-amino-3-trifluoromethyl aniline and 2-methacryloyl chloride into amide, then obtain epoxide through oxidation, obtain important thiophenol intermediate of bicalutamide through ring opening and 4-fluorobenzothiophenol, and further obtain bicalutamide through oxidation (Howard Tucker J.Med.Chem.,1988, 31, 954-:
the physiological activity of the levo bicalutamide is 60 times stronger than that of the dextro isomer, so the asymmetric synthesis of the levo isomer is particularly important. The synthetic route of the levo-bicalutamide (Leonid Kirkovsky, et al, J.Med.chem., 2000,43,581-590) is to condense D-proline and 2-methacryloyl chloride into amide, bromize NBS, react with 4-amino-3-trifluoromethylaniline after acidification and ring opening to obtain amide, generate an (R) -thiophenol intermediate with 4-fluorophenylthiophenol, and finally obtain the levo-bicalutamide by oxidation, wherein the synthetic route is as follows:
there are also a number of patents (WO0128990, WO134563, WO9519770 and US5985868) which also report similar preparations of levobicalutamide.
As seen from the two main routes described above, the two important intermediates for the preparation of thioethers are the epoxy compound (I) and the halohydrin compound (II), which have the following chemical formula:
(Ⅰ)
(Ⅱ)
among them, the preparation of epoxy compounds (i) is reported in many cases, o. Payen et al; J. organomet. chem., 2011,696, 1049-;
halohydrin compounds (ii) are mainly synthesized by the following two routes (WO 2010116342, US2005085449, WO2009036206, WO2007027582, WO2009155481, WO2013067170, etc.):
of the two routes, the first route is long, long in period and moderate in yield, and a methanesulfonyl chloride controlled reagent and an olefin double-hydroxylation reagent (mostly heavy metal reagents such as osmium tetroxide, potassium permanganate and the like) are used, so that the environmental pollution is great, and the industrial production is not facilitated; the second one is an oily substance which is difficult to obtain, the synthetic route is long, and the purification is difficult.
In order to overcome the problems in the above routes as much as possible, the present inventors designed a novel process route for synthesizing the halohydrin compound (ii), and experimentally confirmed the feasibility of this route. The method has the advantages of easily obtained starting materials, high reaction yield, easy reaction operation and the like, and has wide industrial application prospect.
Disclosure of Invention
The technical scheme and content of the invention relate to a preparation method of a bicalutamide intermediate, wherein the bicalutamide intermediate is shown as the following formula (III):
(Ⅲ)
the purpose is as follows: provides a new method for preparing a bicalutamide intermediate, which is suitable for large-scale production, thereby solving the problems of poor safety, environmental pollution, high cost and the like in the existing bicalutamide synthesis technology.
A preparation method of bicalutamide intermediate, in particular to a method for preparing 3-chloro-N- (4-cyano-3-trifluoromethylphenyl) -2-hydroxy-2-methylpropanamide by using N- (4-cyano-3-trifluoromethylphenyl) methacrylamide, and the synthetic route is as follows:
the method comprises the following specific steps:
in a solvent, taking N- (4-cyano-3-trifluoromethylphenyl) methacrylamide as a raw material, adding acid, cooling to 0-15 ℃, stirring, dropwise adding a sodium hypochlorite solution for oxidation, keeping the temperature of a reaction system at 0-15 ℃ after dropwise adding, reacting for 0.5-1 hour to obtain a solution containing a crude product, and separating and purifying to obtain a high-purity compound (III);
wherein the solvent can be any one or mixture of several solvents mutually soluble with water, such as water, acetone, methanol, ethanol, DMSO, DMF, DMA, dioxane, acetonitrile, etc., preferably acetone; the volume weight ratio of the solvent to the N- (4-cyano-3-trifluoromethylphenyl) methacrylamide is 10-20: 1, and preferably 15: 1;
wherein the acid can be one of hydrochloric acid, sulfuric acid, glacial acetic acid or phosphoric acid, preferably sulfuric acid; the molar use ratio of the acid to the N- (4-cyano-3-trifluoromethylphenyl) methacrylamide is 1-3: 1, and preferably 1.5: 1;
wherein the oxidant is sodium hypochlorite solution (bleaching agent) which is commonly used in the market, and the mass percentage concentration of the oxidant is 10-13%, and the preferred mass percentage concentration is 10%; the molar use ratio of the sodium hypochlorite to the N- (4-cyano-3-trifluoromethylphenyl) methacrylamide is 1-5: 1, preferably 2: 1;
wherein the cooling temperature and the reaction system temperature are 0-15 ℃, and 0-5 ℃ is preferred;
the separation and purification comprises the steps of extracting, separating, washing, drying with anhydrous sodium sulfate, filtering and recrystallizing with toluene to obtain a solution containing a crude product; the extraction liquid comprises ethyl acetate, dichloromethane, isopropyl acetate or butyl acetate, and preferably ethyl acetate.
The method has the advantages of easy operation of reaction, mild condition, simple and convenient post-treatment, no environmental pollution, low cost and the like, and the yield can basically reach 75-90 percent and the purity can reach more than 97 percent. The most outstanding advantages are that: firstly, the reaction time is greatly shortened, the reaction time required for preparing the compound (I) by using N- (4-cyano-3-trifluoromethylphenyl) methacrylamide through mCPBA epoxidation reaction is about 10 hours, the compound (II) is prepared by using N- (4-cyano-3-trifluoromethylphenyl) methacrylamide through sodium hypochlorite oxidation reaction, the required time is 0.5-1 hour, the energy consumption is greatly reduced, and the kettle effect and the production efficiency are improved; secondly, the material cost is obviously reduced, the cost of the original commonly used epoxidation reagent m-chloroperoxybenzoic acid (mCPBA) is about 300 yuan per kilogram, the cost of the currently used sodium hypochlorite solution is about 1100 yuan per ton, the cost of the compound (I) prepared by the mCPBA epoxidation is 2200 yuan per kilogram, the cost of the compound (II) prepared by the sodium hypochlorite solution oxidation is 1500 yuan per kilogram by adopting the patent, and the sodium hypochlorite solution is widely used in a plurality of industries, and the raw materials are easy to obtain. The invention provides a novel method for preparing a bicalutamide intermediate, which is suitable for large-scale production, so that the problems of poor safety, environmental pollution, high cost and the like in the existing bicalutamide synthesis technology are solved.
By passing1H-NMR (FIG. 1),13C-NMR (FIG. 2),19the compound (III) was characterized by structure and purity by F-NMR (FIG. 3) and LCMS (FIG. 4), as detailed in the figure.
Drawings
Of the compound (III) of FIG. 11H-NMR spectrum of1HNMR(d6-DMSO,400MHz):δ1.46(s,3H),3.71(d,1H, J=11.2),3.94(d,1H, J=11.2),6.42(s,1H),8.12(d,1H,J=8.8),8.34(dd,1H,J=8.8,1.6),8.57(d,1H,J=1.6),10.57(s,1H)。
FIG. 2 preparation of Compound (III)13C-NMR spectrum of13CNMR(d6-DMSO,100MHz):24.71,51.98,75.56,102.57(d,1C,J=2),116.22,117.91,122.94(q,1C,J=272),123.23,132.01(q,1C,J=32),136.74(q,1C,J=5),143.50,174.27。
FIG. 3 preparation of Compound (III)19F-NMR spectrum of19FNMR(d6-DMSO,376MHz):-61.21。
FIG. 4 LCMS spectrum of compound (III) with ESIMS: m/z305 [ M-H]-
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited thereto.
Example 1
Dissolving N- (4-cyano-3-trifluoromethylphenyl) methacrylamide (1g) in acetone (15 ml), cooling to 0-5 ℃, slowly adding 0.58g concentrated sulfuric acid, stirring, dropwise adding a 10% sodium hypochlorite solution (5.86 g), stirring for 0.5h after dropwise adding, adding ethyl acetate (20 ml) and water (20 ml) into a reaction solution, separating, washing an organic phase with a saturated sodium bicarbonate solution and a saturated salt solution sequentially, drying with anhydrous sodium sulfate, filtering, desolventizing to obtain a yellow crude product (1.2 g), recrystallizing with toluene (10 ml) to obtain a white-like crystal (1g), wherein the yield is 83% and the HPLC purity is 98.02%.
Example 2
Dissolving N- (4-cyano-3-trifluoromethylphenyl) methacrylamide (1g) in methanol (15 ml), cooling to 0-5 ℃, slowly adding concentrated hydrochloric acid (1.17 g), stirring, dropwise adding sodium hypochlorite solution (5.86 g) with 10 percent, stirring for 0.5h after dropwise adding, adding dichloromethane (20 ml) and water (20 ml) into the reaction solution, separating, washing the organic phase with saturated sodium bicarbonate solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, desolventizing to obtain a yellow crude product (1.1 g), recrystallizing with toluene (10 ml) to obtain white-like crystals (0.95 g), yield 79 percent and HPLC purity 97.27 percent.
Example 3
Dissolving N- (4-cyano-3-trifluoromethylphenyl) methacrylamide (1g) in ethanol 25 ml, cooling to 0-5 ℃, slowly adding 0.58g concentrated sulfuric acid, stirring, dropwise adding 10% sodium hypochlorite solution 5.86g, stirring for 0.5h after dropwise adding, adding ethyl acetate 20 ml and 20 ml of water into the reaction solution, separating, washing the organic phase with saturated sodium bicarbonate solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, desolventizing to obtain yellow crude product 1.2g, recrystallizing with 10 ml of toluene to obtain 0.91g of white-like crystals, wherein the yield is 76%, and the HPLC purity is 97.95%.
Example 4
Dissolving N- (4-cyano-3-trifluoromethylphenyl) methacrylamide (1g) in DMF15 ml, cooling to 0-5 ℃, slowly adding 1.16g phosphoric acid, stirring, dropwise adding 5.86g of 10% sodium hypochlorite solution, stirring for 0.5h after dropwise adding, adding 20 ml of ethyl acetate and 20 ml of water into the reaction solution, separating, washing the organic phase with saturated sodium bicarbonate solution and saturated saline solution in turn, drying with anhydrous sodium sulfate, filtering, desolventizing to obtain 1.2g of yellow crude product, recrystallizing with 10 ml of toluene to obtain 0.95g of white-like crystals, yield 79%, and HPLC purity 97.98%.
Example 5
Dissolving N- (4-cyano-3-trifluoromethylphenyl) methacrylamide (1g) in DMSO15 ml, cooling to 0-5 ℃, slowly adding 0.58g concentrated sulfuric acid, stirring, dropwise adding 10.7g of 10% sodium hypochlorite solution, stirring for 0.5h after dropwise adding, adding 20 ml of ethyl acetate and 20 ml of water into the reaction solution, separating, washing the organic phase with saturated sodium bicarbonate solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, desolventizing to obtain 1.1g of yellow crude product, recrystallizing with 10 ml of toluene to obtain 0.90g of white-like crystals, wherein the yield is 75%, and the HPLC purity is 97.12%.
Example 6
Dissolving N- (4-cyano-3-trifluoromethylphenyl) methacrylamide (1g) in acetonitrile 15 ml, cooling to 10-15 ℃, slowly adding 0.58g glacial acetic acid, stirring, dropwise adding 5.86g of 10% sodium hypochlorite solution, stirring for 0.5h after dropwise adding, adding 20 ml of ethyl acetate and 20 ml of water into the reaction solution, separating, washing the organic phase with saturated sodium bicarbonate solution and saturated salt water in sequence, drying with anhydrous sodium sulfate, filtering, desolventizing to obtain 0.9g of yellow crude product, recrystallizing with 10 ml of toluene to obtain 0.7g of white-like crystals, wherein the yield is 58%, and the HPLC purity is 96.68%.
Example 7
Dissolving N- (4-cyano-3-trifluoromethylphenyl) methacrylamide (100g) in acetone (1.5L), cooling to 0-5 ℃, slowly adding 58g concentrated sulfuric acid, dropwise adding sodium hypochlorite solution (586 g) 10% while stirring, stirring for 1h after dropwise adding, adding ethyl acetate (2L) and water (2L) into the reaction solution, separating, washing the organic phase with saturated sodium bicarbonate solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, desolventizing to obtain a yellow crude product (120 g), recrystallizing with toluene (1L) to obtain white-like crystals (106 g), yield 88%, HPLC purity 97.38%, and determining the melting point to be 145.2-147 ℃.

Claims (18)

1. A preparation method of bicalutamide intermediate, in particular to a method for preparing 3-chloro-N- (4-cyano-3-trifluoromethylphenyl) -2-hydroxy-2-methylpropanamide by using N- (4-cyano-3-trifluoromethylphenyl) methacrylamide, which is characterized in that:
in a solvent, adding acid into N- (4-cyano-3-trifluoromethylphenyl) methacrylamide serving as a raw material, cooling to 0-15 ℃, stirring, dropwise adding a sodium hypochlorite solution for oxidation, keeping the temperature of a reaction system at 0-15 ℃ after dropwise adding is finished, reacting for 0.5-1 hour to obtain a solution containing a crude product, and separating and purifying to obtain high-purity 3-chloro-N- (4-cyano-3-trifluoromethylphenyl) -2-hydroxy-2-methylpropionamide (III).
2. The method of claim 1, wherein: the solvent is any one or a mixture of several solvents which are mutually soluble with water.
3. The method of claim 2, wherein: the solvent is one or a mixture of several solvents of water, acetone, methanol, ethanol, DMSO, DMF, DMA, dioxane and acetonitrile.
4. The production method according to claim 3, characterized in that: the solvent is acetone.
5. The method of claim 1, wherein: the acid is one of hydrochloric acid, sulfuric acid, glacial acetic acid or phosphoric acid.
6. The method of claim 5, wherein: the acid is sulfuric acid.
7. The method of claim 1, wherein: the sodium hypochlorite solution for oxidation has a mass percentage concentration of 10-13%.
8. The method of claim 7, wherein: the mass percentage concentration of the sodium hypochlorite solution is 10%.
9. The method of claim 1, wherein: the cooling temperature and the reaction system temperature are 0-5 ℃.
10. The method of claim 1, wherein: and the separation and purification comprises the steps of extracting, separating, washing, drying with anhydrous sodium sulfate, filtering and recrystallizing with toluene to obtain a solution containing the crude product.
11. The method of manufacturing according to claim 10, wherein: the extraction liquid for extraction comprises ethyl acetate, dichloromethane, isopropyl acetate or butyl acetate.
12. The production method according to claim 10 or 11, characterized in that: the extraction liquid used for extraction is ethyl acetate.
13. The production method according to any one of claims 1 to 4, characterized in that: the volume-weight ratio of the solvent to the N- (4-cyano-3-trifluoromethylphenyl) methacrylamide is 10-20: 1, and the volume-weight ratio is ml/g.
14. The method of manufacturing according to claim 13, wherein: the further volume to weight ratio of the solvent to N- (4-cyano-3-trifluoromethylphenyl) methacrylamide was 15:1, the volume to weight ratio being ml/g.
15. The production method according to claim 1, 5 or 6, characterized in that: the molar use ratio of the acid to the N- (4-cyano-3-trifluoromethylphenyl) methacrylamide is 1-3: 1.
16. The method of claim 15, wherein: the molar ratio of the acid to N- (4-cyano-3-trifluoromethylphenyl) methacrylamide was 1.5: 1.
17. The production method according to claim 1, 7 or 8, characterized in that: the molar use ratio of the sodium hypochlorite solution to the N- (4-cyano-3-trifluoromethylphenyl) methacrylamide is 1-5: 1.
18. The method of claim 17, wherein: the molar ratio of the sodium hypochlorite solution to the N- (4-cyano-3-trifluoromethylphenyl) methacrylamide is 2: 1.
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