CN108069887B - Preparation method of (R) -bicalutamide intermediate - Google Patents
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Abstract
The invention relates to a preparation method of an (R) -bicalutamide intermediate, which comprises the following steps: methacrylic acid is used as a raw material, and an (R) -bicalutamide intermediate, namely (R) -3- (4-fluorobenzene mercapto) -2-hydroxy-2-methylpropanoic acid, is obtained through esterification, hydroxylation, sulfonation and other steps of reactions, and the intermediate can obtain (R) -bicalutamide with the enantioselectivity of more than 99% through two simple subsequent reactions.
Description
Technical Field
The invention relates to the technical field of organic compound preparation, in particular to a preparation method of an (R) -bicalutamide intermediate.
Background
Bicalutamide (Bicalutamide), chemical name: (±) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3- [ (4-fluorophenyl) sulfonyl ] -2-hydroxy-2-methylpropanamide, formula as follows:
bicalutamide is a nonsteroidal antiandrogen drug, has strong action specificity, is effective in oral administration, is convenient to administer, has good tolerance and has a long half-life, the 50mg dose of bicalutamide is combined with Luteinizing Hormone Releasing Hormone (LHRH) analogue or surgical orchiectomy to be applied to the treatment of advanced prostate cancer, while the 150mg dose of bicalutamide is used for treating prostate cancer patients with local advanced and no distant metastasis, the patients are not suitable or willing to receive surgical castration or other internal medical treatment, and the bicalutamide is the first-line treatment drug for the prostate cancer at present. In addition, the small dose of bicalutamide can be applied to the treatment of some androgen-dependent diseases, and the small dose of bicalutamide can be used for treating female hirsutism and acne. Bicalutamide can also treat prostatic hyperplasia. Therefore, the bicalutamide has good clinical application prospect.
The bicalutamide is a racemate and has optical isomerism, and experiments prove that the antiandrogen activity of the enantiomer (R) -bicalutamide is far greater than that of (S) -bicalutamide, and the metabolic degradation in the liver is smaller than that of (S) -bicalutamide. The plasma elimination half-life of (R) -bicalutamide is one week. At the daily dose of bicalutamide, (R) -bicalutamide accumulates about 10 times in the plasma due to its long half-life. When bicalutamide is administered at 50mg (/ 150 mg) per day, the steady state plasma concentration of (R) -bicalutamide is about 9 μ g/ml (/ 22 μ g/ml), and the effective (R) -bicalutamide at steady state represents 99% of the total circulating drug. The pharmacokinetics of (R) -bicalutamide are not affected by age, kidney damage or mild to moderate liver damage. There is evidence for a slower plasma clearance of (R) -bicalutamide in cases of severe liver damage. Bicalutamide binds to proteins highly (racemate 96%, R-bicalutamide 99.6%) and is metabolized extensively (by oxidation and glucuronidation), with the metabolites eliminated by the kidney and gallbladder in nearly the same proportion. Therefore, the use of (R) -bicalutamide instead of racemic bicalutamide racemate as an antiandrogen drug would reduce single drug intake, reduce liver burden, and avoid some other side effects. (R) -bicalutamide and (S) -bicalutamide structural formulas:
at present, the synthesis of (R) -bicalutamide mainly comprises the following routes:
the literature Tucker, H, et al, J, Med. chem. 1988, 31, 885-containing 887 uses methacrylic acid as a raw material, and is condensed with (R) -proline, and then reacts with NBS under the induction of chiral carboxyl to generate a key chiral intermediate, and then (R) -bicalutamide is obtained through the steps of condensation, substitution, oxidation and the like, and the synthetic route is as follows:
the synthetic route uses chiral induction reaction, and the application of the reaction in industrial production is restricted because proline is used as a chiral induction reagent, the charge ratio of the proline to a substrate is 1:1, and the dosage is large.
In Jame, K, D et al tetrahedron, 2002, 58, 5905-:
the Guerrini, A, et al, J. Med. chem. 2014, 57, 7263-:
the starting materials of the two routes are chiral hydroxy diacid, the price is high, the commercialization is difficult, and in addition, reaction conditions such as minus 78 ℃ and the like are harsh and are difficult to realize in industrialization are also used in the reaction.
Fujino, A. et al Tetrahedron letters, 2007, 48, 979-. Then (R) -bicalutamide is obtained through the steps of oxidation, condensation, substitution, hydroxyl protection, deprotection, substitution, oxidation and the like, and the synthetic route is as follows:
the biological agent used in the route is expensive, the chiral selectivity is not high, and the post-treatment is more complicated, so the application of the method in industrial production is limited.
In order to overcome the problems in the above routes as much as possible, the inventors designed a novel process route for synthesizing (R) -bicalutamide, specifically a process route for preparing (R) -bicalutamide intermediate (R) -3- (4-fluorophenylmercapto) -2-hydroxy-2-methylpropanoic acid, and experimentally proved the feasibility of finally synthesizing (R) -bicalutamide by the route. The method has the advantages of easily obtained starting materials, high reaction yield, easy reaction operation, high enantioselectivity 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 an (R) -bicalutamide intermediate shown in the following formula I,
the preparation method of the (R) -bicalutamide intermediate I, namely (R) -3- (4-fluorobenzene mercapto) -2-hydroxy-2-methylpropanoic acid, comprises the following synthetic route:
the method comprises the following specific steps:
(a) preparation of 4-methoxybenzyl methacrylate (III)
Adding methacrylic acid (II) and oxalyl chloride into a solvent, stirring to prepare acyl chloride, then adding the acyl chloride, p-methoxybenzyl alcohol and alkali into the solvent, stirring, and carrying out post-treatment after the reaction is finished to obtain 4-methoxybenzyl methacrylate (III);
(b) preparation of (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate (IV)
Adding a catalyst, a ligand, alkali and a compound III into a solvent, stirring, and carrying out post-treatment after the reaction to obtain (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate (IV);
(c) preparation of (S) -2- [ (4-methoxybenzyloxy) carbonyl ] -2-hydroxypropyl methanesulfonate (V)
Adding alkali and substituted sulfonyl chloride into a solvent containing a compound IV, stirring, and carrying out post-treatment after the reaction is finished to obtain (S) -2- [ (4-methoxybenzyloxy) carbonyl ] -2-hydroxypropyl methanesulfonate (V), wherein R groups are methyl, ethyl, aryl and the like;
(d) preparation of (R) -3- (4-fluorophenylmercapto) -2-hydroxy-2-methylpropanoic acid (I)
Adding alkali and p-fluorobenzenethiol into a solvent containing a compound V, stirring for reaction, then adding alkali water into reaction liquid, stirring, and carrying out post-treatment after the reaction is finished to obtain the (R) -3- (4-fluorobenzene mercapto) -2-hydroxy-2-methylpropanoic acid (I), wherein R groups in the compound V are methyl, ethyl, aryl and the like.
In the synthetic route of the invention:
the solvent in the step (a) is dichloromethane, chloroform, tetrahydrofuran, N dimethylformamide and the like, and the base is triethylamine, diisopropylethylamine, pyridine, 4-methylaminopyridine and the like;
the catalyst in the step (b) is K2OsO2(OH)4Or OsO4The ligand is (DHQD)2PYR, wherein the alkali is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium bicarbonate, sodium bicarbonate and the like, and the solvent is water, tert-butanol, isopropanol and the like;
the alkali in the step (c) is pyridine, 4-methylaminopyridine, triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, and the solvent is dichloromethane, trichloromethane, tetrahydrofuran, N-dimethylformamide and the like;
the alkali in the step (d) is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like, the solvent is tetrahydrofuran, N-dimethylformamide, dichloromethane, isopropanol, ethanol, methanol and the like, and the alkaline water is an aqueous solution of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like.
In the synthetic route of the invention:
the solvent in the step (a) is preferably a mixed solvent of dichloromethane and dimethylformamide, and the base is preferably triethylamine;
the catalyst of step (b) is preferably K2OsO2(OH)4The base is preferably potassium carbonate, and the solvent is preferably a mixed solvent of water and tert-butyl alcohol;
the base of step (c) is preferably pyridine and the solvent is preferably dichloromethane;
the base in step (d) is preferably potassium carbonate, the solvent is preferably tetrahydrofuran, and the alkaline water is preferably aqueous sodium hydroxide solution.
The (R) -bicalutamide intermediate I, namely (R) -3- (4-fluorobenzene mercapto) -2-hydroxy-2-methylpropanoic acid, can be prepared into (R) -bicalutamide (Jame, K. D et al. tetrahedron. 2002, 58, 5905-:
by these two reactions, (R) -bicalutamide with an enantioselectivity of more than 99% can be obtained.
Detailed Description
The present invention will be further described with reference to the following specific examples, but the present invention is not limited thereto.
Example 1
(a) Preparation of 4-methoxybenzyl methacrylate
Methacrylic acid (15.0 g, 0.17 mol), oxalyl chloride (43.1 g, 0.34 mol), N, N-dimethylformamide (0.5 mL) was added to dichloromethane (100 mL), stirred at room temperature for 1 h, concentrated under reduced pressure to remove the solvent, and then the crude product was dissolved in dichloromethane (60 mL) for use. The above solution was slowly added dropwise to dichloromethane (100 mL) containing p-methoxybenzyl alcohol (42.2 g, 0.34 mol) at 0 deg.C, and then triethylamine (51.6 g, 0.51 mol) was added dropwise thereto. The mixed solvent was stirred at room temperature for 2 h, a saturated sodium carbonate solution (300 mL) was added to the reaction solution, the aqueous layer was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give 4-methoxybenzyl methacrylate (31.9 g, 155 mmol, y = 91.2%).1H-NMR (400 MHz, CDCl3)：δ 7.33 (m, 2 H), 6.90 (m, 2 H), 6.13 (d, J = 1.2 Hz, 1 H), 5.56 (d, J = 1.2 Hz, 1 H), 5.18 (s, 2 H), 3.81 (s, 3 H), 1.95 (dd, J1= 1.6 Hz, J2= 1.2 Hz)。
(b) Preparation of (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate
To a round bottom flask was added tert-butanol (700 ml), water (700 ml), K3[Fe(CN)6](117.0 g, 0.36 mol), potassium carbonate (48.9 g, 0.36 mol), benzenesulfonamide (18.7 g, 0.12 mol), (DHQD)2PYR (2.1 g, 2.4 mmol), K2OsO2(OH)4 (0.43 g, 1.2 mmol) were stirred at room temperature for 10 min, then cooled to 0 ℃ and 4-methoxybenzyl methacrylate (24.7 g, 0.12 mol) was added to the reaction mixture and reacted at 0 ℃ for 24 h. The reaction was quenched with saturated sodium sulfite solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the residue was subjected to silica gel column chromatography (PE/EA = 1/4) to give (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate (26.4 g, 110 mmol, y = 91.0%, ee = 83%). [ alpha ] to]D20 = +0.4o (c = 0.12 g/10 ml, CHCl3); 1H-NMR (400 MHz, CDCl3) ：δ 7.28 (m, 2 H), 6.91 (m, 2 H), 5.16 (m, 2 H), 3.81 (s, 3 H), 3.80 (d, J = 11.2 Hz, 1 H), 3.56 (d, J = 11.2 Hz, 1 H), 1.36 (s, 3H)。
(c) Preparation of (S) -2- [ (4-methoxybenzyloxy) carbonyl ] -2-hydroxypropyl methanesulfonate
To a round bottom flask was added (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate (23.5 g, 98 mmol), dichloromethane (500 ml), pyridine (15.8 g, 0.20 mol), the solution was cooled to 0 ℃ and methanesulfonyl chloride (22.9 g, 0.20 mol) was slowly added dropwise thereto. The reaction was stirred at 0 ℃ overnight, the reaction solution was washed successively with aqueous sodium bicarbonate and 1M dilute aqueous hydrochloric acid, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic phase, and the residue was subjected to silica gel column chromatography (PE/EA = 2/1) to obtain a product (28.4 g, 89.2 mmol, ee = 87%), which was recrystallized twice from PE/EA = 2/1 to obtain (S) -2- [ (4-methoxybenzyloxy) carbonyl]-2-hydroxypropyl methanesulfonate (21.7 g, 68.2 mmol, y = 69.5%, ee = 98%). [ alpha ] to]D20 = +10.3o (c = 0.22 g/100 ml, CHCl3); 1H-NMR (400 MHz, CDCl3) ：δ 7.24 (m, 2 H), 6.90 (m, 2 H), 5.12 (m, 2 H), 3.80 (s, 3 H), 3.78 (d, J = 11.2 Hz, 1 H), 3.54 (d, J = 11.2 Hz, 1 H), 2.90 (s, 3H), 1.35 (s, 3H)。
(d) Preparation of (R) -3- (4-fluorophenylmercapto) -2-hydroxy-2-methylpropanoic acid
4-Fluorothiophenol (6.4 g, 50 mmol), tetrahydrofuran (100 ml), potassium carbonate (7.9 g, 100 mmol) were added to the flask, the solution was stirred at room temperature for 2 hours, and (S) -2- [ (4-methoxybenzyloxy) carbonyl group was slowly added to the reaction solution]-2-hydroxypropyl methanesulfonate (12.7 g, 40 mmol), stirring at room temperature for 5 h, adding aqueous sodium hydroxide (50 ml, 1M) to the reaction mixture, stirring at room temperature for 5 h, adjusting the PH to neutral with hydrochloric acid, concentrating to remove tetrahydrofuran, extracting the residue with dichloromethane, adding aqueous sodium hydroxide (50 ml, 1M) to the dichloromethane solution, stirring, separating, adjusting the PH of the aqueous phase to neutral with hydrochloric acid, extracting with dichloromethane, and concentrating to remove dichloromethane to obtain (R) -3- (4-fluorophenylmercapto) -2-hydroxy-2-methylpropionic acid (7.5 g, 32.7 mmol, y = 81.9%).1H-NMR (400 MHz, CDCl3) ：δ 7.44 (dd, J1 = 8.8 Hz, J2 = 5.2Hz, 2 H), 6.98 (dd, J1 = 8.8 Hz, J2 = 5.2 Hz, 2 H), 3.42 (dd, J1 = 13.6 Hz, J2 = 0.8 Hz, 1 H), 3.16 (dd, J1 = 13.6 Hz, J2 = 0.8 Hz, 1 H), 1.54 (s, 3H)。
The (R) -bicalutamide intermediate I, namely (R) -3- (4-fluorobenzenethiol) -2-hydroxy-2-methylpropionic acid, is prepared by the following two steps:
preparation of (R) -3- (4-fluorophenylmercapto) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-hydroxy-2-methylpropanamide
To a flask was added (R) -3- (4-fluorophenylmercapto) -2-hydroxy-2-methylpropanoic acid (7.0 g, 30.4 mmol), 4-amino-2-trifluoromethylbenzonitrile (7.3 g, 39.5 mmol), and N, N-dimethylacetamide (70 ml), the solution was cooled to-10 ℃, thionyl chloride (4.35 g, 36.5 mmol) was slowly added dropwise to the reaction, the reaction was stirred at-10 ℃ for a further 30 min, and then stirred overnight at room temperature. The reaction solution was diluted with dichloromethane and then washed with saturated aqueous sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate and concentrated to remove the organic phase, and the crude product was subjected to silica gel column chromatography (EA/DCM = 9/1) to give (R) -3- (4-fluorophenylmercapto) -N- (4-cyano-3- (trifluoromethyl) phenyl-2-hydroxy-2-methylpropanamide (6.3 g, 15.7 mmol, y = 51.7%).1H-NMR (400 MHz, CDCl3) ：δ 8.99 (s, 1 H), 7.92 (s, 1 H), 7.76-7.73 (m, 2 H), 7.39 (dd, J1 = 8.8 Hz, J2 = 5.2Hz, 2 H), 6.82 (dd, J1 = 8.8 Hz, J2 = 8.8 Hz, 2 H), 3.72 (d, J = 13.6 Hz, 1 H), 3.54 (s, 1H), 3.10 (d, J = 13.6 Hz, 1 H), 1.54 (s, 3H)。
Preparation of (R) -3- (4-fluorophenylsulfo) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-hydroxy-2-methylpropanamide
Adding (R) -3- (4-fluorobenzenesulfo) -N- (4-cyano-3- (trifluoromethyl) phenyl-2-hydroxy-2-methylpropanamide (6.0 g, 15.0 mmol) into acetone (50 ml), stirring, adding sodium tungstate (0.08 g, 0.25 mmol) into a solvent, cooling the solution to 5 ℃, slowly dropwise adding 30% hydrogen peroxide (6 ml) into the solution, slowly heating the reaction solution to reflux after the addition is finished, stirring overnight, adding purified water (300 ml) into the reaction solution after the reaction is finished, filtering, and recrystallizing a filter cake (PE/EA) to obtain (R) -3- (4-fluorobenzenesulfo) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]-2-hydroxy-2-methylpropionamide (6.3 g, 14.5 mmol, y = 96.8%, ee =)100%）。[α]D20 = -81o (c = 0.11 g/10 ml, CHCl3); 1H-NMR (400 MHz, CDCl3) ：δ 9.15 (s, 1 H), 7.98 (s, 1 H), 7.90-7.83 (m, 2 H), 7.80-7.78 (m, 2 H), 7.20-7.15 (m, 2 H), 5.01 (s, 1 H), 3.98 (d, J = 14.4 Hz, 1 H), 3.50 (d, J = 14.4 Hz, 1 H), 1.60 (s, 3H)。
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and is not intended to limit the practice of the invention to these descriptions. For those skilled in the art to which the invention pertains, several simple modifications or substitutions can be made without departing from the spirit of the invention, and all shall be deemed to fall within the scope of the invention.
Claims (4)
1. A preparation method of an (R) -bicalutamide intermediate is characterized by comprising the following steps:
(a) preparation of 4-methoxybenzyl methacrylate (III)
Adding methacrylic acid (II) and oxalyl chloride into a solvent, stirring to prepare acyl chloride, then adding the acyl chloride, p-methoxybenzyl alcohol and alkali into the solvent, stirring, and carrying out post-treatment after the reaction is finished to obtain 4-methoxybenzyl methacrylate (III);
(b) preparation of (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate (IV)
Adding a catalyst, a ligand, alkali and a compound III into a solvent, stirring, and carrying out post-treatment after the reaction is finished to obtain (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate (IV), wherein the ligand is (DHQD)2PYR；
(c) Preparation of (S) -2- [ (4-methoxybenzyloxy) carbonyl ] -2-hydroxypropyl methanesulfonate (V)
Adding alkali and substituted sulfonyl chloride into a solvent containing a compound IV, stirring, and carrying out post-treatment after the reaction is finished to obtain (S) -2- [ (4-methoxybenzyloxy) carbonyl ] -2-hydroxypropyl methanesulfonate (V), wherein R groups are methyl, ethyl and aryl;
(d) preparation of (R) -3- (4-fluorophenylmercapto) -2-hydroxy-2-methylpropanoic acid (I)
Adding alkali and p-fluorobenzenethiol into a solvent containing a compound V, stirring for reaction, then adding alkali water into reaction liquid, stirring, and carrying out post-treatment after the reaction is finished to obtain (R) -3- (4-fluorobenzenethiol) -2-hydroxy-2-methylpropanoic acid (I), wherein R groups are methyl, ethyl and aryl.
2. The method of claim 1, wherein:
the solvent in the step (a) is dichloromethane, chloroform, tetrahydrofuran and N, N-dimethylformamide, and the base is triethylamine, diisopropylethylamine, pyridine or 4-methylaminopyridine;
the catalyst in the step (b) is K2OsO2(OH)4Or OsO4The ligand is (DHQD)2PYR, wherein the alkali is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium bicarbonate and sodium bicarbonate, and the solvent is water, tert-butanol and isopropanol;
the alkali in the step (c) is pyridine, 4-methylaminopyridine, triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and the solvent is dichloromethane, trichloromethane, tetrahydrofuran and N, N-dimethylformamide;
the alkali in the step (d) is potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide, the solvent is tetrahydrofuran, N-dimethylformamide, dichloromethane, isopropanol, ethanol and methanol, and the alkaline water is an aqueous solution of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate.
3. The production method according to claim 1 or 2, characterized in that:
the solvent in the step (a) is a mixed solvent of dichloromethane and dimethylformamide, and the base is triethylamine;
the catalyst in the step (b) is K2OsO2(OH)4The alkali is potassium carbonate, and the solvent is a mixed solvent of water and tert-butyl alcohol;
the base of step (c) is pyridine and the solvent is dichloromethane;
the alkali in the step (d) is potassium carbonate, the solvent is tetrahydrofuran, and the alkaline water is sodium hydroxide aqueous solution.
4. The production method according to claim 1 or 2, characterized in that the production method is:
step (a) methacrylic acid and oxalyl chloride were added to DMF: stirring at room temperature in a mixed solvent with a dichloromethane volume ratio of 1:200, dissolving a crude product obtained by removing the solvent in dichloromethane for later use, slowly dropwise adding the solution into dichloromethane containing p-methoxybenzyl alcohol at 0 ℃, then dropwise adding triethylamine, stirring at room temperature, adding a saturated sodium carbonate solution into a reaction solution, extracting a water layer, combining organic phases, drying, filtering, and concentrating the organic phase under reduced pressure to obtain 4-methoxybenzyl methacrylate, wherein methacrylic acid: oxalyl chloride: p-methoxybenzyl alcohol: the molar ratio of triethylamine is 1:2:2: 3;
step (b) to tert-butanol: adding K into a mixed solvent with the water volume ratio of 1:13[Fe(CN)6]Potassium carbonate, benzenesulfonamides, (DHQDs)2PYR、K2OsO2(OH)4Stirring at room temperature, thenCooling to 0 deg.C, adding 4-methoxybenzyl methacrylate into the reaction solution, reacting at 0 deg.C, quenching with saturated sodium sulfite solution, extracting, washing the organic phase with saturated sodium chloride solution, drying, concentrating under reduced pressure to remove solvent, and performing silica gel column chromatography to obtain (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate, wherein K is K3[Fe(CN)6]: potassium carbonate: benzenesulfonamide: (DHQD)2PYR：K2OsO2(OH)4: the molar ratio of the 4-methoxybenzyl methacrylate is 3:3:1:0.02:0.01: 1;
step (c), dichloromethane is used as a solvent, and (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate and pyridine are added, the solution is cooled to 0 ℃, methanesulfonyl chloride is slowly dripped into the solution, the reaction solution is reacted at 0 ℃, the reaction solution is washed by sodium bicarbonate aqueous solution and 1M dilute hydrochloric acid aqueous solution in sequence, an organic phase is collected, dried and concentrated under reduced pressure to remove the organic phase, the remainder is chromatographed by a silica gel column to obtain a crude product, and chromatography recrystallization is carried out twice to obtain (S) -2- [ (4-methoxybenzyloxy) carbonyl ] -2-hydroxypropyl methanesulfonate, wherein (S) -4-methoxybenzyl-2, 3-dihydroxy-2-dimethylpropionate: pyridine: the molar ratio of methylsulfonyl chloride to methylsulfonyl chloride is 1:2: 2;
step (d) adding 4-fluorobenzothiophenol and potassium carbonate into tetrahydrofuran as a solvent, stirring the solution at room temperature, slowly adding (S) -2- [ (4-methoxybenzyloxy) carbonyl ] -2-hydroxypropyl methanesulfonate, stirring for reaction, then adding 1M aqueous sodium hydroxide solution, stirring for reaction, adjusting the pH to be neutral, concentrating to remove tetrahydrofuran, extracting the residual solution with dichloromethane, adding 1M aqueous sodium hydroxide solution into the dichloromethane solution, stirring, separating, adjusting the pH of the aqueous phase to be neutral, extracting with dichloromethane, and concentrating to remove dichloromethane to obtain (R) -3- (4-fluorobenzothio) -2-hydroxy-2-methylpropanoic acid, wherein 4-fluorobenzothiophenol: potassium carbonate: (S) -2- [ (4-methoxybenzyloxy) carbonyl ] -2-hydroxypropyl methanesulfonate in a molar ratio of 1.25:2.5: 1.
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| CN1413188A (en) * | 1999-10-27 | 2003-04-23 | 诺贝克斯公司 | Resolution of intermediates in synthesis of substantially pure bicalutamide |
| US7199257B1 (en) * | 1999-06-10 | 2007-04-03 | Richter Gedeon Vegyeszeti Gyar Rt. | Process for the synthesis of N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropionamide |
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| US7199257B1 (en) * | 1999-06-10 | 2007-04-03 | Richter Gedeon Vegyeszeti Gyar Rt. | Process for the synthesis of N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropionamide |
| CN1413188A (en) * | 1999-10-27 | 2003-04-23 | 诺贝克斯公司 | Resolution of intermediates in synthesis of substantially pure bicalutamide |
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