CN115724759B - Preparation method of enza Lu An intermediate - Google Patents
Preparation method of enza Lu An intermediate Download PDFInfo
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- CN115724759B CN115724759B CN202211476243.3A CN202211476243A CN115724759B CN 115724759 B CN115724759 B CN 115724759B CN 202211476243 A CN202211476243 A CN 202211476243A CN 115724759 B CN115724759 B CN 115724759B
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
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- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of an enzae Lu An intermediate, belonging to the technical field of organic synthesis. The method comprises the following steps: taking a compound II and a compound III as raw materials, and reacting in a nonpolar solvent in the presence of ethylene glycol, cuprous halide and inorganic base to obtain an enza Lu An intermediate: n- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine. The preparation method combines the multifunctional ligand and the nonpolar solvent, reduces the reaction time, improves the reaction conversion rate, reduces the solvent consumption, simplifies the treatment process, achieves the aims of high yield, high purity, less impurities and controllable reaction, has the advantages of low cost, less three wastes, environmental protection and wide application prospect.
Description
Technical Field
The invention relates to a preparation method of an enzae Lu An intermediate, belonging to the technical field of organic synthesis.
Background
Enzam Lu An is an androgen receptor inhibitor drug for the treatment of advanced castration prostate cancer that has spread or recurred. Enzate Lu An was co-developed by An Si tay and Medivation and was FDA approved at 8 of 2012 under the trade name Xtandi. N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is a key intermediate in the synthesis of enzane Lu An.
Patent W02011106570, CN103108549A discloses a method for synthesizing N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine: coupling of compound II and compound III in DMF solvent in the presence of 2-acetyl cyclohexanone gives N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine (i.e. compound I) as follows:
However, the method has longer reaction time, the water which is 16 times of the volume of the compound II is used in the post-treatment, the waste water amount in the production is greatly increased, the crystallization condition criticism is adopted, and the product yield is lower.
Patent CN105985258a reports another method for synthesizing N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine: in the presence of 1- (2, 6-trimethyl-1-cyclohexenyl) butane-1, 3-diketone, carrying out coupling reaction on a compound II and a compound III in a DMF solvent to obtain N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine, wherein the synthetic route is shown as follows:
Although this method increases the yield to 90% -92%, it also uses DMF as a solvent, which has the following problems: (1) The generated product is dissolved in DMF, and DMF and the product are required to be separated or extracted or distilled in the post-treatment process, so that the operation is complicated; (2) Since the base is insoluble in DMF, the reaction belongs to a two-phase reaction, and it is necessary to lengthen the reaction time or raise the reaction temperature in order to complete the reaction, and both of these two methods have negative effects: a) If the reaction time is prolonged, under alkaline conditions and at the temperature of more than 100 ℃, DMF is possibly decomposed to generate dimethylamine impurities, so that the color of the product is darker, and the impurity control risk of the compound I and the subsequent product enzate Lu An is increased; b) If the reaction temperature is increased, the compound I can be degraded at a higher temperature (more than 110 ℃), the generated degradation impurity IV contains a genotoxicity warning structure and can participate in the reaction later to generate a series of derivative impurities which are difficult to remove and seriously affect the product quality.
In order to solve the above problems, there is a need to develop a method for preparing N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine with high purity, high yield, controllable reaction, simple post-treatment operation, less three wastes and environmental protection.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a novel method for preparing an enza Lu An intermediate-N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine.
The invention specifically provides a preparation method of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine, which comprises the following steps: taking a compound II and a compound III as raw materials, and reacting in a nonpolar solvent in the presence of ethylene glycol, cuprous halide and inorganic base to obtain a compound I, namely N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine;
further, the nonpolar solvent is one or more of toluene, ethylbenzene and xylene;
And/or the cuprous halide is one or a mixture of more than two of cuprous chloride, cuprous iodide and cuprous bromide;
And/or the inorganic base is one or a mixture of more than two of potassium carbonate, sodium bicarbonate and cesium carbonate.
Further, the nonpolar solvent is toluene;
and/or the cuprous halide is cuprous chloride;
and/or the inorganic base is potassium carbonate.
Further, the molar ratio of the compound III to the compound II is (1.0-3.0): 1, a step of; and/or the molar ratio of the ethylene glycol to the compound II is (0.05-1.0): 1, a step of;
And/or the volume to mass ratio of the nonpolar solvent to the compound II is 3:1 mL/g-15: 1mL/g.
Further, the molar ratio of the compound III to the compound II is (1.5-1.8): 1, a step of;
And/or the molar ratio of the ethylene glycol to the compound II is (0.1-0.4): 1, a step of;
And/or the volume to mass ratio of the nonpolar solvent to the compound II is 5:1 mL/g-10: 1mL/g.
Further, the molar ratio of the inorganic base to the compound II is (2.0 to 5.0): 1, a step of;
And/or the molar ratio of the cuprous halide to the compound II is (0.1-0.5): 1.
Further, the molar ratio of the inorganic base to the compound II is (2.5 to 3.0): 1, a step of;
And/or the molar ratio of the cuprous halide to the compound II is (0.2-0.25): 1.
Further, the reaction temperature is 80-130 ℃, and the reaction time is 3-18 h.
Further, the temperature of the reaction is 100 to 110 ℃, preferably 105 to 110 ℃.
Further, the reaction time is 5 to 15 hours, preferably 5 to 8 hours.
Further, the reaction is carried out under an atmosphere of inert gas.
Further, the inert gas is one or a mixture of more than two of helium, argon, nitrogen and neon.
Compared with the prior art, the method for preparing the N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine has the following beneficial effects:
1. Compared with the preparation method with the publication number of CN103108549A (original grinding), the method shortens the reaction time, improves the conversion rate, reduces the volume of reaction solvent and the volume of water in post-treatment, and obviously improves the yield.
2. Compared with the preparation method with the publication number of CN105985258A, the method shortens the reaction time, has no steps of filtering inorganic salt, distilling DMF and the like, has no pulping operation, greatly simplifies the post-treatment operation, reduces the operation cost, obviously improves the properties of the product, and improves the purity and the yield.
3. In the preparation method of the invention, ethylene glycol is both a ligand and a phase transfer catalyst. In the reaction, the addition of the glycol greatly improves the activity of the catalyst, and meanwhile, the glycol has the characteristic of a phase transfer catalyst, so that the catalyst and a substrate can more effectively collide with each other, the reaction is easier to carry out, and the reaction rate is improved. In the preparation method, the reaction solvent is a nonpolar solvent, and the generated product can be extracted by a small amount of water, so that the operation is simplified, the waste water amount is greatly reduced, and the aims of small three wastes and environmental protection are fulfilled.
The preparation method combines the multifunctional ligand and the nonpolar solvent, reduces the reaction time, improves the reaction conversion rate, reduces the solvent consumption, simplifies the treatment process, achieves the aims of high yield, high purity, less impurities and controllable reaction, has the advantages of low cost, less three wastes, environmental protection and wide application prospect.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
Drawings
FIG. 1 is a 1 H-NMR spectrum of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine synthesized in example 1.
FIG. 2 is an MS spectrum of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine synthesized in example 1.
Detailed Description
Unless otherwise indicated, all reagents and starting materials used in the practice of the invention may be obtained from commercial products.
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1: preparation of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine
Into a 3L three-necked flask was charged compound II (200.00 g,0.86 mol), compound III (133.32 g,1.29 mol), potassium carbonate (297.80 g,2.15 mol), ethylene glycol (21.40 g,0.34 mol), toluene 1L, nitrogen gas was replaced three times, cuprous chloride (17.07 g,0.17 mol) was further added, nitrogen gas was replaced three times again, and after heating to 105℃and 5 hours, TLC was monitored to complete disappearance of compound II, the reaction was stopped, and cooling to room temperature was performed.
1L of water is added into a reaction bottle, stirring is carried out to fully dissolve, phase separation is carried out to obtain a water phase, 400ml of dichloromethane is added for extraction, and organic impurities in the reaction liquid are removed. The water phase is slowly poured into 3mol/L hydrochloric acid solution under stirring, the pH value of the reaction liquid system is regulated to 3.0-3.5, and then the reaction liquid system is cooled to below 10 ℃ for crystallization for 1h. Filtration and forced air drying at 55deg.C for 12h gave 213.2g of a white solid in 97.3% yield and 99.7% purity by HPLC.
1 H-NMR and MS analyses were carried out on the product obtained in this example, as shown in FIGS. 1 and 2.
1H-NMR(DMSO-D6,400MHz):δ1.44(S,6H),δ2.71～2.73(d,3H),δ6.13～6.17(dd,1H),δ6.32～6.35(dd,1H),δ7.42～7.47(t,1H),δ7.64～7.66(t,1H);MS：253.3(M-H+).
Example 2: preparation of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine
Into a 5L three-necked flask, compound II (200.00 g,0.86 mol), compound III (133.32 g,1.29 mol), potassium carbonate (297.80 g,2.15 mol), ethylene glycol (21.40 g,0.34 mol), toluene 2L, nitrogen gas was replaced three times, cuprous chloride (17.07 g,0.17 mol) was further added, nitrogen gas was replaced three times again, and after heating to 105℃and 5 hours, TLC was monitored to complete disappearance of Compound II, the reaction was stopped, and cooling to room temperature was performed.
2L of water is added into a reaction bottle, stirring is carried out to fully dissolve, phase separation is carried out to obtain a water phase, and then 800ml of dichloromethane is added for extraction to remove organic impurities in the reaction liquid. The water phase is slowly poured into 3mol/L hydrochloric acid solution under stirring, the pH value of the reaction liquid system is regulated to 3.0-3.5, and then the reaction liquid system is cooled to below 10 ℃ for crystallization for 1h. Filtration and forced air drying at 55deg.C for 12h gave 212.8g of a white solid in 97.1% yield and 99.8% HPLC purity.
Example 3: preparation of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine
Into a 3L three-necked flask, compound II (200.00 g,0.86 mol), compound III (133.32 g,1.29 mol), potassium carbonate (297.80 g,2.15 mol), ethylene glycol (5.35 g,0.09 mol), toluene 1L, nitrogen gas were replaced three times, cuprous chloride (17.07 g,0.17 mol) was added, nitrogen gas was replaced three times again, the temperature was raised to 105℃and after 5 hours TLC was monitored, compound II did not disappear completely, the reaction was continued, after 3 hours TLC was monitored again, compound II disappeared completely, and the reaction was cooled to room temperature.
1L of water is added into a reaction bottle, stirring is carried out to fully dissolve, phase separation is carried out to obtain a water phase, 400ml of dichloromethane is added for extraction, and organic impurities in the reaction liquid are removed. The water phase is slowly poured into 3mol/L hydrochloric acid solution under stirring, the pH value of the reaction liquid system is regulated to 3.0-3.5, and then the reaction liquid system is cooled to below 10 ℃ for crystallization for 1h. Filtration and forced air drying at 55deg.C for 12h gave 204.2g of a white solid with a yield of 93.2% and an HPLC purity of 99.6%.
Example 4: preparation of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine
Into a 3L three-necked flask, compound II (200.00 g,0.86 mol), compound III (133.32 g,1.29 mol), potassium carbonate (297.80 g,2.15 mol), ethylene glycol (21.40 g,0.34 mol), toluene 1L, nitrogen gas was replaced three times, cuprous chloride (17.07 g,0.17 mol) was further added, nitrogen gas was replaced three times again, and after 15 hours, TLC was monitored by heating to 105℃and the reaction was stopped with complete disappearance of Compound II.
1L of water is added into a reaction bottle, stirring is carried out to fully dissolve, phase separation is carried out to obtain a water phase, 400ml of dichloromethane is added for extraction, and organic impurities in the reaction liquid are removed. The water phase is slowly poured into 3mol/L hydrochloric acid solution under stirring, the pH value of the reaction liquid system is regulated to 3.0-3.5, and then the reaction liquid system is cooled to below 10 ℃ for crystallization for 1h. Filtration and forced air drying at 55deg.C for 12h gave 212.5g of a white solid in 97.0% yield and 99.5% HPLC purity.
TABLE 1 reaction conditions, product purity and yield for examples 1-4 and comparative example 1
As can be seen from comparing the data of example 1 and example 2 in Table 1, increasing the amount of the reaction solvent had substantially no effect on the yield and purity of the product, indicating that the product was readily extractable with water and no residue in the solvent.
As can be seen from comparing the data of example 1 with comparative example 1 in Table 1, the starting material (compound II) could not be reacted completely without ethylene glycol, the yield was greatly lowered, and the purity was low; as can be seen from comparing the data of example 3 with the data of comparative example 1 in Table 1, the reaction time was greatly shortened by using 0.1 equivalent of ethylene glycol, the reaction of the raw materials was completed, the yield was greatly improved, and the purity was high, indicating that the ethylene glycol can promote the reaction conversion and the reaction efficiency was improved.
As can be seen from comparing the data of example 1 and example 4 in Table 1, the product purity and properties are normal when the reaction time is prolonged, and the problem that the product is degraded into impurities when DMF is taken as a solvent in the prior art is solved. The use of toluene as a solvent and ethylene glycol as a ligand is described as reducing the risk of impurities.
The following is a comparative example for the preparation of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine.
Comparative example 1: preparation of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine Compound II (200.00 g,0.86 mol), compound III (133.32 g,1.29 mol), potassium carbonate (297.80 g,2.15 mol), toluene 1L, displacement of nitrogen three times, further addition of cuprous chloride (17.07 g,0.17 mol), displacement of nitrogen three times again, heating to 105℃and TLC monitoring after 15h, compound II did not disappear completely, cooling to room temperature were added to 3L three-port bottles.
1L of water is added into a reaction bottle, stirring is carried out to fully dissolve, phase separation is carried out to obtain a water phase, 400ml of dichloromethane is added for extraction, and organic impurities in the reaction liquid are removed. The water phase is slowly poured into 3mol/L hydrochloric acid solution under stirring, the pH value of the reaction liquid system is regulated to 3.0-3.5, and then the reaction liquid system is cooled to below 10 ℃ for crystallization for 1h. Filtration and forced air drying at 55deg.C for 12h gave 84.6g of a white solid in 38.6% yield with an HPLC purity of 85.8%.
Comparative example 2: preparation method of publication No. CN103108549A (original grinding)
Referring to the method described in the Chinese patent publication No. CN103108549A, N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is prepared by the following procedure: to the flask were added bromobenzamide (compound II) (10 g,43.1 mmol), aminopropiobutyric acid (compound III) (6.7 g,64.6mmol,1.5 eq.), K 2CO3 (15 g,2.5 eq.), DMF (60 mL,6 volumes) and water (1.8 mL), and the reaction slurry was heated to 30 ℃. To the reaction slurry was added 2-acetylcyclohexanone (1.14 mL,8.1mmol,0.2 eq.) and then stirred under nitrogen at 105℃for 14 hours. HPLC analysis showed 96.6% conversion to the target product. The reaction mixture was then cooled to Room Temperature (RT) and extracted with water (120 mL) and IPAc (60 mL). The lower aqueous layer was re-extracted with IPAc (60 mL) and acidified to pH 4.0 with 180mL1M citric acid. The product started to crystallize at room temperature and the batch was further cooled to 5-7 ℃, filtered, washed with water (40 mL) and dried under vacuum at 50 ℃ for 12 hours. The reaction yielded 8.0g of the product as a tan solid (73.0% yield) with an HPLC purity of 99.4%.
Comparative example 3: preparation method of publication No. CN105985258A
Referring to the method described in the chinese patent application publication No. CN105985258a, N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is prepared as follows: n-methyl-4-bromo-2-fluoro-benzamide (compound II) (200 g,0.86 mol), 2-aminoisobutyric acid (compound III) (133 g,1.29 mol), cuprous chloride (16.8 g,0.17 mol), compound A (1- (2, 6-trimethyl-1-cyclohexenyl) butane-1, 3-dione) (20.8 g,0.1 mol) and potassium carbonate solid (303.6 g,2.2 mol) were added to a 3L three-necked flask, followed by three nitrogen substitutions with 1L DMF and 20ml distilled water. Heating was started to 115℃and TLC detection was performed after 10 hours, with complete disappearance of starting material. The reaction was stopped. Cooled to room temperature.
Filtering to remove solid insoluble substances, washing the filter residue with a little DMF, mixing filtrates, evaporating to dryness under reduced pressure, adding 400ml of water to dissolve the system completely, extracting with 400ml of isopropyl acetate for 2 times, and removing organic impurities in the residual liquid. The aqueous phase was stirred, a saturated citric acid solution was added dropwise thereto, the ph=4-5 of the reaction system was adjusted, and then cooled to below 10 ℃ and a large amount of pale green solid was precipitated. Filtering, pulping the filter cake with 800ml water for 30 minutes, and filtering; the filter cake was slurried with 200ml isopropyl acetate for 1 hour, filtered, and dried under vacuum at 60 degrees to constant weight to give 199.4g of tan solid with 91% yield and 99.2% HPLC purity.
As can be seen from comparison of example 1 and comparative example 2, the preparation of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine by the method of the present invention has the advantages of short reaction time, high conversion rate, reduced volume of reaction solvent and water in post-treatment, and significantly improved yield.
As can be seen from comparison of example 1 and comparative example 3, the method for preparing N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine by the method has the advantages of short reaction time, no steps of filtering inorganic salt, distilling DMF and the like, no beating operation, greatly simplified post-treatment operation, reduced operation cost, obviously improved product properties, and improved purity and yield.
In summary, the invention provides a preparation method of an enza Lu An intermediate. The preparation method combines the multifunctional ligand and the nonpolar solvent, reduces the reaction time, improves the reaction conversion rate, reduces the solvent consumption, simplifies the treatment process, achieves the aims of high yield, high purity, less impurities and controllable reaction, has the advantages of low cost, less three wastes, environmental protection and wide application prospect.
Claims (10)
1. A method for preparing N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine, comprising the steps of: taking a compound II and a compound III as raw materials, and reacting in a nonpolar solvent in the presence of ethylene glycol, cuprous halide and inorganic base to obtain a compound I, namely N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine; the nonpolar solvent is one or more of toluene, ethylbenzene and xylene;
2. The preparation method of claim 1, wherein the cuprous halide is one or more of cuprous chloride, cuprous iodide and cuprous bromide;
And/or the inorganic base is one or a mixture of more than two of potassium carbonate, sodium bicarbonate and cesium carbonate.
3. The method of claim 2, wherein the nonpolar solvent is toluene;
and/or the cuprous halide is cuprous chloride;
and/or the inorganic base is potassium carbonate.
4. The process according to claim 1, wherein the molar ratio of compound III to compound II is (1.0 to 3.0): 1, a step of;
And/or the molar ratio of the ethylene glycol to the compound II is (0.05-1.0): 1, a step of;
And/or the volume to mass ratio of the nonpolar solvent to the compound II is 3:1 mL/g-15: 1mL/g.
5. The process according to claim 4, wherein the molar ratio of compound III to compound II is (1.5 to 1.8): 1, a step of;
And/or the molar ratio of the ethylene glycol to the compound II is (0.1-0.4): 1, a step of;
And/or the volume to mass ratio of the nonpolar solvent to the compound II is 5:1 mL/g-10: 1mL/g.
6. The process according to claim 1, wherein the molar ratio of inorganic base to compound II is (2.0 to 5.0): 1, a step of;
And/or the molar ratio of the cuprous halide to the compound II is (0.1-0.5): 1.
7. The process according to claim 6, wherein the molar ratio of the inorganic base to the compound II is (2.5 to 3.0): 1, a step of;
And/or the molar ratio of the cuprous halide to the compound II is (0.2-0.25): 1.
8. The method according to claim 1, wherein the reaction temperature is 80 to 130 ℃ and the reaction time is 3 to 18 hours.
9. The method according to claim 8, wherein the reaction temperature is 100 to 110℃and the reaction time is 5 to 8 hours.
10. The preparation method according to any one of claims 1 to 9, wherein the reaction is carried out under an inert gas atmosphere.
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