CN108329236B - Preparation method of enzalutamide intermediate - Google Patents
Preparation method of enzalutamide intermediate Download PDFInfo
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- CN108329236B CN108329236B CN201810300947.2A CN201810300947A CN108329236B CN 108329236 B CN108329236 B CN 108329236B CN 201810300947 A CN201810300947 A CN 201810300947A CN 108329236 B CN108329236 B CN 108329236B
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- methylbenzamide
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- ethyl acetate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 206010060862 Prostate cancer Diseases 0.000 claims description 10
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- FUBVMSRDTICINT-UHFFFAOYSA-N 4-(2-cyanopropan-2-ylamino)-2-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=C(NC(C)(C)C#N)C=C1F FUBVMSRDTICINT-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- JQULXIOYDDCNGR-UHFFFAOYSA-N 2-amino-2-methylpropanenitrile Chemical compound CC(C)(N)C#N JQULXIOYDDCNGR-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 claims description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 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 4
- 229960004671 enzalutamide Drugs 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OEKATORRSPXJHE-UHFFFAOYSA-N 2-acetylcyclohexan-1-one Chemical compound CC(=O)C1CCCCC1=O OEKATORRSPXJHE-UHFFFAOYSA-N 0.000 description 1
- -1 4-amino-2-fluoro-N-methylbenzamide compound Chemical class 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 238000010751 Ullmann type reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an enzalutamide intermediate, and belongs to the field of pharmaceutical chemicals. The reaction yield of each step of the invention is very high, which is more than 80 percent, and some reactions can reach as high as 93 percent. The post-treatment process is simple, easy to operate and suitable for industrialization. The invention has mild reaction conditions and does not have harsh reaction conditions of high temperature, high pressure and ultra-low temperature.
Description
Technical Field
The invention relates to a preparation method of an enzalutamide intermediate, and belongs to the field of pharmaceutical chemicals.
Background
Prostate Cancer (PCa) is a common male malignancy, which has rapidly risen in recent years to a global neoplastic disease, with Prostate Cancer incidence accounting for the first and second most cases in many european and american countries. About 220,800 men in the united states suffered from prostate cancer in 2015, of which about 20,710 patients died. First and second in all male tumors, respectively. In recent years, with the improvement of early diagnosis level of prostate cancer, the incidence of prostate cancer in China increases year by year, and the prostate cancer becomes a common malignant tumor affecting the health of men in China.
Enzalutamide is a new drug for androgen inhibitors, a prostate cancer drug developed by the cooperation of anslat and Medivation, which was approved by the FDA in the united states for marketing in 2012. The enzalutamide is sold on the market in 5.8 billion dollars in 2013, 10 billion dollars in 2014 and 22 billion dollars in 2015. The chemical name is 4- [3- [ 4-cyano-3- (trifluoromethyl) phenyl ] -5, 5-dimethyl-4-oxo-2-thione-1-imidazolidinyl ] -2-fluoro-N-methylbenzamide, and the structural formula is as follows:
the compound enzalutamide was first synthesized by university of california research, refer to patent CN101460467B, the synthetic route of which is as follows:
the synthesis method adopts iron powder as a catalyst to prepare the 4-amino-2-fluoro-N-methylbenzamide compound under an acidic condition, a large amount of wastewater is generated in the preparation process, and the product yield and purity are not high, so that the synthesis method is not suitable for large-scale industrial production; in addition, the use of the highly toxic chromium trioxide as the oxidant has a great toxic effect on human bodies and the environment. Therefore, the Medivation company improves the synthesis process, and refer to patent document CN103108549A, the specific synthesis route is as follows:
the synthesis method uses the Ullmann condensation reaction under the catalysis of cuprous chloride, and has the advantages of low total yield, more waste water and large pollution. And the virulent methyl iodide is used for methylation, so that the production cost is high. Is difficult to realize industrial production.
Disclosure of Invention
The invention provides a preparation method of a 4- ((2-cyanopropane-2-yl) amino) -2-fluoro-N-methylbenzamide (compound 6) which is an important intermediate for preparing enzalutamide, and the preparation method provided by the invention overcomes the problems of low synthesis yield, high production cost, environmental pollution and the like in the preparation process of the intermediate in the prior art, and develops a production route which is clean in process and simple and convenient to operate.
A first object of the present invention is to provide a process for the preparation of enzalutamide intermediate 4- ((2-cyanopropan-2-yl) amino) -2-fluoro-N-methylbenzamide, which comprises the steps of:
(1) reacting the propan-2-one with cyanide under the condition of weak base to generate 2-amino-2-methyl propionitrile;
(2) 4-X-2-fluorobenzoic acid is converted into 4-X-2-fluoro-N-methylbenzamide under the action of a chlorinating agent;
(3) 2-amino-2-methylpropanenitrile and 4-X-2-fluoro-N-methylbenzamide are subjected to substitution reaction under the action of a catalyst to generate 4- ((2-cyanopropane-2-yl) amino) -2-fluoro-N-methylbenzamide;
wherein X is F, Cl, Br or I.
In one embodiment of the present invention, the weak base in step (1) is ammonia water with different concentrations.
In one embodiment of the present invention, the concentration of the ammonia water is 18 to 33%.
In one embodiment of the present invention, in the step (1), one or more of water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, diethyl ether, thiazol-2-amine, ethyl acetate, acetonitrile, benzene, toluene, N-dimethylformamide, and dimethylsulfoxide is mixed as a solvent.
In one embodiment of the present invention, the reaction temperature in the step (1) is 0 ℃ or normal temperature.
In one embodiment of the present invention, the chlorinating agent in step (2) is oxalyl chloride, sulfuryl chloride or dichloromethylenemaple.
In one embodiment of the present invention, the solvent in step (2) is one or more selected from dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, diethyl ether, N-dimethylformamide, and dimethylsulfoxide.
In one embodiment of the present invention, the catalyst in the step (3) is cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, barium carbonate, triethylamine, potassium bicarbonate, sodium bicarbonate or calcium bicarbonate.
In one embodiment of the present invention, the catalyst in the step (3) is preferably cesium carbonate.
In one embodiment of the present invention, the solvent in step (3) is one or more selected from dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, diethyl ether, N-dimethylformamide, and dimethylsulfoxide.
In one embodiment of the present invention, the reaction equation of the method is:
the second purpose of the invention is to provide the application of the method in preparing the medicine for treating the prostatic cancer.
The invention has the advantages and effects that:
the reaction yield of each step is very high, more than 80 percent, and some reactions can reach as high as 93 percent.
The post-treatment process is simple, easy to operate and suitable for industrialization.
The reaction conditions are mild, and harsh reaction conditions of high temperature, high pressure and ultralow temperature are avoided.
Detailed description of the preferred embodiments
The present invention is described in detail below by way of examples, and it should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention.
Example 1: preparation of Compound 15
Ammonium chloride (9.6g, 0.18mol), propan-2-one (10.2g, 0.17mol), and ammonia (30% aqueous solution, 10mL) were added to 20mL of purified water, and sodium cyanide (8.6g, 0.17mol) was added with stirring at 0 ℃. The reaction was stopped after the mixed solution was stirred at room temperature for 60h, extracted with dichloromethane (2 x 10mL), and the combined organic layers were washed with saturated sodium chloride (5mL) solution, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white oil in 85-90% yield.
EXAMPLE 2 preparation of Compound 10
Adding compound 9(2.2g,10mmol) into anhydrous ethylene glycol dimethyl ether (20mL), cooling the solution to 0 deg.C, slowly adding thionyl chloride (1.5g, 13mmol) under stirring, the reaction is mild and exothermic, the temperature of the solution is not more than 5 deg.C during the thionyl chloride addition, reacting at 0 deg.C for 1h after the addition is completed, then reacting at 50 deg.C for not less than 6h or TLC monitoring shows complete reaction, cooling the solution to 25 deg.C, slowly adding methylamine (0.9g,30mmol) dissolved in ethylene glycol dimethyl ether (5mL) dropwise into the solution, reacting at 35 deg.C for 0.5h or TLC monitoring shows complete reaction and stopping reaction, adding saturated saline (15mL), extracting with ethyl acetate (2X 15mL), layering, combining organic layers, drying with anhydrous sodium sulfate, filtering, concentrating, drying to obtain white solid, the yield is 88-93%.
EXAMPLE 3 preparation of Compound 10
To a stirred solution of compound 9(1.5g, 6.84mmol) in DCM (15mL) at 0 deg.C was added oxalyl chloride (3.45g, 27.39mmol) dropwise. After the addition was complete, 2-3 drops of DMF were added at 0 ℃ and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in anhydrous THF (20 mL). Methylamine (50mL) was added to the solution at 0 ℃. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue azeotroped with toluene to give the product in 80-85% yield.
EXAMPLE 4 preparation of Compound 6
Mixing compound 10(0.53g, 2.29mmol), compound 15(0.30g, 3.54mmol), CuI (87mg,0.458mmol) K2CO3(0.79g, 5.72mmol) was mixed in DMF (5 mL). Addition of H2O (0.5mL) and TEA (11mg, 0.1mmol) followed by 2-acetylcyclohexanone (60mg, 0.43mmol) was added. The reaction mixture was heated to 95-100 ℃ and held for 4 hours. Reaction mixture with H2O (20mL) was diluted and extracted with ethyl acetate (20mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product in 83-87% yield.
EXAMPLE 5 preparation of Compound 6
Will be transformed intoCompound 10(0.69g, 3mmol) was dissolved in anhydrous DMF (60mL), cesium carbonate (2.44g, 6.45mmol) was added to the solution and the solution was warmed to 80 ℃, compound 15 dissolved in DMF (5mL) was added thereto, the reaction was stopped at 80 ℃ for 6h, cooled to room temperature, added pure water (30mL), stirred for 0.5h, and then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product in 85-90% yield.1H NMR(400MHz,CDCl3)7.76(t,J＝8.7Hz,1H),7.08(d,J＝10.3Hz,1H),6.70(dd,J＝8.7,2.3Hz,1H),6.59(dd,J＝14.7,2.2Hz,1H),6.43(br,1H),2.83(s,3H),1.72(s,6H)；13C NMR(101MHz,CDCl3)164.21,161.43,149.32,132.18,121.43,110.82,110.76,100.75,47.62,27.52,25.87；MS(ESI):calcd for C12H14FN3O[M+H]+236.1194,found 236.1190。
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (9)
1. A process for preparing enzalutamide intermediate 4- ((2-cyanopropan-2-yl) amino) -2-fluoro-N-methylbenzamide comprising the steps of:
(1) reacting the propan-2-one with cyanide under the condition of weak base to generate 2-amino-2-methyl propionitrile;
(2) 4-X-2-fluorobenzoic acid is converted into 4-X-2-fluoro-N-methylbenzamide under the action of a chlorinating agent;
(3) 2-amino-2-methylpropanenitrile and 4-X-2-fluoro-N-methylbenzamide are subjected to substitution reaction under the action of a catalyst to generate 4- ((2-cyanopropane-2-yl) amino) -2-fluoro-N-methylbenzamide;
wherein X is F, Cl, Br or I;
the catalyst in the step (3) is cesium carbonate.
2. The method according to claim 1, wherein the weak base in step (1) is ammonia.
3. The method of claim 2, wherein the concentration of the aqueous ammonia is 18% to 33%.
4. The method according to claim 1, wherein the solvent in step (1) is one or more selected from water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, diethyl ether, thiazol-2-amine, ethyl acetate, acetonitrile, benzene, toluene, N-dimethylformamide and dimethylsulfoxide.
5. The method according to claim 1, wherein the reaction temperature of step (1) is 0 ℃ or normal temperature.
6. The method according to claim 1, wherein the chlorinating agent in the step (2) is oxalyl chloride, sulfuryl chloride or thionyl chloride.
7. The method according to claim 1, wherein the solvent in step (2) is one or more selected from dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, diethyl ether, N-dimethylformamide, and dimethylsulfoxide.
8. The method according to claim 1, wherein the solvent in step (3) is one or more selected from dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, diethyl ether, N-dimethylformamide, and dimethylsulfoxide.
9. Use of the method of claim 1 for the preparation of a medicament for treating prostate cancer.
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