CN113527208A - Method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile by one-step method - Google Patents
Method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile by one-step method Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 46
- BCINLNFBTLIGBU-UHFFFAOYSA-N 2-chloro-4-(1h-pyrazol-5-yl)benzonitrile Chemical compound C1=C(C#N)C(Cl)=CC(C2=NNC=C2)=C1 BCINLNFBTLIGBU-UHFFFAOYSA-N 0.000 title claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 100
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 238000003756 stirring Methods 0.000 claims abstract description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000010992 reflux Methods 0.000 claims abstract description 34
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 27
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000001816 cooling Methods 0.000 claims abstract description 21
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 20
- 238000010438 heat treatment Methods 0.000 claims abstract description 19
- 238000002386 leaching Methods 0.000 claims abstract description 17
- 230000008569 process Effects 0.000 claims abstract description 16
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 14
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000000126 substance Substances 0.000 claims description 9
- 238000007670 refining Methods 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- -1 2-tetrahydropyranyl Chemical group 0.000 claims description 3
- 239000005489 Bromoxynil Substances 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 11
- 238000004821 distillation Methods 0.000 abstract description 6
- 238000000605 extraction Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000000047 product Substances 0.000 description 36
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 20
- 230000000052 comparative effect Effects 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 9
- 238000000643 oven drying Methods 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 6
- 102000001307 androgen receptors Human genes 0.000 description 5
- 108010080146 androgen receptors Proteins 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical class OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000005267 prostate cell Anatomy 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229940123407 Androgen receptor antagonist Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 1
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile by a one-step method, which comprises the following steps: adding a compound I, a compound II and ethanol into a reaction kettle, stirring and dissolving, adding potassium carbonate, vacuumizing under stirring for nitrogen replacement, adding bis (triphenylphosphine) palladium dichloride under the protection of nitrogen, heating to reflux, stirring for reacting overnight, cooling to room temperature, and filtering to obtain an ethanol solution containing a compound III; adding concentrated hydrochloric acid into the obtained ethanol solution of the compound III, stirring at room temperature for reacting overnight, adjusting the pH value to 6-7, continuously stirring, centrifuging, and leaching with ethanol-water to obtain a crude wet product of the compound IV. The preparation method provided by the invention adopts a one-step method for preparation, the intermediate does not need to be purified, the links of distillation, extraction, layering, drying, redistillation and the like in the intermediate treatment process are omitted, and the method is simple, high in efficiency, energy-saving and environment-friendly.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile by a one-step method.
Background
2-chloro-4- (1H-pyrazol-3-yl) benzonitrile is an important intermediate in the synthesis of carboxamide structural Androgen Receptor (AR) antagonists, which are useful in the treatment of cancer, particularly prostate cancer, and other diseases requiring AR antagonism. In vitro experiments prove that the AR antagonist can inhibit the proliferation of prostate cells and promote the apoptosis of the prostate cells; early prostate cancer patients treated with AR antagonists had reduced levels of prostate specific antigen, overall manifested by reduced prostate volume, reduced symptoms to varying degrees, and prolonged patient survival. Therefore, the synthesis of 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile, an intermediate of AR antagonists, is also critical.
In the prior art, the synthesis is generally carried out by Suzuki coupling reaction, but the conventional Suzuki coupling reaction firstly carries out oxidation-addition reaction of Pd (0) and halogenated aromatic hydrocarbon to generate a Pd (II) complex 1, then carries out metal transfer reaction with activated boric acid to generate a Pd (II) complex 2, and finally carries out reduction-elimination to generate a product and Pd (II), and the mechanism is as follows:
although the method has a series of advantages such as allowing various active functional groups to exist and carrying out stereoselective reaction, the reaction needs multiple steps of reaction to be completed, the used solvents are more, multiple processes such as distillation, extraction, drying and the like are needed, and the reaction of the chloride and some heterocyclic boric acid in the reaction is difficult to carry out. Therefore, the development of a preparation method which is simple, uses less solvent and has high efficiency is of great significance.
Disclosure of Invention
In view of the above-identified deficiencies in or needs for improvement in the art, the present invention provides a one-step process for the preparation of 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile. The preparation method adopts a one-step method, the intermediate does not need to be purified, the links of distillation, extraction, layering, drying, redistillation and the like in the intermediate treatment process are omitted, and the method is simple, high in efficiency, energy-saving and environment-friendly.
In order to achieve the above object, the present invention provides a one-step method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile, comprising: adding a compound I, a compound II and ethanol into a reaction kettle, stirring and dissolving, then adding potassium carbonate, vacuumizing for 2-4 times under stirring, adding bis (triphenylphosphine) palladium dichloride under the protection of nitrogen, heating to reflux, stirring for reacting overnight, cooling to room temperature after the reaction is finished, and filtering to remove insoluble substances to obtain an ethanol solution containing a compound III; under the protection of nitrogen, adding concentrated hydrochloric acid into the obtained ethanol solution of the compound III, stirring at room temperature for reacting overnight, adjusting the pH to 6-7 after the reaction is finished, continuing stirring, centrifuging, and leaching with ethanol-water to obtain a crude wet product of the compound IV;
the molar mass ratio of the compound I to the concentrated hydrochloric acid is 1: 1.3-2.5;
the reaction formula is as follows:
wherein, the compound of the formula I is 2-chloro-4-bromoxynil; the compound shown in the formula II is 1- (2-tetrahydropyranyl) -1H-pyrazole-5-boric acid pinacol ester; the compound of formula III is 2-chloro-4- (1- (tetrahydro-2H-pyran-1H-pyrazol-5-yl) benzonitrile); the compound shown in the formula IV is 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile.
In the technical scheme, the deprotection reaction can be completed only when the dosage of the concentrated hydrochloric acid exceeds the catalytic amount, and within the scope of the invention, the more the equivalent, the faster the reaction; however, it is not necessarily the case that the more the equivalent, the better, and when exceeding this range, the more the by-products. The preparation method adopts a one-step method, the intermediate is directly used for subsequent reaction without purification, links such as distillation, extraction, layering, drying, redistillation and the like in an intermediate treatment process are omitted, and the preparation method is energy-saving, environment-friendly and high in efficiency. Specifically, the concentration of the ethanol is more than or equal to 95%.
Further, the technical scheme also comprises a refining process, and the method comprises the steps of adding the obtained crude wet product into ethanol, heating to reflux and dissolve the crude wet product clearly, dripping water at a constant speed for crystallization when the temperature is 60-80 ℃ under reflux, cooling to room temperature after the addition, centrifuging, leaching with ethanol-water, and drying to obtain a white target compound IV. In the technical scheme, the refining mode of dripping water for crystallization after ethanol is adopted and the reflux is maintained is better than the effect of directly using reflux pulping or ethanol recrystallization, and the purity of the obtained final product is up to 99.9 percent. Specifically, the concentration of the ethanol is more than or equal to 95%.
Further, the dosage of the ethanol in the technical scheme is 2.6-4 times of the weight of the compound I; the volume amount of the water added into the crystals is equal to that of the ethanol added into the wet product.
Furthermore, the molar mass ratio of the compound I to the compound II in the technical scheme is 1: 1.1-1.5. In the chemical reaction, too much or too little of the reaction raw material is not favorable for the reaction, and either the reaction cannot be carried out or the by-product is too much. In the technical scheme, the proportion of the compounds I and II is strictly controlled, so that the reaction is more sufficient and no by-product is generated.
Further, the molar mass ratio of the compound I to the potassium carbonate in the technical scheme is 1: 2.2-2.8. According to the technical scheme, potassium carbonate is used as an activation reactant, the addition amount is too small, the reaction cannot be completely carried out, the addition amount is too large, the stirring load is increased, the reaction speed is influenced, and the reaction time is prolonged.
Further, in the technical scheme, the molar mass ratio of the compound I to the bis (triphenylphosphine) palladium dichloride is 1: 0.003-0.010. The bis (triphenylphosphine) palladium dichloride is used as a catalyst for the coupling reaction, the amount is too small, the reaction time is prolonged, the amount is too large, and the reaction cost is directly increased.
Further, in the technical scheme, the reaction temperature is controlled to be 75-85 ℃ after refluxing in the reaction. By controlling the coupling reaction temperature in the technical scheme, the reaction time can be effectively shortened, and the reaction rate is high.
Further, in the above technical scheme, the volume ratio of ethanol to water in the ethanol-water leacheate is 1:1. In the technical scheme, 50% ethanol-water is adopted for leaching, so that the residues of salt and impurities in the reaction product can be effectively removed.
Furthermore, the reaction time of the two times in the technical scheme is more than or equal to 12 hours.
Further, in the above technical scheme, the pH is adjusted by using a sodium hydroxide solution or a potassium hydroxide solution.
Compared with the prior art, the invention has the beneficial effects that:
1. the preparation method adopts a one-step method, 2-chloro-4-bromoxynil and 1- (2-tetrahydropyranyl) -1H-pyrazole-5-pinaborate are taken as reaction raw materials, bis (triphenylphosphine) palladium dichloride is taken as a catalyst, potassium carbonate is taken as an activation reactant, a generated intermediate III does not need to be dissociated, links such as distillation, extraction, layering, drying, redistillation and the like in an intermediate treatment process are omitted, and the process is simplified;
2. according to the invention, the reaction raw material ratio and the reaction conditions are strictly controlled, the reaction speed is high, the efficiency is high, and the purity of the obtained target product is high;
3. the invention saves the links of distillation, extraction, layering, drying, redistillation and the like in the intermediate treatment process, can reduce the preparation cost, simultaneously improve the utilization rate of equipment, greatly shorten the production period and is suitable for industrial production;
4. the invention adopts one-step synthesis, and has the advantages of simple method, high efficiency, energy saving and environmental protection.
Detailed Description
The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials in the following examples are all commercially available products and are commercially available, unless otherwise specified.
The above-mentioned technical features of the present invention and those described in detail below (e.g., in the embodiments) can be combined with each other to form a new or preferred embodiment.
Example 1
Adding a compound I (2kg), a compound II (3.3kg) and ethanol (5L) into a reaction kettle at room temperature, stirring and dissolving, then adding potassium carbonate (3.2kg), vacuumizing and replacing with nitrogen for 4 times under stirring, adding bis (triphenylphosphine) palladium dichloride (25.4g) under the protection of nitrogen, then heating to 75 ℃ to reflux, stirring and reacting overnight (16h), cooling to room temperature after the reaction is finished, filtering to remove insoluble substances to obtain an ethanol solution of a compound III, adding concentrated hydrochloric acid (1.5kg) into the ethanol solution of the compound III under the protection of nitrogen, stirring and reacting overnight at room temperature, adding a 10% sodium hydroxide solution (5kg) to adjust the pH to 6-7 after the reaction is finished, continuously stirring for 30min, centrifuging, and leaching with 50% ethanol-water (1.25L) to obtain a crude wet product of the compound IV; adding the obtained crude wet product into ethanol (6.5L), heating to reflux, dissolving, adding water (6.5L) dropwise under reflux, cooling to room temperature, centrifuging, rinsing with appropriate amount of 50% ethanol-water, and oven drying to obtain 1.7kg of white target compound IV. The calculated yield was 90.4% and the purity was 99.9% by liquid phase (HPLC).
Example 2
Adding a compound I (2kg), a compound II (3.3kg) and ethanol (5L) into a reaction kettle at room temperature, stirring and dissolving, then adding potassium carbonate (3.4kg), vacuumizing and replacing with nitrogen for 3 times under stirring, adding bis (triphenylphosphine) palladium dichloride (25.4g) under the protection of nitrogen, then heating to 80 ℃ to reflux, stirring and reacting overnight (14h), cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, obtaining an ethanol solution of a compound III, adding concentrated hydrochloric acid (1.8kg) into the obtained ethanol solution of the compound III under the protection of nitrogen, stirring and reacting overnight at room temperature, adding a 10% sodium hydroxide solution (5.9kg) after the reaction is finished, adjusting the pH to 6-7, continuously stirring for 30min, centrifuging, and leaching with 50% ethanol-water (1.25L) to obtain a crude wet product of the compound IV; adding the obtained crude wet product into ethanol (6.5L), heating to reflux and dissolving, dripping water (6.5L) under reflux, cooling to room temperature after the addition, centrifuging, leaching with appropriate amount of 50% ethanol-water, and oven drying to obtain 1.68kg of white target compound IV. The calculated yield was 89.6% with a purity of 99.5% by liquid phase (HPLC).
Example 3
Adding a compound I (2kg), a compound II (3.3kg) and ethanol (5L) into a reaction kettle at room temperature, stirring and dissolving, then adding potassium carbonate (3.2kg), vacuumizing and replacing with nitrogen for 2 times under stirring, adding bis (triphenylphosphine) palladium dichloride (25.4g) under the protection of nitrogen, then heating to 85 ℃ to reflux, stirring and reacting overnight (12h), cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, obtaining an ethanol solution of a compound III, adding concentrated hydrochloric acid (2.1kg) into the obtained ethanol solution of the compound III under the protection of nitrogen, stirring and reacting overnight at room temperature, adding a 10% sodium hydroxide solution (7.0kg) after the reaction is finished, adjusting the pH to 6-7, continuously stirring for 30min, centrifuging, and leaching with 50% ethanol-water (1.25L) to obtain a crude wet product of the compound IV; adding the obtained crude wet product into ethanol (6.5L), heating to reflux and dissolving, dripping water (6.5L) under reflux, cooling to room temperature after the addition, centrifuging, leaching with appropriate amount of 50% ethanol-water, and oven drying to obtain 1.67kg of white target compound IV. The calculated yield was 88.7% and the purity was 99.6% by liquid phase (HPLC).
Comparative example 1
Adding a compound I (2kg), a compound II (3.3kg) and toluene/water (5L) into a reaction kettle at room temperature, stirring to dissolve the mixture, then adding potassium carbonate (3.2kg), vacuumizing and replacing with nitrogen for 4 times under stirring, adding bis (triphenylphosphine) palladium dichloride (25.4g) under the protection of nitrogen, then heating to 75 ℃ until the mixture flows back, stirring and reacting overnight (16h), cooling to room temperature after the reaction is finished, filtering to remove insoluble substances to obtain a toluene solution of a compound III, adding concentrated hydrochloric acid (1.5kg) into the toluene solution of the compound III under the protection of nitrogen, stirring and reacting overnight at room temperature, adding a 10% sodium hydroxide solution (5kg) to adjust the pH to 6-7 after the reaction is finished, continuously stirring for 30min, centrifuging, and leaching with 50% ethanol-water (1.25L) to obtain a crude wet product of the compound IV; adding the obtained crude wet product into ethanol (6.5L), heating to reflux, dissolving, adding water (6.5L) dropwise under reflux, cooling to room temperature, centrifuging, rinsing with appropriate amount of 50% ethanol-water, and oven drying to obtain 0.94kg of white target compound IV. The calculated yield was 49.8% and the purity was 98.3% by liquid phase (HPLC).
Comparative example 2
Adding a compound I (2kg), a compound II (3.3kg) and THF (tetrahydrofuran) (5L) into a reaction kettle at room temperature, stirring to dissolve, then adding potassium carbonate (3.4kg), vacuumizing for nitrogen replacement for 3 times under stirring, adding bis (triphenylphosphine) palladium dichloride (25.4g) under the protection of nitrogen, then heating to 80 ℃ to reflux, stirring for reaction overnight (14h), cooling to room temperature after the reaction is finished, filtering to remove insoluble substances to obtain a THF solution of a compound III, adding concentrated hydrochloric acid (1.7kg) into the THF solution of the compound III under the protection of nitrogen, stirring for reaction overnight at room temperature, adding a 10% sodium hydroxide solution (5.7kg) to adjust the pH to 6-7 after incomplete reaction, continuously stirring for 30min, centrifuging, and leaching with 50% ethanol-water (1.25L) to obtain a crude wet compound IV; adding the obtained crude wet product into ethanol (6.5L), heating to reflux and dissolving, dripping water (6.5L) under reflux, cooling to room temperature after the addition, centrifuging, leaching with appropriate amount of 50% ethanol-water, and oven drying to obtain 0.90kg of off-white target compound IV. The calculated yield was 47.9% and the purity by liquid phase (HPLC) detection was 97.4%.
Comparative example 3
Adding a compound I (2kg), a compound II (3.3kg) and ethanol (5L) into a reaction kettle at room temperature, stirring and dissolving, then adding potassium carbonate (3.2kg), vacuumizing and replacing with nitrogen for 3 times under stirring, adding bis (triphenylphosphine) palladium dichloride (25.4g) under the protection of nitrogen, then heating to 75 ℃ to reflux, stirring and reacting overnight (16h), cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, obtaining an ethanol solution of a compound III, adding concentrated hydrochloric acid (0.34kg) into the obtained ethanol solution of the compound III under the protection of nitrogen, stirring and reacting overnight at room temperature, adding a 10% sodium hydroxide solution (1.14kg) after the reaction is finished, adjusting the pH to 6-7, continuously stirring for 30min, centrifuging, and leaching with 50% ethanol-water (1.25L) to obtain a crude wet product of the compound IV; adding the obtained crude wet product into ethanol (6.5L), heating to reflux, dissolving, adding water (6.5L) dropwise under reflux, cooling to room temperature, centrifuging, rinsing with appropriate amount of 50% ethanol-water, and oven drying to obtain 0.98kg of white target compound IV. The calculated yield was 52.0% and the liquid phase (HPLC) assay purity was 97.3%.
Comparative example 4
Adding a compound I (2kg), a compound II (3.3kg) and ethanol (5L) into a reaction kettle at room temperature, stirring and dissolving, then adding potassium carbonate (3.2kg), vacuumizing and replacing with nitrogen for 3 times under stirring, adding bis (triphenylphosphine) palladium dichloride (25.4g) under the protection of nitrogen, then heating to 75 ℃ to reflux, stirring and reacting overnight (16h), cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, obtaining an ethanol solution of a compound III, adding concentrated hydrochloric acid (3.14kg) into the obtained ethanol solution of the compound III under the protection of nitrogen, stirring and reacting overnight at room temperature, adding a 10% sodium hydroxide solution (1.14kg) after the reaction is finished, adjusting the pH to 6-7, continuously stirring for 30min, centrifuging, and leaching with 50% ethanol-water (1.25L) to obtain a crude wet product of the compound IV; adding the obtained crude wet product into ethanol (6.5L), heating to reflux, dissolving, adding water (6.5L) dropwise under reflux, cooling to room temperature, centrifuging, rinsing with appropriate amount of 50% ethanol-water, and oven drying to obtain 1.49kg of white target compound IV. The calculated yield was 79.0% and the liquid phase (HPLC) purity was 95.59%.
Comparative example 5
The preparation method of the crude wet product of the compound IV is the same as that of the example 1, and the refining process is as follows:
and adding the obtained crude wet product into ethanol/water (6.5L/6.5L), directly refluxing and pulping, cooling to room temperature for crystallization, centrifuging, leaching with a proper amount of 50% ethanol-water, and drying to obtain 1.72kg of a white target compound IV. The calculated yield was 91.4% and the purity was 99.1% by liquid phase (HPLC).
Comparative example 6
The preparation method of the crude wet product of the compound IV is the same as that of the example 1, and the refining process is as follows:
dissolving the obtained crude wet product in ethanol (6.5L) at 80 deg.C, stirring for 30min, cooling to room temperature for crystallization, centrifuging, rinsing with appropriate amount of ethanol, and oven drying to obtain 1.16kg of white target compound IV. The calculated yield was 61.4% with a purity of 99.5% by liquid phase (HPLC).
And (4) comprehensive conclusion:
from examples 1-3, it can be seen that the process for synthesizing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile of the present invention is simple, the yield is as high as 90.4%, and the purity is as high as 99.9%, which indicates that the synthesis method of the present invention has the characteristics of high efficiency, high yield, and environmental protection.
From the results of example 1 and comparative example 1, it can be seen that during the coupling reaction, although comparative example 1 uses toluene/water as solvent and is also suitable for the process of the present invention to prepare the target product, the yield is only 49.8%, which is significantly lower than 90.4% of example 1, and the purity is also lower than that of the product in example 1, and it can be seen that the yield and purity are better when ethanol is used as solvent in the present invention.
As can be seen from the results of example 2 and comparative example 2, in the course of the coupling reaction, when comparative example 2 was carried out with THF as a solvent, the reaction was not complete, and the yield of the objective product was only 47.9%, which was significantly lower than 89.6% in example 2, and the purity was also lower than that of the product in example 2, and it was found that THF was not suitable for use as a solvent in the present invention.
From the results of example 1 and comparative example 3, it can be seen that, in the deprotection reaction, when a catalytic amount of hydrochloric acid is used in comparative example 3, the yield of the target product is only 52.0%, which is significantly lower than 90.4% of example 1, and the purity of the target product is 97.3% and lower than that of example 1, indicating that the deprotection reaction is incomplete, and it can be seen that the use of a catalytic amount of hydrochloric acid is not enough to complete the deprotection reaction, while the addition of the hydrochloric acid in an amount of the present invention can fully complete the deprotection reaction, and the yield and purity of the target product are high.
From the results of example 1 and comparative example 4, it can be seen that the yield of the target product in the deprotection reaction is only 79.0% in comparative example 4 using an excess of hydrochloric acid, which is significantly lower than 90.4% in example 1, and the purity is 95.59% and is also lower than that in example 1, indicating that when an excess of hydrochloric acid is used, although the deprotection is complete, the by-products are too much, which affects the quality and yield of the product.
From the results of example 1 and comparative examples 5 to 6, it can be seen that, in the refining process, when ethanol/water is directly used for reflux beating, impurities in the product are not easily removed, and the purity is slightly lower than that obtained by the method of example 1; when only ethanol is used for recrystallization, the product yield is only 61.4 percent and is obviously lower than the yield of 90.4 percent in example 1, which shows that the product yield and purity can be obviously improved by using the method for maintaining the dropwise adding water for crystallization under reflux after ethanol is dissolved and cleaned.
Finally, it should be emphasized that the above-described preferred embodiments of the present invention are merely examples of implementations, rather than limitations, and that many variations and modifications of the invention are possible to those skilled in the art, without departing from the spirit and scope of the invention.
Claims (10)
1. A method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile by using a one-step method is characterized by comprising the following steps: adding a compound I, a compound II and ethanol into a reaction kettle, stirring and dissolving, then adding potassium carbonate, vacuumizing for 2-4 times under stirring, adding bis (triphenylphosphine) palladium dichloride under the protection of nitrogen, heating to reflux, stirring for reacting overnight, cooling to room temperature after the reaction is finished, and filtering to remove insoluble substances to obtain an ethanol solution containing a compound III; under the protection of nitrogen, adding concentrated hydrochloric acid into the obtained ethanol solution of the compound III, stirring at room temperature for reacting overnight, adjusting the pH to 6-7 after the reaction is finished, continuing stirring, centrifuging, and leaching with ethanol-water to obtain a crude wet product of the compound IV;
the molar mass ratio of the compound I to the concentrated hydrochloric acid is 1: 1.3-2.5;
wherein the compound I is 2-chloro-4-bromoxynil; the compound II is 1- (2-tetrahydropyranyl) -1H-pyrazole-5-boric acid pinacol ester; compound iii is 2-chloro-4- (1- (tetrahydro-2H-pyran-1H-pyrazol-5-yl) benzonitrile); the compound IV is 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile.
2. The one-step method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile according to claim 1, further comprising a refining process, wherein the refining process comprises the steps of adding the obtained crude wet product into ethanol, heating to reflux and dissolving, dripping water at a constant speed when the temperature is 60-80 ℃ under reflux for crystallization, cooling to room temperature after the addition, centrifuging, leaching with ethanol-water, and drying to obtain a white target compound IV.
3. The one-step method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile according to claim 2, wherein the amount of ethanol is 2.6 to 4 times the weight of the compound I; the volume amount of the water added into the crystals is equal to that of the ethanol added into the wet product.
4. The one-step method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile according to claim 1, wherein the molar mass ratio of the compound I to the compound II is 1: 1.1-1.5.
5. The one-step method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile according to claim 1, wherein the molar mass ratio of the compound I to the potassium carbonate is 1: 2.2-2.8.
6. The one-step method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile according to claim 1, wherein the molar mass ratio of the compound I to the bis (triphenylphosphine) palladium dichloride is 1; 0.003-0.010.
7. The one-step method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile according to claim 1, wherein the reaction temperature is controlled to be 75-85 ℃ after refluxing.
8. The one-step method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile according to claim 1 or 2, wherein the volume ratio of ethanol to water in the ethanol-water eluate is 1:1.
9. The one-step method for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile according to claim 1, wherein the reaction time of two times of overnight reaction is more than or equal to 12 hours.
10. The one-step process for preparing 2-chloro-4- (1H-pyrazol-3-yl) benzonitrile according to claim 1, wherein the pH is adjusted using a sodium hydroxide solution or a potassium hydroxide solution.
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| CN102596910A (en) * | 2009-10-27 | 2012-07-18 | 奥赖恩公司 | Androgen receptor modulating compounds |
| WO2012143599A1 (en) * | 2011-04-21 | 2012-10-26 | Orion Corporation | Androgen receptor modulating carboxamides |
| CN107428695A (en) * | 2015-04-09 | 2017-12-01 | 奥赖恩公司 | Method for preparing androgen receptor antagonists and its intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102596910A (en) * | 2009-10-27 | 2012-07-18 | 奥赖恩公司 | Androgen receptor modulating compounds |
| WO2012143599A1 (en) * | 2011-04-21 | 2012-10-26 | Orion Corporation | Androgen receptor modulating carboxamides |
| CN107428695A (en) * | 2015-04-09 | 2017-12-01 | 奥赖恩公司 | Method for preparing androgen receptor antagonists and its intermediate |
| CN110590668A (en) * | 2019-07-17 | 2019-12-20 | 江苏君若医药有限公司 | Preparation method of N- [ (1S) -2- [3- (3-chloro-4-cyanophenyl) -1H-pyrazol-1-yl ] -1-methylethyl ] -5- (1-hydroxyethyl) -1H-pyrazole-3-formamide |
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