CN117756670A - Synthesis method of rilpivirine intermediate - Google Patents
Synthesis method of rilpivirine intermediate Download PDFInfo
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- CN117756670A CN117756670A CN202311753723.4A CN202311753723A CN117756670A CN 117756670 A CN117756670 A CN 117756670A CN 202311753723 A CN202311753723 A CN 202311753723A CN 117756670 A CN117756670 A CN 117756670A
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- dimethylaniline
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- 229960002814 rilpivirine Drugs 0.000 title claims abstract description 27
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 title claims abstract description 27
- 238000001308 synthesis method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- JNRBSZUSHVFWIK-UHFFFAOYSA-N 3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile Chemical compound CC1=CC(C=CC#N)=CC(C)=C1N JNRBSZUSHVFWIK-UHFFFAOYSA-N 0.000 claims abstract description 11
- MGNOINHCQPDTPO-UHFFFAOYSA-N 4-amino-3,5-dimethylbenzaldehyde Chemical compound CC1=CC(C=O)=CC(C)=C1N MGNOINHCQPDTPO-UHFFFAOYSA-N 0.000 claims abstract description 11
- HRWCKMHTQMYUSL-UHFFFAOYSA-N 4-amino-3,5-dimethylbenzonitrile Chemical compound CC1=CC(C#N)=CC(C)=C1N HRWCKMHTQMYUSL-UHFFFAOYSA-N 0.000 claims abstract description 10
- QGLAYJCJLHNIGJ-UHFFFAOYSA-N 4-bromo-2,6-dimethylaniline Chemical compound CC1=CC(Br)=CC(C)=C1N QGLAYJCJLHNIGJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims abstract description 8
- JNRBSZUSHVFWIK-ONEGZZNKSA-N (e)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1N JNRBSZUSHVFWIK-ONEGZZNKSA-N 0.000 claims abstract description 7
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 230000000171 quenching effect Effects 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 230000001681 protective effect Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- IGMWDYQIKLLYQH-UHFFFAOYSA-N cyanomethyl diethyl phosphate Chemical compound CCOP(=O)(OCC)OCC#N IGMWDYQIKLLYQH-UHFFFAOYSA-N 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 229910001431 copper ion Inorganic materials 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 7
- 231100000086 high toxicity Toxicity 0.000 abstract description 5
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 abstract description 4
- KWMBADTWRIGGGG-UHFFFAOYSA-N 2-diethoxyphosphorylacetonitrile Chemical compound CCOP(=O)(CC#N)OCC KWMBADTWRIGGGG-UHFFFAOYSA-N 0.000 abstract description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 2
- 150000001299 aldehydes Chemical class 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 230000003321 amplification Effects 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 238000010907 mechanical stirring Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- BJJSUOOEBCCLNY-UHFFFAOYSA-N 4-iodo-2,6-dimethylaniline Chemical compound CC1=CC(I)=CC(C)=C1N BJJSUOOEBCCLNY-UHFFFAOYSA-N 0.000 description 1
- -1 NMP Chemical compound 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizing a rilpivirine intermediate, which comprises the following steps: 4-bromo-2, 6-dimethylaniline is used as a raw material, the raw material reacts with cuprous cyanide in DMF solvent to obtain 4-cyano-2, 6-dimethylaniline, then the 4-cyano-2, 6-dimethylaniline is reduced by DIBAL-H to obtain 4-amino-3, 5-dimethylbenzaldehyde, the aldehyde reacts with diethyl cyanomethylphosphonate under the catalysis of alkali to obtain 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile (trans: cis=5:1), and the cis-trans mixture is purified by isopropanol hydrochloride crystallization to obtain the hydrochloride of (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile. In the synthesis process, the used raw materials are low in cost and easy to obtain, the synthesis process is simple, the reaction condition is mild, the process amplification requirement is met, the route avoids the high-toxicity acrylonitrile and the expensive palladium-carbon catalyst in the original synthesis route, and the method has good environmental protection value and economic value.
Description
Technical Field
The invention belongs to the field of organic synthesis, relates to a method for synthesizing a rilpivirine intermediate, and in particular relates to a method for synthesizing hydrochloride of a rilpivirine intermediate (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile.
Background
Rilpivirine, named Rilpivirine, is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Tibotec corporation in the united states, is marketed in the united states in month 5 of 2011, is used for the treatment of aids, and has the characteristics of easy synthesis, strong antiviral activity, high oral bioavailability, good safety, and the like. The chemical name is: 4- [ [4- [ [4- [ (E) -2-cyanoethylene ] -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile of the chemical structure:
according to the prior art, published literature reports that rilpivirine is synthesized predominantly from two intermediates, intermediate a: (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile, and intermediate B:4- [ (4-chloro-2-pyrimidinyl) amino ] benzonitrile. The chemical structures of the two intermediates are respectively as follows:
wherein, the common transaction and storage modes of the intermediate A are all in the form of hydrochloride, the intermediate A is mainly synthesized by taking 4-iodine-2, 6-dimethylaniline as a starting material and acrylonitrile in a DMAC solvent and palladium-carbon (5%mol) as a catalyst, the reaction temperature is controlled at 130-140 ℃, and the synthesis route is as follows:
in the synthesis process of the intermediate, a palladium catalyst with high price and high toxicity acrylonitrile are used, which is harmful to operators and the environment, and the harm of the raw materials is not easy to be eliminated in the post-treatment, so that the environment pollution is easy to be caused, the large-scale investment and the cost are high, and the method is not suitable for industrial mass production.
For example, reference CN105566162B discloses a synthesis of a rilpivirine intermediate, which cannot avoid the use of palladium catalysts, and the synthesis route would have impurities generated from the reaction product of 4-iodo-2, 6-dimethylaniline with heck, which once generated, would be difficult to remove and interfere with later purification.
There is therefore a need in the art for a safer, efficient synthesis of rilpivirine Lin Zhongjian which does not use expensive catalysts.
Disclosure of Invention
Aiming at the defects, the invention provides a method for synthesizing a rilpivirine intermediate, which has the advantages of cheap and easily available raw materials and simple process, thereby solving the problems of high toxicity of the reagent, high price of the catalyst and easy generation of impurities which are difficult to remove in the prior art; the invention has never been reported in the literature, is an entirely new rilpivirine Lin Zhibei method, and provides a new synthetic thought for similar compounds.
Aiming at the defects of the prior art, the invention provides a method for synthesizing a rilpivirine intermediate.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a synthesis method of a rilpivirine intermediate, wherein the intermediate is (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile, and the structural formula is as follows:
wherein the intermediate is synthesized by the following synthetic route:
preferably, the method further comprises the following reaction steps:
step1: under the protection of protective gas, adding raw material 4-bromo-2, 6-dimethylaniline and cuprous cyanide into an organic solvent, heating and then starting to react, cooling a reaction system to room temperature after the raw material is completely reacted, adding water, washing, extracting a product, and concentrating to obtain 4-cyano-2, 6-dimethylaniline;
step2, under the protection of protective gas, dissolving the 4-cyano-2, 6-dimethylaniline obtained in Step1 into a solvent, controlling the temperature and dropwise adding a toluene solution of DIBAL-H; after the tracking detection of the complete reaction of the raw materials, quenching the reaction liquid, extracting and concentrating to obtain a product, namely 4-amino-3, 5-dimethylbenzaldehyde;
step3, under the protection of protective gas, dissolving 4-amino-3, 5-dimethylbenzaldehyde obtained in Step2 and diethyl cyanomethylphosphate, controlling the temperature and dropwise adding a tetrahydrofuran solution of sodium methoxide; quenching the reaction liquid after the raw materials are reacted completely, extracting and concentrating to obtain 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile;
step4, dissolving the 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile obtained in Step3, heating to 60 ℃ and dropwise adding isopropanol hydrochloride solution, and after the dropwise adding is finished, carrying out heat preservation reaction until the reaction is finished; the reaction solution was filtered, and the cake was collected to give the hydrochloride salt of the product (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile.
Preferably, the organic solvent in Step1 comprises at least one of DMF or NMP, the molar ratio of 4-bromo-2, 6-dimethylaniline to cuprous cyanide is 1:2.0-1:2.5, and the temperature is raised to 140-150 ℃.
Preferably, in Step1, ammonia water is used as a water washing agent to wash copper ions, and ethyl acetate is used as an extracting agent.
Preferably, the solvent in Step2 is anhydrous tetrahydrofuran, the molar ratio of 4-cyano-2, 6-dimethylaniline to DIBAL-H is 1:2.0-1:2.5, and the temperature is controlled to 0-10 ℃.
Preferably, the quenching agent is a dilute hydrochloric acid solution, the concentration of the dilute hydrochloric acid is 1-4N, and the extracting agent is methyl tertiary butyl ether.
Preferably, the solvent used for dissolving Step3 is anhydrous tetrahydrofuran, and the molar ratio of 4-amino-3, 5-dimethylbenzaldehyde to cyanomethyl diethyl phosphate is 1:1.1-1:1.5; the molar ratio of the 4-amino-3, 5-dimethylbenzaldehyde to the sodium methoxide is 1:3.0-1:4.0; controlling the temperature to 0-5 ℃.
Preferably, the quenching agent is a dilute hydrochloric acid solution, the concentration of the dilute hydrochloric acid is 1-4N, the extracting agent is ethyl acetate, and the obtained 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile has the structural formula proportion of trans: cis=5: 1.
preferably, the solvent dissolved in Step4 is absolute ethyl alcohol, the molar ratio of the 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile cis-trans isomer mixture to isopropanol hydrochloride is 1:1.1-1:1.5, the temperature is kept at 60-65 ℃, and the end point mark of the reaction is trans/(cis+trans) x100% = 98% -100%.
Preferably, the shielding gas of Step 1-3 includes one of nitrogen and argon.
The invention has the beneficial effects that:
the invention solves the problems of high toxicity of the reagent, high price of the catalyst and the like in the prior art, provides a preparation method of an all-new rilpivirine intermediate, and has the advantages of cheap and easily available raw materials, simple process and the like; the synthetic route of the invention has not been reported in literature, is a brand new rilpivirine Lin Zhibei method, and provides a new synthetic thought for similar compounds.
Drawings
FIG. 1 is a schematic HPLC diagram of intermediate A;
FIG. 2 is a schematic representation of HNMR of intermediate A;
FIG. 3 is a schematic of the IR spectrum of intermediate A.
Detailed Description
The invention is further described by the following specific examples, which are not intended to limit the scope of the invention.
Example 1:
step1, 1L of three-mouth bottle, drying, cleaning and nitrogen protection. 500ml of DMF,100g of 4-bromo-2, 6-dimethylaniline and 67.5g of cuprous cyanide are added under mechanical stirring, the temperature is raised to 145 ℃ for reaction for about 10 hours, after the reaction is detected to be complete, the heating is stopped, and the temperature is reduced to room temperature. 600g of 12% aqueous ammonia solution was added, and 500ml of ethyl acetate was added to extract twice. The ethyl acetate phases were combined and washed twice with 200ml of 5% aqueous ammonia. Ethyl acetate was removed by rotary evaporator concentration to yield 70.1g of product with 96.5% yield. HNMR (solvent CDCl3; internal standard TMS): δ7.22 (s, 2H), δ2.18 (s, 6H).
Step2, 1L of three-mouth bottle, drying, cleaning and nitrogen protection. 250ml of THF,50g of 4-cyano-2, 6-dimethylaniline are added under mechanical stirring, the ice salt bath is cooled to 0-5℃and 230ml of 1.5M DIBAL-H solution are added dropwise at a temperature of 0-10 ℃. After the completion of the reaction for about 1 hour, the reaction solution was added dropwise to 300ml of 4N diluted hydrochloric acid. 300ml of methyl tert-butyl ether were added and extracted twice. The methyl tert-butyl ether phases were combined and washed once with water and once with saturated brine. Methyl tert-butyl ether was removed by rotary evaporator concentration to give 21.5g of product in 83.7% yield. HNMR (solvent CDCl3; internal standard TMS): δ9.74 (s, 1H), δ7.5 (s, 2H), δ4.21 (s, 2H), δ2.24 (s, 6H).
Step3, 1L of three-mouth bottle, drying, cleaning and nitrogen protection. 250ml of THF,50g of 4-amino-3, 5-dimethylbenzaldehyde and 65.3g of diethyl cyanomethylphosphonate are added under mechanical stirring, the solution is cooled to 0-5 ℃ in an ice salt bath, and 72.4g of sodium methoxide and 350ml of THF are added dropwise under controlled temperature of 0-10 ℃. After the reaction is completed for about 1 hour, 300ml of 4N dilute hydrochloric acid is added dropwise to the reaction solution at the temperature of 0-10 ℃ after the completion of the detection reaction. 300ml of ethyl acetate was added and extraction was carried out twice. The ethyl acetate phases were combined and washed once with saturated aqueous sodium bicarbonate and once with saturated brine. The ethyl acetate was removed by rotary evaporation to give 53.5g of the product in 92.7% yield.
Step4, 2L three-mouth bottle, dry and clean, nitrogen protection. 750ml of absolute ethanol, 100g of 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile (trans: cis=5:1) are added under mechanical stirring, the temperature is raised to 60 to 65 ℃, and 93.4g of 25% isopropanol hydrochloride solution is added dropwise at a temperature of 60 to 65 ℃. After the heat preservation reaction is completed for about 15 hours, detecting the trans: cis is greater than or equal to 98:2, stopping the reaction, and reducing the temperature of the reaction solution to 20-25 ℃. Filtering to obtain crude product. Purifying a crude product: the crude product is added into a mixed solution of 750ml of absolute ethyl alcohol and 100ml of isopropanol, pulped for 2 hours at 50-55 ℃, cooled to room temperature and filtered to obtain 96.3g, and the yield is 79.5 percent. HNMR (solvent DMSO; internal standard TMS): δ8.47 (s, 3.36H), δ7.43 (d, 1H), δ7.34 (s, 2H), δ6.34 (d, 1H), δ2.33 (s, 6H).
Example 2:
step1, 1L of three-mouth bottle, drying, cleaning and nitrogen protection. 500ml of N-methylpyrrolidone, NMP,100g of 4-bromo-2, 6-dimethylaniline and 67.5g of cuprous cyanide are added under mechanical stirring, the temperature is raised to 145 ℃ and the reaction is carried out for about 10 hours, after the reaction is detected to be complete, the heating is stopped and the reaction is cooled to room temperature. 600g of 12% aqueous ammonia solution was added, and 500ml of ethyl acetate was added to extract twice. The ethyl acetate phases were combined and washed twice with 200ml of 5% aqueous ammonia. Ethyl acetate was removed by rotary evaporator concentration to yield 70.1g of product with 96.5% yield. HNMR (solvent CDCl3; internal standard TMS): δ7.22 (s, 2H), δ2.18 (s, 6H).
Step2, 1L of three-mouth bottle, drying, cleaning and nitrogen protection. 250ml of THF,50g of 4-cyano-2, 6-dimethylaniline are added under mechanical stirring, the ice salt bath is cooled to 0-5℃and 230ml of 1.5M DIBAL-H solution are added dropwise at a temperature of 0-10 ℃. After completion of the reaction for about 1 hour, the reaction mixture was added dropwise to 300ml of 1N diluted hydrochloric acid. 300ml of methyl tert-butyl ether were added and extracted twice. The methyl tert-butyl ether phases were combined and washed once with water and once with saturated brine. Methyl tert-butyl ether was removed by rotary evaporator concentration to give 21.5g of product in 83.7% yield. HNMR (solvent CDCl3; internal standard TMS): δ9.74 (s, 1H), δ7.5 (s, 2H), δ4.21 (s, 2H), δ2.24 (s, 6H).
Step3, 1L of three-mouth bottle, drying, cleaning and nitrogen protection. 250ml of THF,50g of 4-amino-3, 5-dimethylbenzaldehyde and 65.3g of diethyl cyanomethylphosphonate are added under mechanical stirring, the solution is cooled to 0-5 ℃ in an ice salt bath, and 72.4g of sodium methoxide and 350ml of THF are added dropwise under controlled temperature of 0-10 ℃. After the reaction is completed for about 1 hour, 300ml of 1N dilute hydrochloric acid is added dropwise to the reaction solution at the temperature of 0-10 ℃ after the completion of the detection reaction. 300ml of ethyl acetate was added and extraction was carried out twice. The ethyl acetate phases were combined and washed once with saturated aqueous sodium bicarbonate and once with saturated brine. The ethyl acetate was removed by rotary evaporation to give 53.5g of the product in 92.7% yield.
Step4, 2L three-mouth bottle, dry and clean, nitrogen protection. 750ml of absolute ethanol, 100g of 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile (trans: cis=5:1) are added under mechanical stirring, the temperature is raised to 60 to 65 ℃, and 93.4g of 25% isopropanol hydrochloride solution is added dropwise at a temperature of 60 to 65 ℃. After the heat preservation reaction is completed for about 15 hours, detecting the trans: cis is greater than or equal to 98:2, the reaction solution is cooled to 20-25 ℃. Filtering to obtain crude product. Purifying a crude product: the crude product is added into a mixed solution of 750ml of absolute ethyl alcohol and 100ml of isopropanol, pulped for 2 hours at 50-55 ℃, cooled to room temperature and filtered to obtain 96.3g, and the yield is 79.5 percent. HNMR (solvent DMSO; internal standard TMS): δ8.47 (s, 3.36H), δ7.43 (d, 1H), δ7.34 (s, 2H), δ6.34 (d, 1H), δ2.33 (s, 6H).
Comparative example 1:
1L three-mouth bottle, dry clean, nitrogen protection. 500ml of N-methylpyrrolidone, namely NMP,100g of 4-bromo-2, 6-dimethylaniline and 67.5g of cuprous cyanide are added under mechanical stirring, the temperature is raised to 135 ℃ for reaction for about 10 hours, and after the reaction is detected to be incomplete, the heating is continued; after the reaction is carried out for about 15 hours and the reaction is detected to be incomplete, heating is continued; after the reaction is carried out for about 25 hours and the reaction is not completed, observing that the color of the reaction system in the bottle is different, stopping the reaction and cooling to room temperature; similarly, 600g of a 12% aqueous ammonia solution was added, and 500ml of ethyl acetate was added to extract twice. The ethyl acetate phases were combined and washed twice with 200ml of 5% aqueous ammonia. Ethyl acetate was removed by rotary evaporator concentration to give 31.3g of the product in 43.1% yield. HNMR (solvent CDCl3; internal standard TMS): δ7.22 (s, 2H), δ2.18 (s, 6H).
Comparison of comparative example 1 with example 1/2 shows that: the feeding ratio of the reactants is within a set range, the yield and purity of the product are not greatly affected by reagent replacement and reasonable concentration change, but in the initial feeding Step1, the reaction temperature is lower than 140 ℃, the reaction time is greatly prolonged, the final raw material is not thoroughly converted, and the yield is low;
the synthesis method avoids the problems of the prior art that a short plate of the high-toxicity reagent acrylonitrile is relied on, a palladium catalyst with high price is not used, and importantly, impurities difficult to purify are not generated, so that the preparation method of the rilpivirine intermediate has the advantages of low cost and easiness in obtaining raw materials, simple process and the like; is a brand new synthesis method, and has objective yield and considerable purity.
The above is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that the present invention is described in detail with reference to the foregoing embodiments, and modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The synthesis method of the rilpivirine intermediate is characterized in that the intermediate is (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile, and the structural formula is as follows:
wherein the intermediate is synthesized by the following synthetic route:
2. the method for synthesizing a rilpivirine intermediate according to claim 1, further comprising the reaction steps of:
step1: under the protection of protective gas, adding raw material 4-bromo-2, 6-dimethylaniline and cuprous cyanide into an organic solvent, heating and then starting to react, cooling a reaction system to room temperature after the raw material is completely reacted, adding water, washing, extracting a product, and concentrating to obtain 4-cyano-2, 6-dimethylaniline;
step2, under the protection of protective gas, dissolving the 4-cyano-2, 6-dimethylaniline obtained in Step1 into a solvent, controlling the temperature and dropwise adding a toluene solution of DIBAL-H; after the tracking detection of the complete reaction of the raw materials, quenching the reaction liquid, extracting and concentrating to obtain a product, namely 4-amino-3, 5-dimethylbenzaldehyde;
step3, under the protection of protective gas, dissolving 4-amino-3, 5-dimethylbenzaldehyde obtained in Step2 and diethyl cyanomethylphosphate, controlling the temperature and dropwise adding a tetrahydrofuran solution of sodium methoxide; quenching the reaction liquid after the raw materials are reacted completely, extracting and concentrating to obtain 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile;
step4, dissolving the 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile obtained in Step3, heating to 60 ℃ and dropwise adding isopropanol hydrochloride solution, and after the dropwise adding is finished, carrying out heat preservation reaction until the reaction is finished; the reaction solution was filtered, and the cake was collected to give the hydrochloride salt of the product (E) -3- (4-amino-3, 5-dimethylphenyl) acrylonitrile.
3. The method for synthesizing a rilpivirine intermediate according to claim 2, characterized in that the organic solvent in Step1 comprises at least one of N, N-dimethylformamide or N-methylpyrrolidone, the molar ratio of 4-bromo-2, 6-dimethylaniline to cuprous cyanide is 1:2.0-1:2.5, and the temperature is raised to 140-150 ℃.
4. A method for synthesizing a rilpivirine intermediate according to claim 3 characterized in that in Step1, ammonia water is used as a water-washing agent to wash out copper ions and ethyl acetate is used as an extraction agent.
5. The method for synthesizing the rilpivirine intermediate according to claim 2, characterized in that the solvent in Step2 is anhydrous tetrahydrofuran, the molar ratio of 4-cyano-2, 6-dimethylaniline to DIBAL-H is 1:2.0-1:2.5, and the temperature is controlled to 0-10 ℃.
6. The method for synthesizing a rilpivirine intermediate according to claim 5, characterized in that the quenching agent is a dilute hydrochloric acid solution, the concentration of the dilute hydrochloric acid is 1-4N, and the extracting agent is methyl tertiary butyl ether.
7. The method for synthesizing the rilpivirine intermediate according to claim 2, characterized in that the solvent used for dissolving Step3 is anhydrous tetrahydrofuran, and the molar ratio of 4-amino-3, 5-dimethylbenzaldehyde to cyanomethyl diethyl phosphate is 1:1.1-1:1.5; the molar ratio of the 4-amino-3, 5-dimethylbenzaldehyde to the sodium methoxide is 1:3.0-1:4.0; controlling the temperature to 0-5 ℃.
8. The method for synthesizing the rilpivirine intermediate according to claim 7, characterized in that the quenching agent is a dilute hydrochloric acid solution, the concentration of the dilute hydrochloric acid is 1-4N, the extracting agent is ethyl acetate, and the obtained 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile has the structural formula ratio of trans: cis=5: 1.
9. the method for synthesizing the rilpivirine intermediate according to claim 2, characterized in that the solvent dissolved in Step4 is absolute ethyl alcohol, the molar ratio of the 3- (4-amino-3, 5-dimethylphenyl) acrylonitrile cis-trans isomer mixture to isopropanol hydrochloride is 1:1.1-1:1.5, the temperature is kept at 60-65 ℃, and the end point mark of the reaction is trans/(cis+trans) x100% = 98% -100%.
10. The method for synthesizing a rilpivirine intermediate according to claim 2, characterized in that the shielding gas of Step 1-3 comprises one of nitrogen or argon.
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