CN115819303A - Preparation method of compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile - Google Patents
Preparation method of compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile Download PDFInfo
- Publication number
- CN115819303A CN115819303A CN202211431147.7A CN202211431147A CN115819303A CN 115819303 A CN115819303 A CN 115819303A CN 202211431147 A CN202211431147 A CN 202211431147A CN 115819303 A CN115819303 A CN 115819303A
- Authority
- CN
- China
- Prior art keywords
- fluoro
- compound
- isothiocyanato
- temperature
- trifluoromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 33
- DGCPSFWIXDMEDU-UHFFFAOYSA-N 3-fluoro-4-isothiocyanato-2-(trifluoromethyl)benzonitrile Chemical compound FC1=C(N=C=S)C=CC(C#N)=C1C(F)(F)F DGCPSFWIXDMEDU-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 19
- YKPDYPPZLUZONK-UHFFFAOYSA-N 2-fluoro-3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1F YKPDYPPZLUZONK-UHFFFAOYSA-N 0.000 claims abstract description 16
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims abstract description 10
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- 238000006640 acetylation reaction Methods 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 230000021736 acetylation Effects 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 12
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- LBUKQBJGILQVMB-UHFFFAOYSA-N n-[2-fluoro-3-(trifluoromethyl)phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC(C(F)(F)F)=C1F LBUKQBJGILQVMB-UHFFFAOYSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- OWIGNTFYLJUGDK-UHFFFAOYSA-N 4-amino-3-fluoro-2-(trifluoromethyl)benzonitrile Chemical compound NC1=CC=C(C#N)C(C(F)(F)F)=C1F OWIGNTFYLJUGDK-UHFFFAOYSA-N 0.000 claims description 4
- QBOBULSXLGYQCV-UHFFFAOYSA-N n-[4-bromo-2-fluoro-3-(trifluoromethyl)phenyl]acetamide Chemical compound CC(=O)NC1=CC=C(Br)C(C(F)(F)F)=C1F QBOBULSXLGYQCV-UHFFFAOYSA-N 0.000 claims description 4
- NBBAHVPJDOIANU-UHFFFAOYSA-N n-[4-cyano-2-fluoro-3-(trifluoromethyl)phenyl]acetamide Chemical compound CC(=O)NC1=CC=C(C#N)C(C(F)(F)F)=C1F NBBAHVPJDOIANU-UHFFFAOYSA-N 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 6
- 229910052794 bromium Inorganic materials 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 5
- 230000000397 acetylating effect Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 28
- 239000000243 solution Substances 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 238000001914 filtration Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000012670 alkaline solution Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000002351 wastewater Substances 0.000 description 4
- 239000012267 brine Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- -1 thiocyanate compound Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile, which comprises the steps of acetylating 2-fluoro-3-trifluoromethyl aniline as a raw material to generate an amino protecting compound, then adding bromine on NBS, and finally reacting with cuprous cyanide, hydrochloric acid and thiophosgene to generate a target product.
Description
Technical Field
The invention relates to the technical field of medical intermediates, in particular to a preparation method of a compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile.
Background
The compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile is a common pharmaceutical and chemical intermediate, can be used for pharmaceutical synthesis for treating androgen receptor related diseases, and the thiocyanate compound has strong biological activity. Along with the continuous increase of market demand, a convenient, efficient and green process is particularly important.
The structural formula of the 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile is as follows:
the 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile is obtained by multi-step reaction of 2-fluoro-3-trifluoromethylaniline, the method has high preparation cost of the required raw materials and intermediates and low yield of the required intermediates, and can not meet the requirements of people on the antibiotic.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of a compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile; the preparation method reduces the amount of waste water, and improves the purity and yield of the required intermediate and target product.
The invention is realized by the following technical scheme:
a process for the preparation of the compound 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile, comprising:
step S1: 2-fluoro-3-trifluoromethylaniline as a starting material and an acetylation reagent are added into a first solvent at a temperature T 1 Time t 1 Reacting to obtain a compound B (N- (2-fluoro-3- (trifluoromethyl) phenyl) acetamide);
step S2: adding compound B and NBS to DMF at temperature T 2 Time t 2 Then reacting to obtain a compound C (N- (4-bromo-2-fluoro-3- (trifluoromethyl) phenyl) acetamide);
and step S3: adding the compound C and cuprous cyanide into DMF at temperature T 3 Time t 3 Then reacting to obtain a compound D (N- (4-cyano-2-fluoro-3- (trifluoromethyl) phenyl) acetamide);
and step S4: adding compound D and hydrochloric acid into ethanol solvent at temperature T 4 Lower reflux t 4 To obtain a compound E (4-amino-3-fluoro-2 (trifluoromethyl) benzonitrile);
step S5: adding the compound E and thiophosgene to tetrahydrofuran at a temperature T 5 Time t 5 Then the reaction is carried out to obtain a target product 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile;
the synthetic route of the preparation method is as follows:
further, the steps S1 to S5:
reaction temperature T 1 At a temperature of between 25 and 60 ℃ T 2 At a temperature of-10 ℃ to 30 ℃ T 3 At 130-160 ℃ and T 4 At 50-100 ℃ T 5 At 0 ℃ to 30 ℃ and T 1 Preferably 40 ℃ T 2 Preferably-10 ℃ to-5 ℃, T 3 Preferably 145-150 ℃, T 4 Preferably 75-80 ℃ and T 5 Preferably from 0 ℃ to 5 ℃.
Further, the steps S1 to S5:
reaction time t 1 Is 1.5 to 4 hours 2 Is 1h to 5h 3 Is 4h to 8h, t 4 Is 0.5 to 3h, t 5 0.5 to 3 hours, t thereof 1 Preferably 2h,t 2 Preferably 2h,t 3 Preferably 5h,t 4 Preferably 1h,t 5 Preferably 0.5h.
Further, the acetylation reagent in step S1 is one of acetyl chloride and acetic anhydride, preferably acetic anhydride
Further, the first solvent in step S1 is one of acetic acid, tetrahydrofuran and dichloromethane, preferably dichloromethane
Further, the step S1: the molar ratio of the 2-fluoro-3-trifluoromethylaniline to the acetylation reagent is 1: 1-2, preferably 1: 1.1
Further, the step S1: the volume ratio of the 2-fluoro-3-trifluoromethylaniline to the first solvent is 1: 1-10, preferably 1: 5
Further, the organic solvent in the step S1 is ethyl acetate, methyl tert-butyl ether, dichloromethane, or diethyl ether, preferably dichloromethane.
Furthermore, the molar ratio of the compound B to the NBS in the step S2 is 1: 1 to 1.1, preferably 1: 1.01.
Furthermore, the volume ratio of the compound B in the step S2 to DMF is 1: 5-20, preferably 1: 5.
Further, the molar ratio of the compound C in the step S3 to the cuprous cyanide is 1: 1-5, preferably 1: 1.1;
furthermore, the volume ratio of the compound C in the step S3 to DMF is 1: 1 (1-10), preferably 1: 1.
Furthermore, the volume ratio of the compound D in the step S4 to the concentrated hydrochloric acid and the ethanol is 1: 0.4-0.5: 1-5, and preferably 1: 0.5: 3.
Further, the molar ratio of the compound E and the thiophosgene in the step S5 is 1: 2-5, preferably 1: 2.5.
Furthermore, the volume ratio of the compound E and the tetrahydrofuran in the step S5 is 1: 3-10, and preferably 1: 5.
Further, the step S1 specifically includes the following steps:
2-fluoro-3-trifluoromethylaniline as a starting material and an acetylation reagent are added into a first solvent at a temperature T 1 Time t 1 And (3) reacting, after the reaction is finished, adding an alkaline solution for neutralization, adding an organic solvent for extraction, and then filtering and concentrating to obtain a compound B (N- (2-fluoro-3- (trifluoromethyl) phenyl) acetamide).
Further, the alkaline solution in the above step is one of sodium hydroxide solution, sodium carbonate solution and sodium bicarbonate solution, preferably sodium bicarbonate solution.
Further, the pH value of the alkaline solution neutralization in the above step is 7 to 10, preferably 7 to 8.
Compared with the prior art, the synthesis process has the advantages that the 2-fluoro-3-trifluoromethyl aniline is firstly acetylated for amino protection; adding bromine into NBS solution containing DMF; finally, the target product is generated by reacting with cuprous cyanide, hydrochloric acid and thiophosgene, on one hand, the preparation method reduces the residual DMF of the raw materials in the acetylation reaction, reduces the generation of wastewater, simplifies the post-treatment operation steps, and improves the yield and the purity of the needed intermediate and the target product; on the other hand, the green and efficient post-treatment process improves the material utilization rate, reduces the cost and is convenient for industrial application.
Drawings
FIG. 1 is a HPLC plot corresponding to intermediate B in an example of the present invention;
FIG. 2 is a HPLC plot corresponding to intermediate C in an example of the present invention;
FIG. 3 is a HPLC plot corresponding to intermediate D in the examples of the present invention;
FIG. 4 is a HPLC plot corresponding to intermediate E in an example of the present invention;
FIG. 5 is a HPLC plot corresponding to intermediate F in an example of the present invention;
FIG. 6 is a LCMS plot corresponding to intermediate F in an example of the invention;
FIG. 7 shows a diagram of the intermediate F in the present example 1 HNMR graph.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, so that those skilled in the art can fully understand the technical contents of the present invention. It should be understood that the following examples are intended to further illustrate the present invention and should not be construed as limiting the scope of the present invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art based on the foregoing description are intended to be covered by the present invention. The following exemplified specific preparation process parameters and the like are also only one example of suitable ranges, that is, those skilled in the art can select them within suitable ranges by the description herein, and are not limited to the specific values exemplified below.
The invention is realized by the following technical scheme:
a process for the preparation of the compound 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile, comprising:
step S1: 2-fluoro-3-trifluoromethylaniline as a starting material and an acetylation reagent are added into a first solvent at a temperature T 1 Time t 1 After the reaction is finished, adding an alkaline solution for neutralization, adding an organic solvent for extraction, and then filtering and concentrating to obtain a compound B [ N- (2-fluoro-3- (trifluoromethyl) phenyl) acetamide]；
Step S2: adding compound B and NBS to DMF at temperature T 2 Time t 2 Then the reaction is carried out to obtain a compound C [ N- (4-bromo-2-fluoro-3- (trifluoromethyl) phenyl) acetamide]；
And step S3: adding compound C and cuprous cyanide into DMF at temperature T 3 Time t 3 Then the reaction is carried out to obtain a compound D [ N- (4-cyano-2-fluoro-3- (trifluoromethyl) phenyl) acetamide]；
And step S4: adding the compound D and hydrochloric acid into an ethanol solvent at a temperature T 4 Lower reflux t 4 To obtain a compound E [ 4-amino-3-fluoro-2 (trifluoromethyl) benzonitrile]；
Step S5: adding the compound E and thiophosgene to tetrahydrofuran at a temperature T 5 Time t 5 Then the reaction is carried out to obtain a target product 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile;
the synthetic route of the preparation method is as follows:
further, the steps S1 to S5:
reaction temperature T 1 At a temperature of 25-60 ℃ and T 2 At a temperature of-10 ℃ to 30 ℃ T 3 At 130-160 ℃ and T 4 At 50-100 ℃ T 5 At 0 ℃ to 30 ℃ and T 1 Preferably 40 ℃ T 2 Preferably-10 ℃ to-5 ℃, T 3 Preferably 145-150 ℃, T 4 Preferably 75-80 ℃ and T 5 Preferably 0 to 5 ℃;
reaction time t 1 Is 1.5 to 4 hours 2 Is 1h to 5h 3 Is 4h to 8h, t 4 Is 0.5 to 3h, t 5 0.5 to 3 hours, t thereof 1 Preferably 2h,t 2 Preferably 2h,t 3 Preferably 5h,t 4 Preferably 1h,t 5 Preferably 0.5h.
Further, the acetylation reagent in the step S1 is one of acetyl chloride and acetic anhydride, preferably acetic anhydride
Further, the first solvent in step S1 is one of acetic acid, tetrahydrofuran and dichloromethane, preferably dichloromethane
Further, the step S1: the molar ratio of the 2-fluoro-3-trifluoromethylaniline to the acetylation reagent is 1: 1-2, preferably 1: 1.1
Further, the step S1: the volume ratio of the 2-fluoro-3-trifluoromethylaniline to the first solvent is 1: 1-10, preferably 1: 5
Further, the alkaline solution in step S1 is one of a sodium hydroxide solution, a sodium carbonate solution and a sodium bicarbonate solution, and preferably a sodium bicarbonate solution.
Further, the pH of the alkaline solution neutralization in the step S1 is 7 to 10, preferably 7 to 8.
Further, the organic solvent in the step S1 is ethyl acetate, methyl tert-butyl ether, dichloromethane, or diethyl ether, preferably dichloromethane.
Further, the molar ratio of the compound B to NBS in the step S2 is 1: 1 (1-1.1), preferably 1: 1.01.
Furthermore, the volume ratio of the compound B in the step S2 to DMF is 1: 5 to 20, and preferably 1: 5.
Further, the molar ratio of the compound C in the step S3 to the cuprous cyanide is 1: 1 to 5, preferably 1: 1.1;
furthermore, the volume ratio of the compound C in the step S3 to DMF is 1: 1 (1-10), and preferably 1: 1.
Furthermore, the volume ratio of the compound D in the step S4 to the concentrated hydrochloric acid and the ethanol is 1: 0.4-0.5: 1-5, and preferably 1: 0.5: 3.
Further, the molar ratio of the compound E and the thiophosgene in the step S5 is 1: 2-5, preferably 1: 2.5.
Further, the volume ratio of the compound E and the tetrahydrofuran in the step S5 is 1: 3-10, preferably 1: 5.
1. The synthesis process of the invention comprises acetylation, wherein the acetylation reaction is commonly used for protecting amino on an aromatic ring from being damaged by a reaction reagent in organic synthesis, and after the amino is subjected to acetylation protection, although the positioning effect is not changed, the activation capability of the amino on the aromatic ring is reduced, so that the reaction is changed from multi-element substitution into useful monobasic substitution; adding bromine into an NBS solution containing DMF, wherein the NBS generates bromine free radical to complete chain initiation under the action of illumination, so as to provide bromine free radicals for reaction, and the bromine free radicals and the raw materials generate nucleophilic substitution; finally, the target product is generated by the reaction of the raw materials with cuprous cyanide, hydrochloric acid and thiophosgene, the process sequence reduces the residual DMF in the raw materials in the acetylation reaction, reduces the generation of waste water, and improves the yield and the purity of the needed intermediate and the target product;
2. the synthesis process of the step S1 of the invention takes 2-fluoro-3-trifluoromethylaniline as a starting material and an acetylation reagent to be added into a first solvent to react at the temperature of 25-60 ℃ for 1.5-4 h, and after the reaction is finished, an alkaline solution is added in the post-treatment process to neutralize and adjust the pH value so as to neutralize excessive acid, reduce the generation of acidic wastewater and reduce the pollution to the environment; then adding an organic solvent dichloromethane for extraction, filtering impurities, and distilling and recovering redundant dichloromethane conveniently, so that the utilization rate of the dichloromethane can be improved, and the cost is reduced;
3. by combining the steps S1 to S5 and the post-treatment process distillation recovery process of the embodiment of the invention, the solvents comprise dichloromethane, ethyl acetate, ethanol and tetrahydrofuran, the solvent utilization rate is improved, the cost is reduced, and the batch size is enlarged.
The following examples are presented to further illustrate and describe the concepts of the present invention and are not meant to limit the invention to the specific embodiments described below. Any specific numerical value, which is within the scope of the invention, may be practiced in the examples.
Step S1 preparation of intermediate B [ N- (2-fluoro-3- (trifluoromethyl) phenyl) acetamide ]
Example 1
100g of 2-fluoro-3-trifluoromethylaniline and 62.7g of acetic anhydride were added to 500ml of DCM at room temperature. Heated and stirred at reflux for 2 hours. Reaction feed was monitored by HPLC < 0.2%. Then the temperature is reduced in an ice bath, and an ice sodium bicarbonate solution is poured in. The layers were separated and the aqueous layer was extracted 2 times with DCM. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave 100g of a white solid in 81% yield, see FIG. 1: HPLC purity 99.7%.
Example 2:
100g of 2-fluoro-3-trifluoromethylaniline and 85.5g of acetic anhydride were added to 500ml of DCM at room temperature. Heated and refluxed for 2 hours. Reaction feed was monitored by HPLC < 0.2%. Then cooled in ice bath and poured into ice sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted 2 times with DCM. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave 105g of intermediate B in 85% yield and 99.5% purity.
Step S2 preparation of intermediate C [ N- (4-bromo-2-fluoro-3- (trifluoromethyl) phenyl) acetamide ]
Example 1:
100g of intermediate B are added to 200ml of DMF and stirred at room temperature under nitrogen. 81.3g NBS was dissolved in 300ml DMF. The DMF solution of NBS was added dropwise to the reaction flask at-10- -5 ℃. After the dripping is finished, the temperature is kept for reaction for 2h. The reaction was monitored by HPLC with less than 0.5% starting material remaining. The reaction was quenched by adding 2000ml of ice water. Extraction was performed with methyl tert-ether (500ml. Times.3), and the organic phase was washed with sodium bicarbonate solution, sodium chloride solution, and dried by adding anhydrous sodium sulfate. Filtration and concentration of the organic phase gave 130g of intermediate C in 95.8% yield, see fig. 2: HPLC purity 98%.
Example 2:
100g of intermediate B are added to 200ml of DMF and stirred at room temperature under nitrogen. 84.5g NBS was dissolved in 300ml DMF. The DMF solution of NBS was added dropwise to the reaction flask at-10- -5 ℃. After the dripping is finished, the reaction is kept for 2 hours. The reaction was monitored by HPLC with less than 0.5% starting material remaining. The reaction was quenched by adding 2000ml of ice water. Extraction with methyl tert-ether (500ml. X.3), washing of the organic phase with sodium bicarbonate solution, sodium chloride solution, drying by addition of anhydrous sodium sulfate. Filtration and concentration of the organic phase gave 128g of intermediate C in 94.3% yield and 95% purity.
Step S3 preparation of intermediate D [ N- (4-cyano-2-fluoro-3- (trifluoromethyl) phenyl) acetamide ]
The embodiment is as follows:
100g of intermediate C, 32.9g of CuCN were added to 100ml of DMF under nitrogen protection. Heating and stirring for 5h at the temperature of 145-150 ℃. The reaction was monitored by HPLC and starting material < 0.2%. The reaction mixture was cooled to room temperature and then slowly poured into ice water. Ethyl acetate was added and stirred for 0.5h. Filter and wash the filter cake with hot ethyl acetate. Separating the filtrate, and using NaHCO for organic phase 3 Washed with aqueous solution and brine, over Na 2 SO 4 And (5) drying. Filtration and concentration in vacuo afforded 73g of intermediate D, 89.5% yield, see figure 3: HPLC purity 99.9%.
Step S4 preparation of intermediate E [ 4-amino-3-fluoro-2 (trifluoromethyl) benzonitrile ]
Example (b):
100g of intermediate D were added to 300ml of EtOH solution and 50ml of concentrated HCl solution were added. The mixture was heated under reflux for l hours. The reaction was monitored by HPLC and starting material was < 0.2%. Cooling to room temperature, and concentrating under reduced pressure to remove ethanol. 500ml of ethyl acetate was added thereto and dissolved by stirring. With saturated NaHCO 3 Washing with aqueous solution and aqueous sodium chloride solution, and purifying with Na 2 SO 4 And (5) drying. Concentration gave 81g of intermediate E in 98% yield, see fig. 4: HPLC purity 99.9%.
Step S5 preparation of Compound 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile
Example (b):
50g of intermediate E and 75ml of water are added to 250ml of THF, and the temperature is reduced in an ice bathTo 0-5 ℃. 70.4g of thiophosgene is added dropwise under the temperature controlled below 10 ℃. After the addition, the reaction is carried out for 0.5h under the condition of heat preservation. Reaction feed monitored by HPLC < 0.5%. THF was concentrated under reduced pressure and extracted with DCM (250ml × 2). The organic phase is washed with sodium chloride solution and dried by addition of anhydrous sodium sulfate. Filtration and concentration of the organic phase gave a yellow oily liquid. Column purification (PE/DCM = 10: 1-5: 1) gave 58g of 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile in 96.1% yield, with reference to FIG. 5: HPLC purity 99.58%, refer to fig. 6: LCMS nuclear to cytoplasmic ratio 247.1, see fig. 7: 1 HNMR(400MHz，CDCl 3 )δ7.62(s，1H)，δ7.47(s，1H)。
it should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. A preparation method of a compound 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile is characterized by comprising the following steps:
step S1: 2-fluoro-3-trifluoromethylaniline and an acetylation reagent are added into a first solvent at a temperature T 1 Time t 1 Then reacting to obtain a compound B [ N- (2-fluoro-3- (trifluoromethyl) phenyl) acetamide]；
Step S2: adding compound B and NBS to DMF at temperature T 2 Time t 2 Then the reaction is carried out to obtain a compound C [ N- (4-bromo-2-fluoro-3- (trifluoromethyl) phenyl) acetamide]；
And step S3: adding compound C and cuprous cyanide into DMF at temperature T 3 Time t 3 Then the reaction is carried out to obtain a compound D [ N- (4-cyano-2-fluoro-3- (trifluoromethyl) phenyl) acetamide]：
And step S4: adding compound D and hydrochloric acid into ethanol solvent at temperature T 4 Lower reflux t 4 To obtain a compound E [ 4-amino-3-fluoro-2 (trifluoromethyl) benzonitrile]；
Step S5: the compound E is subjected to sulfhydrationGas is added to tetrahydrofuran at a temperature T 5 Time t 5 Then the reaction is carried out to obtain a target product 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile;
the synthetic route of the preparation method is as follows:
2. the process for producing 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile according to claim 1, wherein the steps S1 to S5:
reaction temperature T 1 At a temperature of 25-60 ℃ and T 2 At a temperature of-10 ℃ to 30 ℃ T 3 At 130-160 ℃ and T 4 At 50-100 ℃ T 5 Is 0 to 30 ℃.
3. The process for producing 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile according to claim 1, wherein the steps S1 to S5:
reaction time t 1 Is 1.5 to 4 hours 2 Is 1h to 5h 3 Is 4h to 8h, t 4 Is 0.5 to 3h, t 5 Is 0.5 to 3 hours.
4. The process for producing 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile according to claim 1, wherein the step S1:
the acetylation reagent is one of acetyl chloride and acetic anhydride;
the first solvent is one of acetic acid, tetrahydrofuran and dichloromethane.
5. The process for producing 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile according to claim 1, wherein the step S1:
the molar ratio of the 2-fluoro-3-trifluoromethylaniline to the acetylation reagent is 1: 1-2:
the volume ratio of the 2-fluoro-3-trifluoromethyl aniline to the first solvent is 1: 1-10.
6. The method of claim 1, wherein the organic solvent used in step S1 is one of ethyl acetate, methyl tert-butyl ether, dichloromethane, and diethyl ether.
7. The process for preparing 3 fluoro 4 isothiocyanato 2 trifluoromethylbenzonitrile of claim 1, wherein the step S2:
the mol ratio of the compound B to the NBS is 1: 1-1.1;
the volume ratio of the compound B to DMF is 1: 5-20.
8. The process for producing 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile according to claim 1, wherein the step S3:
the molar ratio of the compound C to the cuprous cyanide is 1: 1-5;
the volume ratio of the compound C to DMF is 1: 1-10.
9. The method of claim 1, wherein the volume ratio of the compound D of step S4 to the concentrated hydrochloric acid and ethanol is 1: 0.4-0.5: 1-5.
10. The process for producing 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile according to claim 1, wherein the step S5:
the molar ratio of the compound E to the thiophosgene is 1: 2-5;
the volume ratio of the compound E to the tetrahydrofuran is 1: 3-10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211431147.7A CN115819303A (en) | 2022-11-15 | 2022-11-15 | Preparation method of compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211431147.7A CN115819303A (en) | 2022-11-15 | 2022-11-15 | Preparation method of compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115819303A true CN115819303A (en) | 2023-03-21 |
Family
ID=85528310
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211431147.7A Pending CN115819303A (en) | 2022-11-15 | 2022-11-15 | Preparation method of compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115819303A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102482230A (en) * | 2009-09-10 | 2012-05-30 | 童友之 | Androgen receptor antagonists and uses thereof |
| CN103608333A (en) * | 2011-03-10 | 2014-02-26 | 苏州开拓药业有限公司 | Androgen receptor antagonists and uses thereof |
| CN107400073A (en) * | 2017-08-31 | 2017-11-28 | 武汉工程大学 | A kind of 4 isothiocyanos 2（Trifluoromethyl）The synthetic method of benzonitrile |
| WO2022123310A1 (en) * | 2020-12-11 | 2022-06-16 | Ildong Pharmaceutical Co., Ltd. | Novel compounds as androgen receptor and phosphodiesterase dual inhibitor |
-
2022
- 2022-11-15 CN CN202211431147.7A patent/CN115819303A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102482230A (en) * | 2009-09-10 | 2012-05-30 | 童友之 | Androgen receptor antagonists and uses thereof |
| CN103608333A (en) * | 2011-03-10 | 2014-02-26 | 苏州开拓药业有限公司 | Androgen receptor antagonists and uses thereof |
| CN107400073A (en) * | 2017-08-31 | 2017-11-28 | 武汉工程大学 | A kind of 4 isothiocyanos 2（Trifluoromethyl）The synthetic method of benzonitrile |
| WO2022123310A1 (en) * | 2020-12-11 | 2022-06-16 | Ildong Pharmaceutical Co., Ltd. | Novel compounds as androgen receptor and phosphodiesterase dual inhibitor |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106866553A (en) | A kind of synthetic method of Favipiravir | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| KR20170016754A (en) | New method for preparation of chromanone derivatives | |
| JP2964041B2 (en) | Novel process for producing phenyl-1-diethylaminocarbonyl-1-phthalimidomethyl-2-cyclopropane Z | |
| EP1377544B2 (en) | Purification of 2-nitro-4-methylsulphonylbenzoic acid | |
| CN109503513B (en) | One-pot synthesis method of febuxostat intermediate | |
| CN111116591A (en) | Method for preparing sildenafil citrate | |
| CN108864084B (en) | Apixaban related substances and preparation method thereof | |
| CN111099975A (en) | Preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone | |
| CN115819303A (en) | Preparation method of compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile | |
| CN111072656B (en) | Praziquantel synthesis method | |
| KR101894091B1 (en) | New method for preparation of chromanone derivatives | |
| CN111018833B (en) | Apixaban intermediate and preparation method thereof | |
| CN113861167A (en) | Preparation method of Voranolan fumarate | |
| CN111233835A (en) | Preparation and purification method of 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde | |
| CN111269149A (en) | Production process of 5- (3,3-dimethylguanidino) -2-oxopentanoic acid | |
| CN112125844B (en) | Synthetic method of 3, 7-dichloro-8-quinolinecarbonyl chloride | |
| CN113773235B (en) | Synthesis method of clorsulon | |
| CN109320472B (en) | Preparation method of 3, 4-dichloro 5-cyanoisothiazole | |
| CN111039838B (en) | Preparation method of 3-acetylmercapto-2-methylpropanoic acid | |
| CN114163362B (en) | Preparation method of N-benzenesulfonyl-4-halo-2-nitroaniline | |
| CN109369618B (en) | Method for preparing 2-chloro-5- ((2- (nitromethylene) imidazoline-1-yl) methyl) pyridine in one pot | |
| CN108358866A (en) | A kind of preparation method of Febustat intermediate and its application in preparing Febustat | |
| CN110452097B (en) | Preparation method of 1-hydroxypyrene | |
| JP2002255954A (en) | METHOD FOR PRODUCING 2-n-BUTYL-5-NITROBENZOFURAN |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |