CN114426496A - Preparation method of benzophenone pharmaceutical intermediate - Google Patents
Preparation method of benzophenone pharmaceutical intermediate Download PDFInfo
- Publication number
- CN114426496A CN114426496A CN202210038399.7A CN202210038399A CN114426496A CN 114426496 A CN114426496 A CN 114426496A CN 202210038399 A CN202210038399 A CN 202210038399A CN 114426496 A CN114426496 A CN 114426496A
- Authority
- CN
- China
- Prior art keywords
- reaction
- benzophenone
- aniline
- temperature
- solution
- 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
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 239000012965 benzophenone Substances 0.000 title claims abstract description 19
- 239000012450 pharmaceutical intermediate Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 24
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims abstract description 17
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000543 intermediate Substances 0.000 claims abstract description 12
- KPHBPYVKMUFDIS-UHFFFAOYSA-N NC1=CC=CC=C1C=NC1=CC=C(F)C=C1 Chemical compound NC1=CC=CC=C1C=NC1=CC=C(F)C=C1 KPHBPYVKMUFDIS-UHFFFAOYSA-N 0.000 claims abstract description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 9
- AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 claims abstract description 8
- FFFXIQFESQNINT-UHFFFAOYSA-N (2-aminophenyl)-(4-fluorophenyl)methanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=C(F)C=C1 FFFXIQFESQNINT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 238000012544 monitoring process Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 239000002253 acid Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 239000012467 final product Substances 0.000 abstract description 2
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 238000007336 electrophilic substitution reaction Methods 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 5
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229960003296 pitavastatin calcium Drugs 0.000 description 3
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- AJICENVKEVJWIA-UHFFFAOYSA-N 1-nitro-2-(trichloromethyl)benzene Chemical compound [O-][N+](=O)C1=CC=CC=C1C(Cl)(Cl)Cl AJICENVKEVJWIA-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- HWPJEJBDGWNMRM-UHFFFAOYSA-N formyl isocyanate Chemical compound O=CN=C=O HWPJEJBDGWNMRM-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NBYVSCDYHOKNQJ-UHFFFAOYSA-N (4-fluorophenyl)-(2-nitrophenyl)methanone Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=C(F)C=C1 NBYVSCDYHOKNQJ-UHFFFAOYSA-N 0.000 description 1
- WIFSDCDETBPLOR-UHFFFAOYSA-N 2-aminobenzoic acid Chemical compound NC1=CC=CC=C1C(O)=O.NC1=CC=CC=C1C(O)=O WIFSDCDETBPLOR-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- PLAZTCDQAHEYBI-UHFFFAOYSA-N 2-nitrotoluene Chemical compound CC1=CC=CC=C1[N+]([O-])=O PLAZTCDQAHEYBI-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
Abstract
The invention discloses a preparation method of a benzophenone pharmaceutical intermediate, which comprises the following steps: a, performing aromatic electrophilic substitution reaction on aniline and p-fluorobenzonitrile in the presence of boron trichloride and anhydrous aluminum trichloride to obtain a reaction solution of 2- ((4-fluorophenyl) iminomethyl) aniline; and b, hydrolyzing the reaction liquid of the 2- ((4-fluorophenyl) iminomethyl) aniline under an acid condition to obtain a final product, namely the benzophenone medical intermediate 2-amino-4' -fluorobenzophenone. According to the preparation method of the benzophenone pharmaceutical intermediate, the starting raw materials in the preparation method are low in price and easy to obtain, the production cost is low, each specific step of the synthesis method is a conventional reaction, the operation is simple, and the yield is high; in addition, the synthesis steps are few, the production period is short, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, in particular to a preparation method of a benzophenone pharmaceutical intermediate.
Background
The benzophenone pharmaceutical intermediate is an important pharmaceutical intermediate, is mainly used for synthesizing the lipid-lowering drug pitavastatin calcium, and has a large application in the field of liquid crystal materials. As a third generation statin, pitavastatin calcium has a significant effect of reducing low density lipoprotein cholesterol (LDL-C), has a similar effect to atorvastatin but is stronger than other 5 statins, and is called "supertiin-super-strong statin". Pitavastatin calcium has good tolerance and safety, is marketed at present and enters the medical insurance catalogue. The benzophenone medical intermediate is used as a key intermediate, and the currently reported synthetic routes mainly comprise the following methods.
The method comprises the following steps: tetrahedron Letters,1993, vol.34, P8267-8270/Journal of Medicinal Chemistry,2007, vol.50, P1213-1221 respectively disclose the synthesis method of the intermediate, wherein anthranilic acid (anthranilic acid) is used as a raw material, P-toluenesulfonyl chloride is used for amino protection, then Friedel-crafts acylation reaction is carried out on the anthranilic acid and fluorobenzene, and finally deprotection is carried out to obtain the product. The process has longer steps, the raw materials are first-grade easy-to-prepare toxin tube products, the side reactions are more, the subsequent purification is difficult, and the yield is low and is only about 49 percent; the second method comprises the following steps: in the synthetic method disclosed in Journal of Organic Chemistry,1961, vol.26, P2239-2242/CN 16933, phthalic anhydride is used as an initial raw material, Friedel-crafts acylation reaction is firstly carried out on phthalic anhydride and fluorobenzene to synthesize P-fluorobenzoylbenzoic acid, acyl chloride is generated under the action of thionyl chloride, ammonia gas is introduced to obtain amide, and finally the final product is obtained through Hofmann degradation. The process has long steps and long production period, and can generate a large amount of acid water and acid gas (especially sulfur dioxide is not easy to be completely absorbed) in the reaction, thereby having serious environmental pollution and being not beneficial to industrial production. The third method comprises the following steps: journal of Medicinal Chemistry,2013, vol.56, P6434-6456/Organic Letters,2017, vol.19, P4476-4479 discloses another synthesis method, which comprises the steps of taking isatoic anhydride as a raw material, reacting with thionyl chloride to generate formyl isocyanate, carrying out Friedel-crafts acylation reaction on the formyl isocyanate and fluorobenzene, and finally carrying out deprotection to obtain a product. The second step of the process has more Friedel-crafts-acylation side reactions, the yield is only 44 percent lower, the market supply of raw materials is less, the price is higher, the integral cost is high, and the process is not suitable for industrial production. The method four comprises the following steps: in the synthesis method disclosed by Chemical and pharmaceutical Bulletin,1989, vol.37, P110-115/CN107652192, o-nitrobenzoic acid is used as a raw material, chloro-chloride is produced, Friedel-crafts acylation reaction is carried out on the chloro-benzoic acid and fluorobenzene, and finally nitro is reduced to obtain the product. In the process, anhydrous aluminum trichloride is used to generate a large amount of acid water and acid gas, so that the process is dangerous and waste and causes environmental pollution, Pd/C is used as a reducing agent, the cost is increased, in addition, the price of main raw materials is higher, the market supply is less, and the whole process is not beneficial to industrial amplification. The method five comprises the following steps: in the synthesis method disclosed in CN107673982, o-nitrotoluene is used as a raw material, chlorine is chlorinated to obtain o-nitrotrichlorotoluene, then Friedel-crafts reaction is performed with fluorobenzene under catalysis of lewis acid to obtain 2-nitro-4' fluorobenzophenone, and finally hydrogenation reduction is performed in the presence of palladium-carbon to obtain the product. The process uses chlorine chlorination (the first step), and hydrogenation reduction (the fourth step) belongs to the 15 dangerous process categories of the first major supervision of the national emergency administration; upgrading the preparation process; in addition, the intermediate o-nitrotrichlorotoluene (CAS: 10542-55-9) has strong lacrimation property, and the dried product has explosion hidden trouble, so that the industrial production is not easy to realize and has larger potential safety hazard.
The existing synthetic route mainly has the defects of long steps (at least 4 steps and more), high cost, low yield, high risk of process conditions and the like, so that the industrial production is difficult and potential safety hazards exist. Based on the above, in order to solve the disadvantages in the synthesis process, the application aims to provide a preparation method of benzophenone pharmaceutical intermediates, which has the advantages of few steps, low cost, safe and reliable process and industrial production prospect.
Disclosure of Invention
The preparation method of the benzophenone medical intermediate in the embodiment of the invention comprises the following steps:
step a, dissolving compound aniline and p-fluorobenzonitrile in toluene, reducing the internal temperature to 0 ℃, controlling the temperature below 5 ℃, dropping boron trichloride solution, adding anhydrous aluminum trichloride into a reaction system after the dropping is finished, heating to 100 ℃ and 110 ℃, carrying out TLC monitoring reaction for 12-15 hours, and cooling to room temperature after the reaction is finished to obtain a reaction solution of 2- ((4-fluorophenyl) iminomethyl) aniline;
and step b, adding 25-35% of hydrochloric acid into the reaction liquid of the 2- ((4-fluorophenyl) iminomethyl) aniline obtained in the previous step, heating to 75-85 ℃, keeping the temperature for reaction for 1-1.2 hours, cooling after the reaction is finished, adding 30% liquid alkali to adjust the pH value to be 7-8, adding dichloromethane for extraction, separating an organic layer, drying, filtering and concentrating to obtain a benzophenone medical intermediate 2-amino-4 ' -fluorobenzophenone crude product, and recrystallizing the 2-amino-4 ' -fluorobenzophenone crude product with ethanol to obtain an orange 2-amino-4 ' -fluorobenzophenone product.
According to some embodiments of the present invention, in the step a, the molar ratio of aniline, p-fluorobenzonitrile, boron trichloride and anhydrous aluminum trichloride is 1: 1.0-3.0: 1.0-3.0: 1.0-2.0; the boron trichloride solution is 1.0M boron trichloride/dichloromethane solution or 1.0M boron trichloride/xylene solution.
According to some embodiments of the present invention, in the step a, the reaction temperature is 110 ℃ and the reaction time is 12 hours.
According to some embodiments of the invention, in the step b, the reaction temperature is 75 ℃, the reaction time is 1.2 hours, and the concentration of hydrochloric acid is 35%.
Drawings
In order to more clearly illustrate the embodiments of the present invention, we will briefly introduce the drawings that need to be used in the embodiments, and the drawings described below are only exemplary illustrations of the present application.
Fig. 1 is a process scheme of a method for preparing benzophenone-based pharmaceutical intermediates according to an embodiment of the present invention.
Detailed Description
Reference will now be made in detail to the embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar chemical structures represent like or similar compounds throughout. The embodiments described below with reference to the accompanying drawings are illustrative and intended to explain the present invention and should not be construed as limiting the present invention.
The following describes the preparation method of the benzophenone-based pharmaceutical intermediate according to an embodiment of the present invention with reference to specific examples, and the solvents, reagents, raw materials and the like used in the present invention are all commercially available chemically pure or analytically pure products.
Example 1:
step a: synthesis of 2- ((4-fluorophenyl) iminomethyl) aniline
Weighing 27.7g of 1.0M boron trichloride/xylene solution, adding the solution into a reaction bottle, cooling to 0 ℃, dissolving 14.7g of aniline and 28.7g of p-fluorobenzonitrile into 180mL of toluene, controlling the temperature to be less than 5 ℃, dropwise adding the solution into the boron trichloride solution, controlling the temperature to be less than 10 ℃ after the dropwise adding, adding 23.2g of anhydrous aluminum trichloride into the reaction system in batches, heating to 110 ℃, carrying out heat preservation reaction for 12 hours, monitoring by TLC (PE: EA is 3:1), cooling to room temperature after the reaction is finished, and directly putting the mixture into the next step without aftertreatment.
Step b: synthesis of benzophenone pharmaceutical intermediates
Cooling the reaction liquid to 0 ℃, sequentially adding 10mL of water and 150mL of 25% hydrochloric acid, heating to 85 ℃, reacting for 1 hour, monitoring by TLC (PE: EA is 3:1), cooling after the reaction is finished, controlling the temperature to be less than 10 ℃, dropwise adding liquid caustic soda to adjust the pH to 7-8, adding 150mL of dichloromethane, extracting, standing, layering, extracting the water phase once by using 50mL of dichloromethane, combining the organic phase, drying by using anhydrous sodium sulfate, filtering, concentrating, removing the solvent to obtain a crude product, adding anhydrous ethanol into the crude product, and recrystallizing to obtain an orange solid (20.7g, the total yield is 60.9%).
Example 2:
step a: synthesis of 2- ((4-fluorophenyl) iminomethyl) aniline
Weighing 36.1g of 1.0M boron trichloride/xylene solution, adding the solution into a reaction bottle, cooling to 0 ℃, dissolving 14.7g of aniline and 38.2g of p-fluorobenzonitrile into 180mL of toluene, controlling the temperature to be less than 5 ℃, dropwise adding the solution into the boron trichloride solution, controlling the temperature to be less than 10 ℃ after the dropwise adding, adding 31.6g of anhydrous aluminum trichloride into the reaction system in batches, heating to 100 ℃, carrying out heat preservation reaction for 12 hours, monitoring by TLC (PE: EA is 3:1), cooling to room temperature after the reaction is finished, and directly putting the mixture into the next step without aftertreatment.
Step b: synthesis of benzophenone pharmaceutical intermediates
Cooling the reaction liquid to 0 ℃, sequentially adding 10mL of water and 120mL of 35% hydrochloric acid, heating to 75 ℃, reacting for 1.2 hours, monitoring by TLC (PE: EA is 3:1), cooling after the reaction is finished, controlling the temperature to be less than 10 ℃, dropwise adding liquid caustic soda to adjust the pH to 7-8, adding 150mL of dichloromethane for extraction, standing for layering, extracting an aqueous phase once by using 50mL of dichloromethane, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating to remove a solvent to obtain a crude product, adding anhydrous ethanol into the crude product, and recrystallizing to obtain an orange solid (21.2g, the total yield is 62.4%).
Example 3:
step a: synthesis of 2- ((4-fluorophenyl) iminomethyl) aniline
Weighing 27.7g of 1.0M boron trichloride/dichloromethane solution, adding the solution into a reaction bottle, cooling to 0 ℃, dissolving 14.7g of aniline and 28.7g of p-fluorobenzonitrile into 180mL of toluene, controlling the temperature to be less than 5 ℃, dropwise adding the solution into the boron trichloride solution, controlling the temperature to be less than 10 ℃ after dropwise adding, adding 23.2g of anhydrous aluminum trichloride into a reaction system, evaporating DCM under normal pressure, heating to 110 ℃, keeping the temperature for reaction for 15 hours, monitoring by TLC (PE: EA is 3:1), evaporating the reaction solvent after the reaction is finished, adding 150mL of ethyl acetate, cooling, dropwise adding 150mL of water, quenching and reacting, standing, separating liquid, extracting the water phase once by using 50mL of ethyl acetate, combining organic phases, drying, filtering, concentrating to obtain a crude product, and directly putting the crude product into the next step without refining.
Step b: synthesis of benzophenone pharmaceutical intermediates
Adding 10mL of water and 120mL of 35% hydrochloric acid into the product in sequence, heating to 85 ℃, reacting for 1 hour, monitoring by TLC (PE: EA is 3:1), cooling after the reaction is finished, controlling the temperature to be less than 10 ℃, dropwise adding liquid alkali to adjust the pH to be 7-8, adding 150mL of dichloromethane, extracting, standing, demixing, extracting the water phase once by 50mL of dichloromethane, combining the organic phase, drying by anhydrous sodium sulfate, filtering, concentrating, removing the solvent to obtain a crude product, adding anhydrous ethanol into the crude product, and recrystallizing to obtain an orange solid (19.1g, the total yield is 56.2%).
According to the preparation method of the benzophenone medicinal intermediate, the starting raw materials are cheap and easy to obtain in the market, the production cost is low, each step of the synthesis method is a conventional reaction, the operation is simple, the yield is high, the synthesis steps are few, the production period is short, the method is suitable for industrial large-scale production, and the industrial application prospect is good.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined and combined by one skilled in the art without being mutually inconsistent.
While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (4)
1. A preparation method of a benzophenone medical intermediate is characterized by comprising the following steps:
step a, dissolving compound aniline and p-fluorobenzonitrile in toluene, reducing the internal temperature to 0 ℃, controlling the temperature below 5 ℃, dropping boron trichloride solution, adding anhydrous aluminum trichloride into a reaction system after the dropping is finished, heating to 100 ℃ and 110 ℃, carrying out TLC monitoring reaction for 12-15 hours, and cooling to room temperature after the reaction is finished to obtain a reaction solution of 2- ((4-fluorophenyl) iminomethyl) aniline;
and step b, adding 25-35% of hydrochloric acid into the reaction liquid of the 2- ((4-fluorophenyl) iminomethyl) aniline obtained in the previous step, heating to 75-85 ℃, keeping the temperature for reaction for 1-1.2 hours, cooling after the reaction is finished, adding 30% liquid alkali to adjust the pH value to be 7-8, adding dichloromethane for extraction, separating an organic layer, drying, filtering and concentrating to obtain a benzophenone medical intermediate 2-amino-4 ' -fluorobenzophenone crude product, and recrystallizing the 2-amino-4 ' -fluorobenzophenone crude product with ethanol to obtain an orange 2-amino-4 ' -fluorobenzophenone product.
2. The method for preparing a benzophenone-type pharmaceutical intermediate according to claim 1, wherein in the step a, the molar ratio of aniline, p-fluorobenzonitrile, boron trichloride and anhydrous aluminum trichloride is 1: 1.0-3.0: 1.0-3.0: 1.0-2.0;
the boron trichloride solution is 1.0M boron trichloride/dichloromethane solution or 1.0M boron trichloride/xylene solution.
3. The process for preparing a benzophenone-type medicinal intermediate according to claim 1, wherein in the step a, the reaction temperature is 110 ℃ and the reaction time is 12 hours.
4. The process for producing a benzophenone-type medicinal intermediate according to claim 1, wherein in the step b, the reaction temperature is 75 ℃, the reaction time is 1.2 hours, and the concentration of hydrochloric acid is 35%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210038399.7A CN114426496A (en) | 2022-01-13 | 2022-01-13 | Preparation method of benzophenone pharmaceutical intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210038399.7A CN114426496A (en) | 2022-01-13 | 2022-01-13 | Preparation method of benzophenone pharmaceutical intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114426496A true CN114426496A (en) | 2022-05-03 |
Family
ID=81311742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210038399.7A Pending CN114426496A (en) | 2022-01-13 | 2022-01-13 | Preparation method of benzophenone pharmaceutical intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114426496A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4160784A (en) * | 1976-02-18 | 1979-07-10 | Shionogi & Co., Ltd. | Process for the production of o-aminophenyl ketone derivatives |
| JPS6019753A (en) * | 1983-07-13 | 1985-01-31 | Shionogi & Co Ltd | O-(monosubstituted amino)phenylimine compound and its preparation |
| US4579685A (en) * | 1983-08-11 | 1986-04-01 | Shionogi & Co., Ltd. | Process for preparing 1-substituted-1,4-benzodiazepine derivatives |
| CN103086899A (en) * | 2013-02-01 | 2013-05-08 | 黄河三角洲京博化工研究院有限公司 | Synthesizing method of 2-amino-4'-fluoro-benzophenone |
| CN107673982A (en) * | 2017-09-28 | 2018-02-09 | 安徽省庆云医药股份有限公司 | A kind of preparation method of the ＇ fluorine benzophenone of 2 amino 4 |
| CN108200760A (en) * | 2015-07-22 | 2018-06-22 | 英安塔制药有限公司 | Benzodiazepine * derivatives as RSV inhibitor |
| CN111386118A (en) * | 2017-09-29 | 2020-07-07 | 英安塔制药有限公司 | Combination pharmaceutical agents as RSV inhibitors |
-
2022
- 2022-01-13 CN CN202210038399.7A patent/CN114426496A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4160784A (en) * | 1976-02-18 | 1979-07-10 | Shionogi & Co., Ltd. | Process for the production of o-aminophenyl ketone derivatives |
| JPS6019753A (en) * | 1983-07-13 | 1985-01-31 | Shionogi & Co Ltd | O-(monosubstituted amino)phenylimine compound and its preparation |
| US4579685A (en) * | 1983-08-11 | 1986-04-01 | Shionogi & Co., Ltd. | Process for preparing 1-substituted-1,4-benzodiazepine derivatives |
| CN103086899A (en) * | 2013-02-01 | 2013-05-08 | 黄河三角洲京博化工研究院有限公司 | Synthesizing method of 2-amino-4'-fluoro-benzophenone |
| CN108200760A (en) * | 2015-07-22 | 2018-06-22 | 英安塔制药有限公司 | Benzodiazepine * derivatives as RSV inhibitor |
| CN107673982A (en) * | 2017-09-28 | 2018-02-09 | 安徽省庆云医药股份有限公司 | A kind of preparation method of the ＇ fluorine benzophenone of 2 amino 4 |
| CN111386118A (en) * | 2017-09-29 | 2020-07-07 | 英安塔制药有限公司 | Combination pharmaceutical agents as RSV inhibitors |
Non-Patent Citations (5)
| Title |
|---|
| ALEXANDER S. ANTONOV，等: "Ortho-ketimines of 1, 8-bis(dimethylamino)naphthalene: synthesis, hydrolytic stability and transfer of basicity from proton sponge moiety to the imino function", SYNTHESIS, vol. 46, no. 23, 26 August 2014 (2014-08-26), pages 3273 - 3282 * |
| CARLOS MATEOS，等: "Efficient and scalable synthesis of ketones via nucleophilic Grignard addition to nitriles using continuous flow chemistry", TETRAHEDRON LETTERS, vol. 54, no. 18, 1 May 2013 (2013-05-01), pages 2226 - 2230, XP028527036, DOI: 10.1016/j.tetlet.2013.02.069 * |
| JIN-JUN LIU，等: "Discovery of a Highly Potent, Orally Active Mitosis/Angiogenesis Inhibitor R1530 for the Treatment of Solid Tumors", ACS MEDICINAL CHEMISTRY LETTERS, vol. 04, no. 02, 15 January 2013 (2013-01-15), pages 259 - 263 * |
| VALERY A. OZERYANSKII，等: "Out-Basicity of 1, 8-bis(dimethylamino)naphthalene: the experimental and theoretical challenge", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 12, no. 15, 20 December 2013 (2013-12-20), pages 2360 - 2369 * |
| 石浜洋，等: "Synthesis of carbon-14-labeled prazepam", RADIOISOTOPES, vol. 27, no. 05, 31 May 1978 (1978-05-31), pages 235 - 240 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106810426B (en) | Method for synthesizing cannabidiol | |
| CN106083691B (en) | A kind of preparation method of arbidol HCl monohydrate | |
| EP3381888A1 (en) | Method of co-producing long chain amino acid and dibasic acid | |
| CN102548966B (en) | Method for synthesis of N-alkyl carbazole and derivatives thereof | |
| CN114040906A (en) | Novel preparation method of peramivir trihydrate and water system drying method thereof | |
| CN111333658A (en) | Preparation method of pemetrexed disodium hydrate | |
| CN110903248A (en) | Synthesis method of 5-chloro-4-aminopyridazine | |
| CN110563652B (en) | Intermediate compound, carbamazepine and derivatives thereof, and preparation method of oxcarbazepine and derivatives thereof | |
| US9102589B2 (en) | Reactive distillation process for preparation of acetaminophen | |
| CN114426496A (en) | Preparation method of benzophenone pharmaceutical intermediate | |
| CN102887902A (en) | Preparation process for synthesizing high-purity Pemedolac | |
| CN103086907A (en) | Aceclofenac preparation method | |
| CN110551052A (en) | Preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate | |
| CN115340481A (en) | Method for industrially producing deuterated medical intermediate by adopting immobilized nickel catalysis | |
| CN112125817A (en) | Synthesis method of tertiary amide compound | |
| CN111269168A (en) | Preparation method of arbidol intermediate | |
| CN101492412B (en) | Synthesis of carprofen | |
| CN111732534A (en) | Method for synthesizing 2-amino-5-chloropyridine under catalysis of microwave and Lewis acidic ionic liquid | |
| CN103709116A (en) | Preparation method for 4-(4-alkoxycarbonylamino)phenyl-3-morpholine | |
| CN115677456B (en) | Preparation method of cannabidiol | |
| WO2023058050A1 (en) | A process for preparation of pharmaceutically active compounds via selective nitro reduction reactions | |
| CN115108918B (en) | Preparation method of 3,3', 4' -tetraminobiphenyl | |
| CN112225700B (en) | Preparation method of atemezole | |
| CN114773316B (en) | Preparation method of 2- (2,6-dioxo-piperidine-3-yl) -5-fluoro-isoindole-1,3-diketone | |
| CN109535025B (en) | Preparation method of Evonib intermediate 3, 3-difluorocyclobutylamine hydrochloride |
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 |