CN114907234B - Preparation method of 2-fluoro-5-formylbenzonitrile - Google Patents
Preparation method of 2-fluoro-5-formylbenzonitrile Download PDFInfo
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- CN114907234B CN114907234B CN202210490885.2A CN202210490885A CN114907234B CN 114907234 B CN114907234 B CN 114907234B CN 202210490885 A CN202210490885 A CN 202210490885A CN 114907234 B CN114907234 B CN 114907234B
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- formylbenzonitrile
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- MOFRJTLODZILCR-UHFFFAOYSA-N 2-fluoro-5-formylbenzonitrile Chemical compound FC1=CC=C(C=O)C=C1C#N MOFRJTLODZILCR-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 18
- GDHXJNRAJRCGMX-UHFFFAOYSA-N 2-fluorobenzonitrile Chemical compound FC1=CC=CC=C1C#N GDHXJNRAJRCGMX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 150000004820 halides Chemical class 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- 230000002378 acidificating effect Effects 0.000 claims abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 229920002866 paraformaldehyde Polymers 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000008098 formaldehyde solution Substances 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 231100000331 toxic Toxicity 0.000 abstract description 5
- 230000002588 toxic effect Effects 0.000 abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000005893 bromination reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 4
- 229960000572 olaparib Drugs 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- CMAOLVNGLTWICC-UHFFFAOYSA-N 2-fluoro-5-methylbenzonitrile Chemical compound CC1=CC=C(F)C(C#N)=C1 CMAOLVNGLTWICC-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- MMFGGDVQLQQQRX-UHFFFAOYSA-N 5-bromo-2-fluorobenzaldehyde Chemical compound FC1=CC=C(Br)C=C1C=O MMFGGDVQLQQQRX-UHFFFAOYSA-N 0.000 description 1
- GYCNHFWRPJXTSB-UHFFFAOYSA-N 5-bromo-2-fluorobenzonitrile Chemical compound FC1=CC=C(Br)C=C1C#N GYCNHFWRPJXTSB-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000005935 Sulfuryl fluoride Substances 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Inorganic materials Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 1
- UAYWVJHJZHQCIE-UHFFFAOYSA-L Zinc iodide Inorganic materials I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229910001513 alkali metal bromide Inorganic materials 0.000 description 1
- 229910001514 alkali metal chloride Inorganic materials 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229910000423 chromium oxide Inorganic materials 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 2-fluoro-5-formylbenzonitrile, which comprises the following steps: s1: o-fluorobenzonitrile, aldehyde, halide and a catalyst react under an acidic condition to obtain an intermediate I; s2: hydrolyzing the intermediate I obtained in the step S1 to obtain an intermediate II; s3: oxidizing the intermediate II obtained in the step S2 to obtain a target product; wherein the intermediate I isThe intermediate II isThe target product is
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 2-fluoro-5-formylbenzonitrile.
Background
2-Fluoro-5-formylbenzonitrile is an important intermediate for the synthesis of olaparib (olaparib). Olaparib (Olaparib) is an inhibitor of poly ADPglycan polymerase (PARP) that preferentially kills cancer cells through defects in the tumor DNA repair pathway. After having been approved by the FDA for the treatment of advanced ovarian cancer and metastatic breast cancer in 2014, the FDA was approved for the treatment of adult patients with metastatic castration resistant prostate cancer in 2020. The 2-fluoro-5-formylbenzonitrile is used as an important intermediate of the medicine, and has higher economic value and synthetic significance.
At present, the main preparation methods of the 2-fluoro-5-formylbenzonitrile comprise the following two methods:
1. the patent WO201271684A1 and US2013224107A1 report that 4-fluorobenzaldehyde is taken as a raw material, and a target product is obtained through bromination and cyanidation two-step reaction:
The first bromination reaction requires the use of liquid bromine or fuming sulfuric acid. Liquid bromine belongs to a highly toxic and volatile and highly corrosive raw material, and fuming sulfuric acid has stronger corrosiveness and danger; the second step of cyanidation reaction needs to be carried out at high temperature, and cuprous cyanide belongs to a highly toxic substance. The whole route has higher requirements on equipment and personnel protection, the industrialized production is more limited, the production cost is high, and the three wastes are large.
2. The patent US20026339099B1 reports that the target product is obtained by using 2-fluoro-5-methylbenzonitrile as a raw material through two steps of bromination and hydrolysis:
The solvent carbon tetrachloride of the bromination reaction in the first step has high toxicity and damages the ozone layer, and the use is greatly limited; the selectivity of the reaction is poor and the yield is low. The second step of hydrolysis needs a large amount of acid, and the three wastes are large in amount and high in pollution.
3. The patent WO200420414A1 reports that 5-bromo-2-fluorobenzaldehyde is taken as a raw material to obtain a target product through condensation, rearrangement and addition reaction:
The first condensation reaction uses hydroxylamine hydrochloride to condense at room temperature, and the condition is milder; the sulfuryl fluoride required to be used in the second step of rearrangement belongs to highly toxic gas and has great harm to the environment; and thirdly, the target product is obtained by adding the 5-bromo-2-fluorobenzonitrile and N, N-dimethylformamide after reacting with the format reagent, and the yield is low. The production cost of the whole route is higher.
Disclosure of Invention
The purpose of the invention is that: overcomes the defects in the prior art and provides a preparation method of 2-fluoro-5-formylbenzonitrile with low cost and high yield.
In order to achieve the above object, the present invention adopts the following technical scheme:
a method for preparing 2-fluoro-5-formylbenzonitrile, comprising the following steps:
S1: o-fluorobenzonitrile, aldehyde, halide and a catalyst react under an acidic condition to obtain an intermediate I;
S2: hydrolyzing the intermediate I obtained in the step S1 to obtain an intermediate II;
s3: oxidizing the intermediate II obtained in the step S2 to obtain a target product;
Wherein the intermediate I is The intermediate II isThe target product is
Further, in step S1, the aldehyde is one of formaldehyde pure, methanol solution or paraformaldehyde.
Further, in step S1, the halide is alkali metal chloride, bromide or iodide.
Further, in step S1, the catalyst is zinc chloride, bromide or iodide.
Further, in the step S1, the acid is one of sulfuric acid, phosphoric acid, acetic acid or an organic acid.
Further, in step S2, the hydrolysis is performed in an alkaline aqueous solution, and the base is one of inorganic base or organic base such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, etc.
Further, in step S3, the oxidizing agent used in the oxidation reaction includes one of potassium permanganate, manganese dioxide, chromium oxide, sodium hypochlorite, calcium hypochlorite, and sodium chlorite.
Further, the reaction temperature of the steps S1, S2 and S3 is 0-100 ℃.
The technical scheme of the invention has the beneficial effects that:
Compared with other reported synthetic routes, the invention has the following advantages:
1. The main raw materials such as o-fluorobenzonitrile, paraformaldehyde, sodium carbonate, sodium hypochlorite and the like are common chemical raw materials in the market, and are low in cost, easy to obtain and wide in source.
2. The reaction condition is mild, and the whole route has no high temperature, high pressure or extremely toxic condition. The use of extremely toxic dangerous articles such as liquid bromine, cuprous cyanide and the like is avoided, the requirement on production equipment is low, and the industrial production is convenient.
3. The crude intermediate products in each step of the synthetic route are directly fed for the next reaction, and are refined and purified in the final step, so that the operation is simple and convenient, and the mass production cost is saved.
4. The reaction production efficiency of each step is high, the three wastes are less discharged, and compared with other synthetic routes, the method has obvious cost advantage.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications. Unless otherwise stated, the temperature is usually at room temperature, and in the present invention, the room temperature is 10 to 30 ℃.
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1: preparation of intermediate I
250G of concentrated sulfuric acid, 30g of paraformaldehyde, 60g of o-fluorobenzonitrile, 58.5g of sodium chloride and 6.8g of anhydrous zinc chloride are sequentially added into a 500ml bottle, and the mixture is stirred at room temperature for reaction. HPLC monitored the progress of the reaction until the starting material content was less than 5%. The reaction mixture was poured into 500g of an ice-water mixture and quenched, and extracted 2 times with 500ml of methylene chloride. The organic layer was washed with sodium carbonate solution and brine, and the solvent was concentrated under reduced pressure to give 76.3g of crude intermediate I in 90% yield.
Example 2: preparation of intermediate II
200Ml of water, 20g of sodium carbonate, 76.3g of crude intermediate I prepared in example 1 were successively charged into a 500ml bottle, heated to 90℃and reacted under stirring. HPLC monitored the progress of the reaction until the content of intermediate I was less than 3%. The reaction mixture was extracted with 500ml ethyl acetate 3 times, and the organic layer was concentrated under reduced pressure to give 64.2g of crude intermediate II in 85% yield.
Example 3: preparation of the target product 2-fluoro-5-formylbenzonitrile
Into a 1000ml bottle, 100ml of water, 100ml of methylene chloride, 10.2g of sodium bromide, 42g of sodium hydrogencarbonate and 64.2g of crude intermediate II obtained in example 2 were successively charged. Cooling and stirring in ice bath, adding 0.5g of 2, 6-tetramethylpiperidine oxide (TEMPO) at the temperature of 0-5 ℃, and dripping 430g of 8% sodium hypochlorite solution. The incubation reaction was completed for 2-3 hours and monitored by HPLC until the conversion of intermediate II was complete. The organic layer was separated and the aqueous layer was extracted with 500ml of dichloromethane in 2 portions. The organic layers were combined, the solvent was removed under reduced pressure, and the residue was recrystallized from toluene to give 47.5g of the desired product, 2-fluoro-5-formylbenzonitrile, with an HPLC purity of > 98% and a yield of 75%.
Example 4: preparation of intermediate I
400G of concentrated sulfuric acid, 200g of 30% formaldehyde solution, 121g of o-fluorobenzonitrile, 205g of sodium bromide and 20g of anhydrous zinc chloride are sequentially added into a 1000ml bottle, and the mixture is stirred at room temperature for reaction. HPLC monitored the progress of the reaction until the starting material content was less than 5%. The reaction mixture was poured into 800g of an ice-water mixture and quenched, and extracted 2 times with 1000ml of methylene chloride. The organic layer was washed with sodium carbonate solution and brine, and the solvent was concentrated under reduced pressure to give 193.8g of crude intermediate I.
Example 5: preparation of intermediate II
500Ml of water, 80g of sodium hydroxide, 193.8g of crude intermediate I prepared in example 4 were placed in a 1000ml bottle, heated to 80℃and reacted with stirring. HPLC monitored the progress of the reaction until the content of intermediate I was less than 3%. 1000ml of ethyl acetate is used for extracting the reaction liquid for 3 times, and the organic layer is decompressed and concentrated to obtain 138.9g of crude intermediate II with 92 percent of yield.
Example 6: preparation of the target product 2-fluoro-5-formylbenzonitrile
500Ml of methylene chloride was charged into a 1000ml bottle, 138.9g of crude intermediate II prepared in example 5 was stirred by cooling in a cold water bath. 200g of pyridinium chlorochromate was added in portions, the reaction was kept stirring at room temperature and monitored by HPLC until complete conversion of intermediate II. The reaction solution is filtered by suction, the filter cake is rinsed with 200ml of dichloromethane, the solvent is removed under reduced pressure, and the residue is recrystallized by toluene to obtain 84.7g of yellow solid, namely the target product 2-fluoro-5-formylbenzonitrile, the purity is more than 97%, and the yield is 65%.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of the invention should be assessed as that of the appended claims.
Claims (1)
1. A preparation method of 2-fluoro-5-formylbenzonitrile is characterized in that: the method comprises the following steps:
S1: o-fluorobenzonitrile, aldehyde, halide and a catalyst react under an acidic condition to obtain an intermediate I;
S2: hydrolyzing the intermediate I obtained in the step S1 to obtain an intermediate II;
s3: oxidizing the intermediate II obtained in the step S2 to obtain a target product;
Wherein the intermediate I is The intermediate II isThe target product is；
In step S1, the halide is sodium chloride; the aldehyde is paraformaldehyde or 30% formaldehyde solution, the acid is concentrated sulfuric acid,
In step S1, the catalyst is anhydrous zinc chloride;
in the step S2, the hydrolysis is carried out in an alkaline aqueous solution, wherein the alkali is one of sodium carbonate, potassium carbonate, sodium hydroxide and triethylamine;
in step S3, the oxidizing agent used in the oxidation reaction is sodium hypochlorite; x in the intermediate I is Cl,
The reaction temperature of the step S1, the step S2 and the step S3 is 0-100 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000078768A1 (en) * | 1999-06-23 | 2000-12-28 | Abbott Laboratories | Potassium channel openers |
| CN103880775A (en) * | 2012-12-21 | 2014-06-25 | 安徽省庆云医药化工有限公司 | Preparation methods of compound 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate and febuxostat |
| CN112745270A (en) * | 2020-12-30 | 2021-05-04 | 河北医科大学 | Novel compound and method for preparing topramezone intermediate by using same |
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| US10336707B2 (en) * | 2014-12-16 | 2019-07-02 | Eudendron S.R.L. | Heterocyclic derivatives modulating activity of certain protein kinases |
| CN109574951A (en) * | 2017-09-28 | 2019-04-05 | 安徽省庆云医药股份有限公司 | A kind of preparation method of Febuxostat |
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| WO2000078768A1 (en) * | 1999-06-23 | 2000-12-28 | Abbott Laboratories | Potassium channel openers |
| CN103880775A (en) * | 2012-12-21 | 2014-06-25 | 安徽省庆云医药化工有限公司 | Preparation methods of compound 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate and febuxostat |
| CN112745270A (en) * | 2020-12-30 | 2021-05-04 | 河北医科大学 | Novel compound and method for preparing topramezone intermediate by using same |
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