WO2020147803A1 - 3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成 - Google Patents

3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成 Download PDF

Info

Publication number
WO2020147803A1
WO2020147803A1 PCT/CN2020/072582 CN2020072582W WO2020147803A1 WO 2020147803 A1 WO2020147803 A1 WO 2020147803A1 CN 2020072582 W CN2020072582 W CN 2020072582W WO 2020147803 A1 WO2020147803 A1 WO 2020147803A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
compound
reagent
sodium
solvent
Prior art date
Application number
PCT/CN2020/072582
Other languages
English (en)
French (fr)
Inventor
史东方
傅长金
顾杰
张敏
龚维伟
李鹏飞
Original Assignee
江苏新元素医药科技有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 江苏新元素医药科技有限公司 filed Critical 江苏新元素医药科技有限公司
Priority to US17/310,123 priority Critical patent/US20220041593A1/en
Priority to KR1020217026328A priority patent/KR102674919B1/ko
Priority to JP2021541467A priority patent/JP7237385B2/ja
Priority to EP20740931.9A priority patent/EP3915984B1/en
Publication of WO2020147803A1 publication Critical patent/WO2020147803A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a method for synthesizing the compound 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile.
  • Gout is a chronic metabolic disease caused by hyperuricemia (Hyper-uricemia) caused by purine metabolism disorder and/or uric acid excretion disorder in the human body.
  • hyperuricemia Hemo-uricemia
  • purine metabolism disorder and/or uric acid excretion disorder in the human body The severe pain caused by the deposition of urate in joints and other parts is the Main features.
  • urate When the serum uric acid level in the body exceeds 6.8mg/dL, urate will deposit monosodium urate crystals in the synovial fluid of human tissues, the cartilage of peripheral joints, the pinna of the ear and the olecranon sac of the elbow. When there are such symptoms, it can be diagnosed as gout.
  • URAT1 plays an important role in the process of reabsorption of uric acid from the cell to the lumen of the renal tubules. It is the main uric acid reabsorption protein in the human body and controls more than 90% of the reabsorption of uric acid after glomerular filtration. Therefore, inhibiting the transport of URAT1 can reduce the reabsorption of uric acid, promote the excretion of uric acid in the kidney, and achieve the effect of reducing the blood uric acid level in the body.
  • 3-Bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile is a kind of uric acid that has the ability to inhibit the transport of uric acid in URAT1, and it can also significantly increase the body's Uric acid excretion;
  • Candidate drugs that can reduce the toxicity to normal liver cells to prevent or treat hyperuricemia, kidney disease or gout.
  • the purpose of the present invention is to provide a method for synthesizing (2-ethylimidazolpyridin-3-yl)(phenyl)methanone compound in view of the deficiencies in the prior art.
  • Another object of the present invention is to provide a 3-bromo-5-(2-ethylimidazo[1,2-a] in view of the harsh reaction conditions, low yield, and immature synthetic route in the existing process ] Pyridine-3-carbonyl)-2-hydroxybenzonitrile synthesis method, the method is easy to operate, mild conditions, high yield, suitable for industrial production.
  • Step B The compound of formula (I), the compound of formula (II) and the base are heated in an organic solvent to react, and the resulting reaction product is heated in the presence of water to continue the reaction to obtain the compound of formula (III);
  • R 1 is H or C 1-3 alkyl
  • R 2 is H, -CN, I or Br
  • R 3 is H, I or Br
  • R 4 is Cl, Br or I.
  • the synthesis reaction of the compound of formula (III) is divided into two stages. First, the two substrates are reacted for a period of time under heating in an organic solvent, and then heated in the presence of water to continue the reaction. In the first and/or second stage Adding alkali in the stage, we found that using this method of alkali addition and two-step reaction can greatly promote the conversion of intermediate products generated in the reaction to the target product, reduce and avoid the generation of by-products, and greatly increase the yield of the target product .
  • step B alkali is required to be added.
  • alkali may be added continuously or not. Both methods are within the protection scope of the present application.
  • step A the amount of alkali added is such that the pH value of the reaction solution that continues to react reaches 4-7; in step B, the amount of alkali added is moles of the compound of formula (II) 0.1 to 2.5 times the amount, preferably 0.5 to 2.5 times, preferably 0.6 to 1.5 times, more preferably 0.8 to 1.2 times.
  • step (2) is: halogenation reaction of 4-methoxyacetophenone with iodination reagent or bromination reagent under acidic conditions at 5 ⁇ 25°C to obtain compound V; Or halogenation reaction with chlorinating reagent, iodinating reagent or brominating reagent under non-acidic conditions at 5 to 60°C to obtain compound VI.
  • different reaction temperatures can be used.
  • halogenation reaction temperature can be controlled at 30 ⁇ 60°C, such as chlorinating reagents.
  • the halogenation reaction temperature can be controlled at 5 ⁇ 60°C.
  • acidic or non-acidic environment can be selected according to the conditions.
  • the chlorinating reagent is selected from chlorine, NCS, ammonium chloride, hydrogen chloride or sulfonyl chloride
  • the iodination reagent is selected from iodine, NIS, sodium iodide or potassium iodide
  • the brominating reagent is selected from NBS, Bromine or dibromohydantoin, etc.
  • the reaction solvent is selected from one or more of water, methanol, THF, acetonitrile, acetic acid, propionic acid, and methyl tert-butyl ether; in one scheme, the solvent is a mixed solvent of water and methanol, or THF , Acetonitrile, acetic acid, propionic acid, methyl tert-butyl ether, and their mixed solvents.
  • the solvent for the first halogenation reaction is preferably selected from water, methanol, acetonitrile or a mixed solvent of two or three of them, and the solvent for the second halogenation reaction is preferably methyl tert-butyl ether, acetic acid, and propionic acid.
  • the acid in the acidic condition may be acetic acid, p-toluenesulfonic acid, sulfuric acid, methanesulfonic acid, etc., preferably sulfuric acid, and the bromination reagent is preferably NBS.
  • Step (3) Compound VI and compound 1 are first heated in an organic solvent to react, and the resulting reaction product and base are then heated in the presence of water to continue the reaction to obtain compound VII; or compound VI, compound 1 and base are first in the organic
  • the reaction is carried out by heating in a solvent, and the resulting reaction product is heated in the presence of water to continue the reaction to obtain compound VII.
  • the reaction temperature of compound VI and compound 1 is 75 to 150°C, preferably 77 to 100°C.
  • the temperature at which the base is added to continue the reaction is 50-100°C, preferably 60-100°C.
  • the molar ratio of compound VI to compound 1 is 1:1.0 to 2.0, preferably 1:1.2.
  • the organic solvent is toluene, xylene, NMP, ethyl acetate, isopropyl acetate, isopropanol, ethanol, tert-butanol, acetonitrile, DMF, etc., preferably ethyl acetate.
  • the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the amount of alkali added is such that the pH value of the reaction solution that continues to react reaches 4-7; in the second case of this step, the amount of alkali added is moles of the compound of formula (II) 0.1 to 2.5 times the amount, preferably 0.5 to 2.5 times, more preferably 0.6 to 1.5 times, still more preferably 0.8 to 1.2 times.
  • the demethylation reagent can be BBr 3 , sodium ethanethiolate, lithium bromide and the like.
  • the bromine source of the bromination reaction is NBS, dibromohydantoin, bromine, etc.
  • the reaction solvent can be acetic acid, DMF, NMP, water, etc.
  • the pH of the reaction can be acidic or basic
  • the acid can be acetic acid or propylene.
  • Organic acids such as acids and bases include inorganic bases such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • inorganic bases such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • the temperature of the demethylation reaction is -50 ⁇ 150°C.
  • the reaction temperature is -50 ⁇ 20°C, and when sodium ethanethiolate or lithium bromide is used as the demethylation reagent.
  • the reaction temperature is 0 to 150°C, preferably 40 to 90°C.
  • the bromine source of the bromination reaction is selected from NBS, dibromohydantoin or bromine, and the temperature of the bromination reaction is 20 ⁇ 45°C; the reaction solvent in the demethylation reaction or the bromination reaction is selected from dichloromethane, acetic acid, and DMF One or more of, NMP and water.
  • R 7 is I or Br
  • R 8 is Cl, Br or I.
  • the iodination reagent is selected from iodine or NIS, and the bromination reagent is selected from NBS, bromine or dibromohydantoin.
  • the temperature of the iodination or bromination reaction is 5-25°C, and the reaction solvent can be an existing solvent for the iodination or bromination reaction, such as acetonitrile, methanol, etc., and an acid can be appropriately added during the reaction as required.
  • the cyanide is selected from one or more of sodium cyanide, potassium cyanide, cuprous cyanide or zinc cyanide, preferably cuprous cyanide;
  • the reaction solvent is selected from NMP, DMF or DMA, preferably NMP;
  • the reaction temperature is 120-200°C.
  • step (3) of Route 2 compound 9 undergoes a halogenation reaction with a halogenating reagent.
  • Halogenating reagents include chlorinating reagents, iodinating reagents or brominating reagents, which are specifically selected from chlorine, NCS, ammonium chloride, hydrogen chloride, sulfonyl chloride, iodine, NIS, sodium iodide, potassium iodide, NBS, bromine or dibromohydantoin Wait.
  • the reaction temperature in this step is 5-25°C, and the reaction solvent can be an existing halogenation solvent, such as acetonitrile, methanol, acetic acid, and propionic acid.
  • the reaction temperature of compound VIII and compound 1 is 75 to 150°C, preferably 77 to 100°C; the reaction temperature after the reaction of compound VIII and compound 1 is 50 to 100°C, preferably 60 ⁇ 100°C; organic solvent is selected from toluene, xylene, NMP, ethyl acetate, isopropyl acetate, isopropanol, ethanol, tert-butanol, acetonitrile or DMF; base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate , Potassium bicarbonate, triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the amount of alkali added is such that the pH value of the reaction solution that continues to react reaches 4-7; in the second case of this step, the amount of alkali added is moles of the compound of formula (II) 0.1 to 2.5 times the amount, preferably 0.5 to 2.5 times, more preferably 0.6 to 1.5 times, still more preferably 0.8 to 1.2 times.
  • a demethylation reagent is used in the demethylation reaction, and the demethylation reagent is selected from BBr 3 , sodium ethanethiolate or lithium bromide.
  • the temperature of the demethylation reaction is -50 ⁇ 150°C.
  • the reaction temperature is -50 ⁇ 20°C, and when sodium ethanethiolate or lithium bromide is used as the demethylation reagent.
  • the reaction temperature is 0 to 150°C, preferably 40 to 90°C.
  • the bromine source of the bromination reaction is selected from NBS, dibromohydantoin or bromine, and the temperature of the bromination reaction is 20 ⁇ 45°C; the reaction solvent in the demethylation reaction or the bromination reaction is selected from dichloromethane, acetic acid, and DMF One or more of, NMP and water.
  • R 9 is Cl, Br or I.
  • the demethylation reagent in the demethylation reaction is selected from BBr 3 , sodium ethanethiolate or lithium bromide.
  • the temperature of the demethylation reaction is -50 ⁇ 150°C.
  • the reaction temperature is -50 ⁇ 20°C, and when sodium ethanethiolate or lithium bromide is used as the demethylation reagent.
  • the reaction temperature is 0 to 150°C, preferably 40 to 90°C.
  • the reaction solvent can be dichloromethane, DMF, NMP and the like.
  • the bromination reagent of the bromination reaction is NBS, dibromohydantoin or bromine; preferably, NBS is used in the first bromination reaction, and the temperature of the bromination reaction is 20 ⁇ 45°C
  • the solvent is selected from DMF;
  • the second reaction of step (2) is a halogenation reaction, and the halogenation reagent in the reaction includes a chlorinating reagent, an iodinating reagent or a brominating reagent, which is specifically selected from chlorine, NCS, ammonium chloride, Hydrogen chloride, sulfonyl chloride, iodine, NIS, sodium iodide, potassium iodide, NBS, bromine or dibromohydantoin, etc.
  • the reaction temperature of the halogenation reaction is 5-25°C
  • the reaction solvent can be an existing halogenation reaction solvent, such as acetonitrile, methanol, acetic acid, propionic acid, chloroform or ethyl acetate.
  • the reaction temperature of compound IX and compound 1 is 75 to 150°C, preferably 77 to 100°C; the reaction temperature of compound IX and compound 1 is 50 to 100°C, preferably 60 ⁇ 100°C.
  • Organic solvent is selected from toluene, xylene, NMP, ethyl acetate, isopropyl acetate, isopropanol, ethanol, tert-butanol, acetonitrile or DMF; base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate , Triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the amount of alkali added is such that the pH value of the reaction solution that continues to react reaches 4-7; in the second case of this step, the amount of alkali added is moles of the compound of formula (II) 0.1 to 2.5 times the amount, preferably 0.5 to 2.5 times, more preferably 0.6 to 1.5 times, still more preferably 0.8 to 1.2 times.
  • the method of preparing the compound of formula (III) is divided into two stages. First, the two substrates are reacted for a period of time under heating in an organic solvent, and then heated in the presence of water to continue the reaction. In the first stage and/ Or adding alkali in the second stage, using this method of alkali addition and two-step reaction can greatly promote the conversion of intermediate products generated in the reaction to target products, reduce and avoid the generation of by-products, and greatly increase the yield of target products. Correspondingly, the yield and benefit of other compound synthetic routes using the method for preparing the compound of formula (III) of the present invention are also greatly improved;
  • the present invention provides a preparation method of the compound of formula (III) and multiple preparation routes of compound 7.
  • Each method has mild reaction conditions, simple operation, low equipment requirements, and is suitable for laboratory preparation and industrial production;
  • the raw materials required for the reaction of the present invention can be produced industrially, and the price is low and easy to obtain.
  • Step A Add dichloromethane (30L) to the reactor, then add 2-aminopyridine (5.0kg, 53.1mol), triethylamine (10.7kg, 106mol) and propionic anhydride (8.3kg) at 20 ⁇ 25°C , 63.8mol). After the addition, the resulting mixture was stirred under reflux for 22-24 hours. After the reaction is over, 10% sodium hydroxide solution (25L) is added at 20-25°C. The layers were separated, and the organic layer was washed with water (15L ⁇ 2). The combined aqueous layer was extracted with dichloromethane (30L).
  • Step B Add water (27L) and concentrated sulfuric acid (3L) to the reaction kettle, then add methanol (35L), 4-methoxyacetophenone (10kg, 6.66mol) and NBS (23.7) at 10 ⁇ 15°C kg, 13.3mol). After the addition is complete, the resulting mixture is stirred at 15-20°C for 24-28 hours. After the reaction, water (40L) was added, filtered, and the filter cake was rinsed with water (4L). The obtained solid was recrystallized from n-heptane to obtain crude 1-(3-bromo-4-methoxyphenyl)ethanone (2) (16.6 kg), which was directly used in the next reaction without purification.
  • Step C Add methyl tert-butyl ether (82.9L) and concentrated sulfuric acid (0.71 kg, 7.24 mol) to the reaction kettle, then add the crude compound (2) (16.6 kg), and stir the resulting mixture under reflux for 2 hours. Then NBS (7.12 kg, 4.0 mol) was added, and stirring was continued for 2 to 3 hours under reflux. After the reaction is over, cool to 5 ⁇ 10°C, filter, the filter cake is slurried with water (50L) and 5% sodium thiosulfate solution (50L) successively, and then recrystallized with n-heptane to obtain white solid 2-bromo-1- (3-Bromo-4-methoxyphenyl)ethanone (3) (13.3 kg).
  • Step D Add ethyl acetate (75L), compound 1 (4.42kg, 29.4mol) and compound 3 (7.50kg, 24.3mol) to the reaction kettle. After the addition is complete, the resulting mixture is refluxed and stirred under nitrogen for 48-60 hours . After the reaction, it is cooled to 20-30°C. Filter and rinse the filter cake with ethyl acetate (7.5L). Then add water (75L) and the solid obtained by filtration into the reaction kettle, adjust the pH value to 4-6 by adding 10% sodium bicarbonate solution dropwise at 90-100°C, and then continue to stir at this temperature for 3-5 hour.
  • step D the mixture containing ethyl acetate (45 mL), compound 1 (1.70 g, 11.3 mmol) and compound 3 (2.90 g, 9.42 mmol) was stirred under reflux for 48 hours under nitrogen. After the reaction, it was cooled to 20-30°C, filtered, and the filter cake was rinsed with ethyl acetate (15 mL). Then the filter cake was added to water (30 mL), the temperature was raised to 90-100°C, and the pH value was adjusted to 5-6 by adding triethylamine dropwise. After the addition was complete, the resulting mixture was stirred overnight under reflux. Adjust the pH to 7-8 with 10% sodium bicarbonate solution.
  • Step E Add NMP (8.1L), compound 4 (2.70 kg, 7.52 mol) and cuprous cyanide (0.86 kg, 9.60 mol) to the reaction kettle. After the addition is complete, the resulting mixture is stirred at 145-155°C for 24-28 hours under nitrogen. After the reaction, it was cooled to 85-95°C, and 13% ammonia water (27L) was added. Then cool to 15-25°C and continue stirring for 2 hours. After filtering, the filter cake was rinsed with 13% ammonia water (2.7L). The obtained solid was slurried with dichloromethane (13.5L ⁇ 2), and the product was in the filtrate. The combined filtrates were washed with 13% ammonia water (13.5L ⁇ 3).
  • Step F Add NMP (9.8L) and compound 5 (1.95kg, 6.39mol) to the reactor, and then add lithium bromide (1.66kg, 19.1mol) and sodium acetate (2.09kg, 25.5mol) at 75 ⁇ 85°C . After the addition is complete, the resulting mixture is stirred at 120 to 130°C for 10 to 12 hours. After the reaction is over, cool to room temperature, add water (29L), and adjust the pH to 5-6 with acetic acid. After filtering, the filter cake was recrystallized with NMP/acetonitrile to obtain 5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (6) (1.59kg) as a yellow solid . The HPLC purity was 99.7%, and the yield was 85.4%. LCMS: 292.0 [M+H] + .
  • Step G Add water (15.6L), sodium hydroxide (0.22kg, 5.5mol) and compound 6 (1.56kg, 5.36mol) into the reaction kettle, and then add NBS (0.95kg, 5.34mol) at 25 ⁇ 30°C ). After the addition is complete, the resulting mixture is continuously stirred at this temperature for 0.5 to 1.5 hours. After the reaction is over, add isopropyl acetate (7.8L) and adjust the pH to 5-6 with acetic acid.
  • Step A-1 Add iodine (518g, 2.04mol) and 1-chloromethyl-4-fluoro-1,4 to 4-methoxyacetophenone (600g, 4.0mol) in acetonitrile (5.4L) solution -Diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (1.42kg, 4.0mol), after the addition, the resulting mixture was stirred at 12-20°C for 20 hours. After the reaction, water (24L) was added, stirred for 15 minutes, and filtered. The filter cake was washed with 5% sodium thiosulfate solution (1.5L) and water (3.0L) successively. After drying, 3-iodo-4-methoxyacetophenone (8) (894g) was obtained as a yellow solid. The yield was 81.0%.
  • step A-2 The experimental operation of step A-2 is the same as that of step B in Example 1, to obtain 1-(3-bromo-4-methoxyphenyl)ethanone (2).
  • Step B-1 Add cuprous cyanide (228g, 2.55mol) to the DMF (2.0L) solution of compound 8 (467g, 1.69mol). After the addition is complete, the resulting mixture is stirred at 110-120°C under nitrogen overnight . Cool to room temperature and add dichloromethane (5.0L). Stir for 15 minutes, then filter through diatomaceous earth, and rinse the filter cake with an appropriate amount of dichloromethane. Water (7.0L) was added, the layers were separated, and the aqueous layer was extracted with dichloromethane (5.0L). The combined organic layer was washed successively with water (3.0L ⁇ 3) and saturated brine (2.0L).
  • Step B-2 Add cuprous cyanide (32.8 g, 366 mol) to the NMP (300 mL) solution of compound 2 (56.0 g, 244 mmol). After the addition is complete, the resulting mixture is stirred at 150-160° C. under nitrogen overnight. Cool to room temperature and add dichloromethane (850 mL). Stir for 15 minutes, then filter through diatomaceous earth, and rinse the filter cake with an appropriate amount of dichloromethane. Water (1.2L) was added, the layers were separated, and the aqueous layer was extracted with dichloromethane (400 mL ⁇ 2). The combined organic layer was washed sequentially with water (250 mL ⁇ 3) and saturated brine (200 mL).
  • Step C At 7 ⁇ 15°C, bromine (422g, 2.64mol) was added dropwise to the mixture containing compound 9 (385g, 2.20mol) and methanol (2.9L), after the addition, the resulting mixture was stirred at 20°C overnight. After the reaction, it was filtered, and the filter cake was dissolved with dichloromethane (4.0L), and then washed with saturated brine (1.3L ⁇ 2). The solvent was evaporated under reduced pressure, and the obtained product was slurried with petroleum ether (400 mL) to obtain 5-(2-bromo-acetyl)-2-hydroxy-3-methylbenzonitrile (10) (458 g) as a white solid. The yield was 81.9%.
  • Step D-1 A mixture containing compound 1 (118 g, 785 mmol), compound 10 (200 g, 787 mmol) and ethyl acetate (2.5 L) was stirred under reflux under nitrogen for 48 hours. Cool to room temperature, filter, and rinse the filter cake with ethyl acetate (500 mL). The obtained mixture of solid and water (3L) was heated to 90-100°C, and the pH value was adjusted to 5-6 by adding 10% sodium bicarbonate solution dropwise, and then stirring was continued at this temperature for 3 hours. After the completion of the reaction, it was cooled to room temperature, and the pH value was adjusted to 7-8 with 10% sodium bicarbonate solution.
  • Step D-2 The mixture containing compound 1 (8.87 g, 59.1 mmol), compound 10 (15.0 g, 59.0 mmol), sodium bicarbonate (4.96 g, 59.0 mmol) and ethyl acetate (200 mL) was refluxed under nitrogen Stir for 48 hours. The solvent was evaporated under reduced pressure, then ethanol (10 mL) was added, stirred for 10 minutes, and filtered. The mixture of the obtained solid and water (225 mL) was stirred at 90-100°C for 3 hours. After the completion of the reaction, it was cooled to room temperature, and the pH value was adjusted to 7-8 with 10% sodium bicarbonate solution.
  • Step E Sodium ethanethiolate (39.9 g, 467 mmol) was added to the DMF (350 mL) solution of compound 5 (70.0 g, 239 mmol). After the addition, the resulting mixture was stirred at 48-55°C for 0.5 hours. After the reaction, it was cooled to room temperature and poured into water (1.05L). Remove insoluble matter by filtration. The pH value of the filtrate is adjusted to 5-6 with 10% citric acid solution. Filter, rinse the filter cake with an appropriate amount of water, and recrystallize the obtained solid with acetonitrile to obtain 5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (6) (59.0g). The yield was 88.3%.
  • Step F At 15-20°C, bromine (36.6 g, 229 mmol) was added dropwise to a mixture containing compound 6 (58.0 g, 199 mmol), sodium acetate (33.0 g, 402 mmol) and acetic acid (580 mL). After the addition was complete, the resulting mixture was continuously stirred at this temperature for 2 hours. The above reaction solution was poured into water (580 mL). After filtering, the obtained solid was suspended in water (600 mL), and the pH value was adjusted to 5-6 with 2M sodium hydroxide solution.
  • Step A The mixture containing compound 9 (50.0 g, 285 mmol), sodium ethanethiolate (28.8 g, 342 mmol) and DMF (200 mL) was stirred at 70-80°C for 1 hour. Cool to room temperature, add water (700 mL), filter to remove insoluble materials, and extract the filtrate with ethyl acetate (100 mL). The product is in the aqueous phase. The aqueous phase was adjusted to pH 5-6 with 10% citric acid solution, and extracted with ethyl acetate (200 mL ⁇ 3).
  • Step B NBS (36.8 g, 207 mmol) was added to the solution of compound 11 (30.3 g, 188 mmol) in DMF (150 mL) in batches. After the addition, the resulting mixture was stirred at room temperature for 1.5 hours. Water (530 mL) was added, and extraction was performed with ethyl acetate (150 mL ⁇ 3). Wash the combined organic phase with water (90mL ⁇ 2) and saturated brine (45mL) successively, distill the solvent off under reduced pressure, and recrystallize the product with petroleum ether/ethyl acetate to obtain 5-acetyl-3-bromo-2 -Hydroxybenzonitrile (12) (39.0g). The yield was 86.4%.
  • Step C Bromine (16.7 g, 104 mmol) was added dropwise to the chloroform (360 mL) solution of compound 12 (24.0 g, 100 mmol). After the addition, the resulting mixture was stirred at 10-15°C overnight. After the reaction, it was washed with 5% sodium thiosulfate solution (50 mL) and saturated brine (90 mL) in sequence. The solvent was evaporated under reduced pressure to obtain 3-bromo-5-(2-bromoacetyl)-2-hydroxybenzonitrile (13) (29.7g). The yield was 93.1%.
  • Step D The mixture containing compound 1 (9.66 g, 64.3 mmol), compound 13 (20.5 g, 64.3 mmol) and ethyl acetate (300 mL) was stirred under reflux for 48 hours under nitrogen. Cool to room temperature, filter, and rinse the filter cake with ethyl acetate (40 mL). The resulting mixture of solid and water (300 mL) was heated to 60-70° C., the pH value was adjusted to 5-6 by adding 10% sodium bicarbonate solution dropwise, and then the temperature was raised to reflux and stirring was continued for 3 hours. After the completion of the reaction, it was cooled to room temperature, and the pH value was adjusted to 7-8 with 10% sodium bicarbonate solution.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明公开了一种3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成方法，特别是涉及一种式(III)化合物的合成方法，具体涉及步骤A或者步骤B；步骤A：式(I)化合物与式(II)化合物先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到式(III)化合物；步骤B：式(I)化合物与式(II)化合物和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到式(III)化合物。

Description

3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成 技术领域
本发明属于药物化学领域，具体涉及一种化合物3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成方法。
背景技术
痛风(Gout)是由于人体内嘌呤代谢紊乱和/或尿酸排泄障碍导致高尿酸血症(Hyper-uricemia)所引起的慢性代谢性疾病，以尿酸盐沉积在关节等部位而引起的剧烈疼痛为主要特征。当体内血清尿酸水平超过6.8mg/dL时，尿酸盐将在人体组织的滑膜液、外周关节的软骨、耳朵的耳廓和手肘的鹰嘴囊等处出现尿酸单钠盐结晶沉积。当有此类症状时，即可诊断为痛风。URAT1在尿酸从细胞内重吸收到肾小管腔内的过程中发挥重要作用，是人体内主要的尿酸重吸收蛋白，控制着约90％以上的肾小球滤过后尿酸的重吸收。因此，抑制URAT1转运作用可降低尿酸重吸收，促进尿酸在肾脏的排泄，而达到降低体内血尿酸水平的效果。3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈是一种具有抑制URAT1转运尿酸能力、同时还可显著增加体内的尿酸排泄；并可降低对正常肝脏细胞的毒性的候选药物，用以预防或治疗高尿酸血症、肾病或痛风。
目前，3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈尚处在临床实验阶段，未能大规模投入生产使用，现有工艺(CN201610810990)中使用选择氟和碘在苯环上进行碘代反应，然后将碘进行氰基化，再将氰基化以后的溴代苯乙酮与N-(吡啶-2-基)丙酰胺进行关环反应。该路线中，关环反应是在单一溶剂中加热反应，反应不彻底，而且转化率不高，导致纯化难度大，分离收率低，不利于工业化生产。
发明内容
本发明的目的是针对现有技术中的不足，提供一种(2-乙基咪唑吡啶-3-基)(苯基)甲酮类化合物的合成方法。
本发明的另一目的是针对现有工艺中反应条件苛刻、产率不高、合成路线不成熟等问题，提供一种3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成方法，该方法操作简便，条件温和，产率较高，适合于工业化生产。
本发明的目的可以通过以下措施达到：
一种式(III)化合物的合成方法，其特征在于它包括步骤A或者步骤B，
Figure PCTCN2020072582-appb-000001
步骤A：式(I)化合物与式(II)化合物先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到式(III)化合物；
步骤B：式(I)化合物与式(II)化合物和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到式(III)化合物；
Figure PCTCN2020072582-appb-000002
其中，R 1为H或C 1-3烷基，R 2为H、-CN、I或Br，R 3为H、I或Br，R 4为Cl、Br或I。
式(III)化合物的合成反应分两个阶段，首先是两个底物在有机溶剂中加热条件下反应一段时间，然后在水存在的条件下加热继续反应，在第一阶段和/或第二阶段中加入碱，我们发现采用这种加碱和两步反应的方式，可以极大地促进反应中生成的中间产物向目标产物的转化，降低和避免副产物的生成，大幅提高目标产物的收率。
步骤B的第一阶段需要加入碱，在其第二阶段中，也可以继续加入碱，还可以不加碱，这两种方式都在本申请的保护范围内。
在式(III)化合物的合成中，式(I)化合物与式(II)化合物的反应温度为75～150℃，优选77～100℃；继续反应的温度为50～100℃，优选60～100℃。
在式(III)化合物的合成中，有机溶剂选自甲苯、二甲苯、NMP、乙酸乙酯、乙酸异丙酯、异丙醇、乙醇、叔丁醇、乙腈或DMF，优选乙酸乙酯。
在式(III)化合物的合成中，碱选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、 二异丙基乙基胺、氢氧化锂、氢氧化钠或氢氧化钾，优选碳酸氢钠。
在式(III)化合物的合成中，在步骤A中，碱的加入量至使继续反应的反应液的pH值达到4～7；在步骤B中，碱的加入量为式(II)化合物摩尔量的0.1～2.5倍，优选0.5～2.5倍，优选0.6～1.5倍，进一步优选0.8～1.2倍。
本发明还提供了三种3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成路线。
路线一，3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成包括如下步骤：
(1)2-氨基吡啶与酰基化试剂进行酰化反应得到化合物1；
(2)4-甲氧基苯乙酮通过两次卤化反应得到化合物VI；
(3)化合物VI与化合物1先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到化合物VII；或者化合物VI与化合物1和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到化合物VII；
(4)化合物VII与氰化物反应生成化合物5；
(5)化合物5先进行脱甲基化反应得到化合物6，再进行溴化反应，得到化合物7；
Figure PCTCN2020072582-appb-000003
其中，R 5为I或Br，R 6为Cl、Br或I。
以下对路线一的各步骤做详细说明。
步骤(1)：2-氨基吡啶跟丙酸酐进行酰化反应得到相应的酰胺(化合物1)；进一步的，2-氨基吡啶与酰基化试剂在缚酸剂作用下进行酰化反应得到化合物1。该酰化反应中，酰基化试剂可以用丙酸酐或丙酰氯，缚酸剂可以用二异丙基乙基胺、三乙胺、N-甲基哌啶、碳酸钾、碳酸钠等碱，反应溶剂可以为二氯甲烷、THF、乙腈等溶剂。通过实验发现用丙酰氯有部分二酰基化的副产物生成。而使用丙酸酐，可以实现几乎定量转化。在该反应中以三乙胺作缚酸剂时，2-氨基吡啶与丙酸酐的摩尔比可以为1.0:1.0～2.0，优选配比为1.0:1.1～1.4。其反应温度为20～45℃。与其他步骤不同，本方法中的步骤(1)与步骤(2)并无明确的先后顺序，在具体实施中可以先进行步骤(1)以制备化合物1，也可以先进行步骤(2)以制备化合物VI，或者步骤(1)和步骤(2)可同时实施。
步骤(2)：4-甲氧基苯乙酮通过两次卤化反应得到取代的α-卤代苯乙酮(化合物VI)。首先是在酸性条件下，4-甲氧基苯乙酮发生苯环上卤化反应，然后酮的α位氢原子发生取代反应生成α-卤代苯乙酮。本步骤中的卤化是在卤化试剂存在的条件下完成，其中卤化试剂包括氯化试剂、碘化试剂或溴化试剂。
在一种优选方案中，步骤(2)为：4-甲氧基苯乙酮在酸性条件下与碘化试剂或溴化 试剂在5～25℃下进行卤化反应，得到化合物V；再在酸性或非酸性条件下与氯化试剂、碘化试剂或溴化试剂在5～60℃下进行卤化反应，得到化合物VI。第二步的卤化反应中采用不同试剂时，可采用不同的反应温度，如采用碘化试剂或溴化试剂时，第二步的卤化反应温度可控制在30～60℃，如采用氯化试剂时卤化反应温度可控制在5～60℃。第二步的卤化反应可根据条件选择酸性或非酸性环境，。
步骤(2)中，氯化试剂选自氯气、NCS、氯化铵、氯化氢或磺酰氯等，碘化试剂选自碘、NIS、碘化钠或碘化钾等，所述溴化试剂选自NBS、溴或二溴海因等。反应溶剂选自水、甲醇、THF、乙腈、乙酸、丙酸、甲基叔丁基醚中的一种或几种；在一种方案中，溶剂是水和甲醇的混合溶剂，也可以是THF、乙腈、乙酸、丙酸、甲基叔丁基醚，以及它们的混合溶剂。本步骤反应中，第一次卤化反应的溶剂优选选自水、甲醇、乙腈或者它们两者或三者的混合溶剂，第二次卤化反应的溶剂优选甲基叔丁基醚、乙酸、丙酸、丙酮、乙酸乙酯或氯仿。酸性条件中的酸可以是乙酸、对甲苯磺酸、硫酸、甲磺酸等，优选硫酸，溴化试剂优选NBS。
步骤(2)中有两步卤化反应，故卤化试剂分两个阶段投料。优选第一阶段加入总投料量的40～85％的卤化试剂，在第二阶段加入剩余部分的卤化试剂。实验发现，与使用其他原料进行一次卤化反应相比，本申请以4-甲氧基苯乙酮作为卤化反应的原料，采用两次精确控制且选择性不同的卤化反应，可以大幅提高化合物VI的收率，抑制副反应的发生，降低反应难度，使得本制备工艺更具有工业应用前景。
步骤(3)：化合物VI与化合物1先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到化合物VII；或者化合物VI与化合物1和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到化合物VII。化合物VI与化合物1的反应温度为75～150℃，优选77～100℃。化合物VI与化合物1反应后，加入碱继续反应的温度为50～100℃，优选60～100℃。化合物VI与化合物1的摩尔比例为1:1.0～2.0，优选1:1.2。在该反应中，有机溶剂为甲苯、二甲苯、NMP、乙酸乙酯、乙酸异丙酯、异丙醇、乙醇、叔丁醇、乙腈、DMF等，优选乙酸乙酯。碱选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙基胺、氢氧化锂、氢氧化钠或氢氧化钾。在本步骤的第一种情况下，碱的加入量至使继续反应的反应液的pH值达到4～7；在本步骤的第二种情况下，碱的加入量为式(II)化合物摩尔量的0.1～2.5倍，优选0.5～2.5倍，更优选0.6～1.5倍，进一步优选0.8～1.2倍。
步骤(4)：溴代的咪唑并[1,2-a]吡啶类化合物与氰化物反应生成苯甲腈类化合物(化合物5)。氰化物可以是氰化钠、氰化钾、氰化亚铜、氰化锌等，以及它们的混合物，优选氰化亚铜。反应溶剂为NMP、DMF、DMA等，优选NMP。反应温度为120～200℃，优选140～160℃。
步骤(5)：化合物5先后进行脱甲基化及溴化反应，得到3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈(化合物7)。脱甲基化试剂可以用BBr 3、乙硫醇钠、溴化锂等。而溴化反应的溴源为NBS、二溴海因、溴等，反应溶剂可以是乙酸、DMF、NMP和水等，反应pH值可以是酸性，也可以是碱性，酸可以是乙酸、丙酸等有机酸，碱为氢氧化钠、氢氧化钾、氢氧化锂等无机碱。本文优选用溴化锂脱甲基，然后在水中进行溴化反应，相比于其他条件，这样可以达到非常好的反应及分离效果。脱甲基化反应的温度为-50～150℃，如采用BBr 3为脱甲基化试剂时其反应温度为-50～20℃，而采用乙硫醇钠或溴化锂为脱甲基化试剂时其反应温度为0～150℃，优选40～90℃。溴化反应的溴源选自NBS、二溴海因或溴，溴化反应的温度为20～45℃；脱甲基化反应或溴化反应中的反应溶剂选自二氯甲烷、乙酸、DMF、NMP和水中的一种或几种。
路线二，3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成包括如下步骤：
(1)4-甲氧基苯乙酮与碘化试剂或溴化试剂反应得到化合物IV；
(2)化合物IV与氰化物反应生成化合物9；
(3)化合物9经过卤化反应得到化合物VIII；
(4)化合物VIII与化合物1先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到化合物5；或者化合物VIII与化合物1和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到化合物5；
(5)化合物5先进行脱甲基化反应得到化合物6，再进行溴化反应，得到化合物7；
Figure PCTCN2020072582-appb-000004
其中，R 7为I或Br，R 8为Cl、Br或I。
以下对路线二的各步骤做详细说明。
在路线二的步骤(1)中，碘化试剂选自碘或NIS，溴化试剂选自NBS、溴或二溴海因。碘化或溴化反应的温度为5～25℃，其反应溶剂可采用现有碘化或溴化反应的溶剂，例如乙腈、甲醇等，反应中可根据需要适当的加入酸。
在路线二的步骤(2)中，氰化物选自氰化钠、氰化钾、氰化亚铜或氰化锌中的一种或几种，优选氰化亚铜；反应溶剂选自NMP、DMF或DMA，优选NMP；反应温度为120～200℃。
在路线二的步骤(3)中，化合物9与卤化试剂进行卤化反应。卤化试剂包括氯化试剂、碘化试剂或溴化试剂，其具体选自氯气、NCS、氯化铵、氯化氢、磺酰氯、碘、NIS、碘化钠、碘化钾、NBS、溴或二溴海因等。该步骤的反应温度为5～25℃，反应溶剂可采用现有卤化反应的溶剂，例如乙腈、甲醇、乙酸、丙酸等。
在路线二的步骤(4)中，化合物VIII与化合物1的反应温度为75～150℃，优选77～100℃；化合物VIII与化合物1反应后的继续反应的温度为50～100℃，优选60～100℃；有机溶剂选自甲苯、二甲苯、NMP、乙酸乙酯、乙酸异丙酯、异丙醇、乙醇、叔丁醇、乙腈或DMF；碱选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙基胺、氢氧化锂、氢氧化钠或氢氧化钾。在本步骤的第一种情况下，碱的加入量至使继 续反应的反应液的pH值达到4～7；在本步骤的第二种情况下，碱的加入量为式(II)化合物摩尔量的0.1～2.5倍，优选0.5～2.5倍，更优选0.6～1.5倍，进一步优选0.8～1.2倍。
在路线二的步骤(5)中，脱甲基化反应中采用脱甲基化试剂，脱甲基化试剂选自BBr 3、乙硫醇钠或溴化锂。脱甲基化反应的温度为-50～150℃，如采用BBr 3为脱甲基化试剂时其反应温度为-50～20℃，而采用乙硫醇钠或溴化锂为脱甲基化试剂时其反应温度为0～150℃，优选40～90℃。溴化反应的溴源选自NBS、二溴海因或溴，溴化反应的温度为20～45℃；脱甲基化反应或溴化反应中的反应溶剂选自二氯甲烷、乙酸、DMF、NMP和水中的一种或几种。
路线三，3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成包括如下步骤：
(1)化合物9进行脱甲基化反应，得到化合物11；
(2)化合物11通过溴化反应得到化合物12，再通过卤化反应得到化合物IX；
(3)化合物IX与化合物1先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到化合物7；或者化合物IX与化合物1和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到化合物7；
Figure PCTCN2020072582-appb-000005
其中，R 9为Cl、Br或I。
以下对路线三的各步骤做详细说明。
在路线三的步骤(1)中，脱甲基化反应中的脱甲基化试剂选自BBr 3、乙硫醇钠或溴 化锂。脱甲基化反应的温度为-50～150℃，如采用BBr 3为脱甲基化试剂时其反应温度为-50～20℃，而采用乙硫醇钠或溴化锂为脱甲基化试剂时其反应温度为0～150℃，优选40～90℃。反应溶剂可以是二氯甲烷、DMF和NMP等。
在路线三的步骤(2)中，溴化反应的溴化试剂为NBS、二溴海因或溴；优选的，第一次溴化反应中采用NBS，溴化反应的温度为20～45℃；溶剂选自DMF；步骤(2)的第二次反应为卤化反应，该反应中的卤化试剂包括氯化试剂、碘化试剂或溴化试剂，其具体选自氯气、NCS、氯化铵、氯化氢、磺酰氯、碘、NIS、碘化钠、碘化钾、NBS、溴或二溴海因等。卤化反应的反应温度为5～25℃，反应溶剂可采用现有卤化反应的溶剂，例如乙腈、甲醇、乙酸、丙酸、氯仿或乙酸乙酯等。
在路线三的步骤(3)中，化合物IX与化合物1的反应温度为75～150℃，优选77～100℃；化合物IX与化合物1反应后的继续反应的温度为50～100℃，优选60～100℃。有机溶剂选自甲苯、二甲苯、NMP、乙酸乙酯、乙酸异丙酯、异丙醇、乙醇、叔丁醇、乙腈或DMF；碱选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙基胺、氢氧化锂、氢氧化钠或氢氧化钾。在本步骤的第一种情况下，碱的加入量至使继续反应的反应液的pH值达到4～7；在本步骤的第二种情况下，碱的加入量为式(II)化合物摩尔量的0.1～2.5倍，优选0.5～2.5倍，更优选0.6～1.5倍，进一步优选0.8～1.2倍。
本发明的方法有以下特点：
(1)制备式(III)化合物的方法分成两个阶段，首先是两个底物在有机溶剂中加热条件下反应一段时间，然后在水存在的条件下加热继续反应，在第一阶段和/或第二阶段中加入碱，采用这种加碱和两步反应的方式，可以极大地促进反应中生成的中间产物向目标产物的转化，降低和避免副产物的生成，大幅提高目标产物的收率；相应的，也大幅提高了采用本发明的式(III)化合物制备方法的其他化合物合成路线的收率和效益；
(2)本发明在化合物VI以及与之类似的化合物的制备过程中，采用了两次精确控制且选择性不同的卤化反应，可以大幅提高目标的收率，抑制副反应的发生，降低反应难度，使得本制备工艺更具有工业应用前景；
(3)本发明提供了式(III)化合物的制备方法和多条化合物7的制备路线，各方法反应条件温和，操作简便，设备要求低，适合实验室制备和工业化生产；
(4)本发明每步反应产物的分离纯化较简便，不需要柱层析纯化，分离收率高；
(5)本发明反应所需原料都可由工业化生产，价格低廉易获得。
具体实施方式
以下结合实施例对本发明做进一步描述，但本发明的保护范围并不局限于下述各实施例。
实施例1：
Figure PCTCN2020072582-appb-000006
步骤A：向反应釜中加入二氯甲烷(30L)，然后在20～25℃下加入2-氨基吡啶(5.0kg，53.1mol)、三乙胺(10.7kg，106mol)和丙酸酐(8.3kg，63.8mol)。加完后，所得混合物在回流下搅拌22～24小时。反应结束后，在20～25℃下加入10％氢氧化钠溶液(25L)。分层，有机层用水(15L×2)洗涤。合并的水层用二氯甲烷(30L)萃取。合并的有机层经过减压蒸馏除去大部分溶剂后，通过正庚烷/二氯甲烷重结晶，得黄色固体N-(吡啶-2-基)丙酰胺(1)(7.7kg)。HPLC纯度为100％，收率为96.6％。 1H NMR(DMSO-d6，300MHz)δ10.38(s，1H)，8.30-8.28(m，1H)，8.11-8.08(m，1H)，7.78-7.73(m，1H)，7.08-7.04(m，1H)，2.39(q，J＝7.5Hz，2H)，1.07(t，J＝7.5Hz，3H)。LCMS：151.2[M+H] +。
步骤B：向反应釜中加入水(27L)和浓硫酸(3L)，然后在10～15℃下加入甲醇 (35L)、4-甲氧基苯乙酮(10kg，6.66mol)和NBS(23.7kg，13.3mol)。加完后，所得混合物在15～20℃下搅拌24～28小时。反应结束后，加入水(40L)，过滤，滤饼用水(4L)淋洗。所得固体用正庚烷重结晶，得1-(3-溴-4-甲氧基苯基)乙酮(2)粗品(16.6kg)，该化合物不经纯化直接用于下一步反应。
步骤C：向反应釜中加入甲基叔丁基醚(82.9L)和浓硫酸(0.71kg，7.24mol)，然后加入化合物(2)粗品(16.6kg)，所得混合物在回流下搅拌2小时。然后加入NBS(7.12kg，4.0mol)，在回流下继续搅拌2～3小时。反应结束后，冷却到5～10℃，过滤，滤饼依次用水(50L)和5％硫代硫酸钠溶液(50L)打浆，再用正庚烷重结晶，得白色固体2-溴-1-(3-溴-4-甲氧基苯基)乙酮(3)(13.3kg)。HPLC纯度为98.7％，步骤B和C两步反应总收率为65.4％。 1H NMR(CDCl 3，300MHz)δ8.23-8.22(m，1H)，8.00-7.96(m，1H)，7.00-6.97(m，1H)，4.40(s，2H)，4.01(s，3H)。LCMS：308.9[M+H] +。
步骤D：向反应釜中加入乙酸乙酯(75L)、化合物1(4.42kg，29.4mol)和化合物3(7.50kg，24.3mol)，加完后，所得混合物在氮气下回流搅拌48～60小时。反应结束后，冷却到20～30℃。过滤，滤饼用乙酸乙酯(7.5L)淋洗。然后将水(75L)和过滤得到的固体加入到反应釜中，在90～100℃下，通过滴加10％碳酸氢钠溶液调节pH值至4～6，然后该温度下继续搅拌3～5小时。反应结束后，冷却到室温，用10％碳酸氢钠溶液调节pH值至7～8。过滤，滤饼用水(7.5L)洗涤，然后用乙腈/甲基叔丁基醚重结晶，得白色固体(3-溴-4-甲氧基苯基)(2-乙基咪唑并[1,2-a]吡啶-3-基)甲酮(4)(5.68kg)。HPLC纯度为99.6％，收率为64.7％。 1H NMR(DMSO-d6，300MHz)δ9.18-9.15(m，1H)，8.11-8.03(m，3H)，7.94-7.82(m，1H)，7.64-7.55(m，1H)，7.40-7.32(m，1H)，3.96(s，3H)，2.58(q，J＝7.5Hz，2H)，1.23(t，J＝7.5Hz，3H)。LCMS：359.1[M+H] +。
或者，步骤D：将含有乙酸乙酯(45mL)、化合物1(1.70g，11.3mmol)和化合物3(2.90g，9.42mmol)的混合物在氮气下回流搅拌48小时。反应结束后，冷却到20～30℃，过滤，滤饼用乙酸乙酯(15mL)淋洗。然后将该滤饼加入到水(30mL)中，升温到90～100℃，再通过滴加三乙胺调节pH值至5～6。加完后，所得混合物在回流下搅拌过夜。用10％碳酸氢钠溶液调节pH值至7～8。冷却到室温，过滤，滤饼用水洗涤，然后用乙腈/甲基叔丁基醚重结晶，得(3-溴-4-甲氧基苯基)(2-乙基咪唑并[1,2-a]吡啶-3-基)甲酮(4)(1.68g)。收率为49.6％。
步骤E：向反应釜中加入NMP(8.1L)、化合物4(2.70kg，7.52mol)和氰化亚铜(0.86kg，9.60mol)。加完后，所得混合物在氮气下145～155℃搅拌24～28小时。反应结束后，冷却到85～95℃，加入13％氨水(27L)。然后冷却到15～25℃，并继续搅拌2小时。过滤，滤饼用13％氨水(2.7L)淋洗。所得固体用二氯甲烷(13.5L×2)打浆，产品在滤液中。合并的滤液用13％氨水(13.5L×3)洗涤。有机层经过减压蒸馏除去大部分溶剂后，通过乙酸异丙酯/二氯甲烷重结晶，得黄色固体5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈(5)(1.91kg)。HPLC纯度为98.6％，收率为83.2％。
步骤F：向反应釜中加入NMP(9.8L)和化合物5(1.95kg，6.39mol)，然后在75～85℃下加入溴化锂(1.66kg，19.1mol)和乙酸钠(2.09kg，25.5mol)。加完后，所得混合物在120～130℃下搅拌10～12小时。反应结束后，冷却到室温，加入水(29L)，用乙酸调节pH值至5～6。过滤，滤饼用NMP/乙腈重结晶，得黄色固体5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈(6)(1.59kg)。HPLC纯度为99.7％，收率为85.4％。LCMS：292.0[M+H] +。
步骤G：向反应釜中加入水(15.6L)、氢氧化钠(0.22kg，5.5mol)和化合物6(1.56kg，5.36mol)，然后在25～30℃下加入NBS(0.95kg，5.34mol)。加完后，所得混合物在该温度下继续搅拌0.5～1.5小时。反应结束后，加入乙酸异丙酯(7.8L)，用乙酸调节pH值至5～6。过滤，滤饼用水(3.9L×2)洗涤，再用DMSO/乙酸异丙酯重结晶，得黄色固体3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈(7)(1.59kg)。HPLC纯度为99.9％，收率为80.1％。。 1H NMR(DMSO-d6，300MHz)δ9.13-9.11(m，1H)，8.12-8.11(m，1H)，8.03-7.97(m，1H)，7.86-7.83(m，1H)，7.77-7.72(m，1H)，7.34-7.29(m，1H)，2.57-2.50(m，2H)，1.19(t，J＝7.5Hz，3H)。LCMS:370.0[M+H] +。
实施例2：
Figure PCTCN2020072582-appb-000007
步骤A-1：向4-甲氧基苯乙酮(600g，4.0mol)的乙腈(5.4L)溶液中加入碘(518g，2.04mol)和1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(1.42kg，4.0mol)，加完后，所得混合物在12～20℃搅拌20小时。反应结束后，加入水(24L)，搅拌15分钟，过滤。滤饼依次用5％硫代硫酸钠溶液(1.5L)和水(3.0L)洗涤。干燥，得黄色固体3-碘-4-甲氧基苯乙酮(8)(894g)。收率为81.0％。
步骤A-2的实验操作同实施例1中的步骤B，得1-(3-溴-4-甲氧基苯基)乙酮(2)。
步骤B-1：向化合物8(467g，1.69mol)的DMF(2.0L)溶液中加入氰化亚铜(228g，2.55mol)，加完后，所得混合物在110～120℃及氮气下搅拌过夜。冷却到室温，加入二氯甲烷(5.0L)。搅拌15分钟，然后通过硅藻土过滤，滤饼用适量二氯甲烷淋洗。加入水(7.0L)，分层，水层用二氯甲烷(5.0L)萃取。合并的有机层依次用水(3.0L×3)和饱和食盐水(2.0L)洗涤。减压蒸除溶剂，所得产物用石油醚(500mL)打浆，得黄色固体5-乙酰基-2-甲氧基苯甲腈(9)(263g)。收率为88.8％。
步骤B-2：向化合物2(56.0g，244mmol)的NMP(300mL)溶液中加入氰化亚铜(32.8g，366mol)，加完后，所得混合物在150～160℃及氮气下搅拌过夜。冷却到室温，加入二氯甲烷(850mL)。搅拌15分钟，然后通过硅藻土过滤，滤饼用适量二氯甲烷淋洗。加入水(1.2L)，分层，水层用二氯甲烷(400mL×2)萃取。合并的有机层依次用水(250mL×3)和饱和食盐水(200mL)洗涤。减压蒸除溶剂，所得产物用石油醚(110mL)打浆，得黄色固体5-乙酰基-2-甲氧基苯甲腈(9)(29.1g)。收率为68.1％。
步骤C：在7～15℃下，将溴(422g，2.64mol)滴加到含有化合物9(385g，2.20mol)和甲醇(2.9L)的混合物中，加完后，所得混合物在20℃搅拌过夜。反应结束后，过滤，滤饼用二氯甲烷(4.0L)溶解，然后用饱和食盐水(1.3L×2)洗涤。减压蒸除溶剂，所得产物用石油醚(400mL)打浆，得白色固体5-(2-溴-乙酰基)-2-羟基-3-甲基苯甲腈(10)(458g)。收率为81.9％。
步骤D-1：将含有化合物1(118g，785mmol)、化合物10(200g，787mmol)和乙酸乙酯(2.5L)的混合物在氮气下回流搅拌48小时。冷却到室温，过滤，滤饼用乙酸乙酯(500mL)淋洗。再将所得固体和水(3L)的混合物升温到90～100℃，通过滴加10％碳酸氢钠溶液调节pH值至5～6，然后该温度下继续搅拌3小时。反应结束后，冷却到室温，用10％碳酸氢钠溶液调节pH值至7～8。过滤，滤饼用乙醇重结晶，得浅黄色固体5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈(5)(160g)。收率为69.5％。 1H NMR(DMSO-d6，400MHz)δ9.27-9.25(m，1H)，8.10(d，J＝2.4Hz，1H)，8.02(dd，J＝2.4，8.8Hz，1H)，7.79-7.76(m，1H)，7.64-7.60(m，1H)，7.42(d，J＝8.8Hz，1H)，7.23-7.20(m，1H)，4.03(s，3H)，2.39(q，J＝7.6Hz，2H)，1.26(t，J＝7.6Hz，3H)。LCMS:306.0[M+H] +。
步骤D-2：将含有化合物1(8.87g，59.1mmol)、化合物10(15.0g，59.0mmol)、碳酸氢钠(4.96g，59.0mmol)和乙酸乙酯(200mL)的混合物在氮气下回流搅拌48小时。减压蒸除溶剂，然后加入乙醇(10mL)，搅拌10分钟后，过滤。再将所得固体和水(225mL)的混合物在90～100℃下搅拌3小时。反应结束后，冷却到室温，用10％碳酸氢钠溶液调节pH值至7～8。过滤，滤饼用乙醇重结晶，得浅黄色固体5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈(5)(11.1g)。收率为64.2％。
步骤E：将乙硫醇钠(39.9g，467mmol)加入到化合物5(70.0g，239mmol)的DMF(350mL)溶液中，加完后，所得混合物在48～55℃搅拌0.5小时。反应结束后，冷却到室温，倒入水(1.05L)中。过滤除去不溶物。滤液用10％柠檬酸溶液调节pH值至5～6。过滤，滤饼用适量水淋洗，所得固体用乙腈重结晶，得5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈(6)(59.0g)。收率为88.3％。
步骤F：在15～20℃下，向含有化合物6(58.0g，199mmol)、乙酸钠(33.0g，402mmol)和乙酸(580mL)的混合物中滴加溴(36.6g，229mmol)。加完后，所得混合物在该温 度下继续搅拌2小时。将上述反应液倒入水(580mL)中。过滤，将所得固体悬浮在水(600mL)中，用2M氢氧化钠溶液调节pH值至5～6。过滤，所得固体用水(120mL)洗涤，再用DMSO/乙酸异丙酯重结晶，得黄色固体3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈(7)(63.7g)。收率为86.5％。化合物7  1H NMR和MS与实施例1一致。
实施例3：
Figure PCTCN2020072582-appb-000008
步骤A：将含有化合物9(50.0g，285mmol)、乙硫醇钠(28.8g，342mmol)和DMF(200mL)的混合物在70～80℃搅拌1小时。冷却到室温，加入水(700mL)，过滤除去不溶物，滤液用乙酸乙酯(100mL)萃取，产物在水相中。水相用10％柠檬酸溶液调节pH值至5～6，用乙酸乙酯(200mL×3)萃取。用合并的有机相依次用水(100mL×2)和饱和食盐水(100mL)洗涤，减压蒸除溶剂，所得产物用石油醚/乙酸乙酯重结晶，得5-乙酰基-2-羟基苯甲腈(11)(42.3g)。收率为92.1％。
步骤B：将NBS(36.8g，207mmol)分批加入到化合物11(30.3g，188mmol)的DMF(150mL)溶液中。加完后，所得混合物在室温下搅拌1.5小时。加入水(530mL)，用乙酸乙酯(150mL×3)萃取。用合并的有机相依次用水(90mL×2)和饱和食盐水(45mL)洗涤，减压蒸除溶剂，所得产物用石油醚/乙酸乙酯重结晶，得5-乙酰基-3-溴-2-羟基苯甲腈(12)(39.0g)。收率为86.4％。
步骤C：将溴(16.7g，104mmol)滴加到化合物12(24.0g，100mmol)的氯仿(360mL)溶液中，加完后，所得混合物在10～15℃下搅拌过夜。反应结束后，依次用5％硫代硫酸钠溶液(50mL)和饱和食盐水(90mL)洗涤。减压蒸除溶剂，得3-溴-5-(2-溴乙酰基)-2-羟基苯甲腈(13)(29.7g)。收率为93.1％。
步骤D：将含有化合物1(9.66g，64.3mmol)、化合物13(20.5g，64.3mmol)和乙酸乙酯(300mL)的混合物在氮气下回流搅拌48小时。冷却到室温，过滤，滤饼用乙酸乙酯(40mL)淋洗。再将所得固体和水(300mL)的混合物升温到60～70℃，通过滴加10％碳酸氢钠溶液调节pH值至5～6，然后升温到回流并继续搅拌3小时。反应结束后，冷却到室温，用10％碳酸氢钠溶液调节pH值至7～8。过滤，滤饼用DMSO/乙酸异丙酯重结晶，得黄色固体3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈(7)(10.5g)。收率为45.7％。化合物7  1H NMR和MS与实施例1一致。

Claims (16)

  1. 一种式(III)化合物的合成方法，其特征在于它包括步骤A或者步骤B，
    Figure PCTCN2020072582-appb-100001
    步骤A：式(I)化合物与式(II)化合物先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到式(III)化合物；
    步骤B：式(I)化合物与式(II)化合物和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到式(III)化合物；
    Figure PCTCN2020072582-appb-100002
    其中，R 1为H或C 1-3烷基，R 2为H、-CN、I或Br，R 3为H、I或Br，R 4为Cl、Br或I。
  2. 根据权利要求1所述的合成方法，其特征在于式(I)化合物与式(II)化合物的反应温度为75～150℃，优选77～100℃；所述继续反应的温度为50～100℃，优选60～100℃。
  3. 根据权利要求1所述的合成方法，其特征在于所述有机溶剂选自甲苯、二甲苯、NMP、乙酸乙酯、乙酸异丙酯、异丙醇、乙醇、叔丁醇、乙腈或DMF，优选乙酸乙酯。
  4. 根据权利要求1所述的合成方法，其特征在于所述碱选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙基胺、氢氧化锂、氢氧化钠或氢氧化钾，优选碳酸氢钠；在步骤A中，碱的加入量至使继续反应的反应液的pH值达到4～7；在步骤B中，碱的加入量为式(II)化合物摩尔量的0.1～2.5倍，优选0.5～2.5倍。
  5. 一种3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成方法，其特征在于它包括如下步骤：
    (1)2-氨基吡啶与酰基化试剂进行酰化反应得到化合物1；
    (2)4-甲氧基苯乙酮通过两次卤化反应得到化合物VI；
    (3)化合物VI与化合物1先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到化合物VII；或者化合物VI与化合物1和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到化合物VII；
    (4)化合物VII与氰化物反应生成化合物5；
    (5)化合物5先进行脱甲基化反应得到化合物6，再进行溴化反应，得到化合物7；
    Figure PCTCN2020072582-appb-100003
    其中，R 5为I或Br，R 6为Cl、Br或I。
  6. 根据权利要求5所述的合成方法，其特征在于在步骤(1)中，2-氨基吡啶与酰基化试剂在缚酸剂作用下进行酰化反应得到化合物1，所述酰基化试剂选自丙酸酐或丙酰氯，所述缚酸剂选自二异丙基乙基胺、三乙胺、N-甲基哌啶、碳酸钾或碳酸钠；其反应温度为20～45℃，反应溶剂为二氯甲烷、THF或乙腈。
  7. 根据权利要求5所述的合成方法，其特征在于在步骤(2)中，4-甲氧基苯乙酮在酸性条件下与碘化试剂或溴化试剂在5～25℃下进行卤化反应，得到化合物V；再在酸 性或非酸性下与氯化试剂、溴化试剂或碘化试剂在5～60℃下进行卤化反应，得到化合物VI；所述氯化试剂选自氯气、NCS、氯化铵、氯化氢或磺酰氯，所述碘化试剂选自碘、NIS、碘化钠或碘化钾，所述溴化试剂选自NBS、溴或二溴海因；酸性条件中的酸选自乙酸、对甲苯磺酸、硫酸或甲磺酸；反应溶剂选自水、甲醇、THF、乙腈、乙酸、丙酸、甲基叔丁基醚中的一种或几种；优选的，第一次卤化反应的溶剂选自水、甲醇、乙腈或者它们两者或三者的混合溶剂，第二次卤化反应的溶剂选自甲基叔丁基醚、乙酸、丙酸、丙酮、乙酸乙酯或氯仿。
  8. 根据权利要求5所述的合成方法，其特征在于在步骤(3)中，化合物VI与化合物1的反应温度为75～150℃，优选77～100℃；所述继续反应的温度为50～100℃，优选60～100℃；所述有机溶剂选自甲苯、二甲苯、NMP、乙酸乙酯、乙酸异丙酯、异丙醇、乙醇、叔丁醇、乙腈或DMF；所述碱选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙基胺、氢氧化锂、氢氧化钠或氢氧化钾。
  9. 根据权利要求5所述的合成方法，其特征在于在步骤(4)中，所述氰化物选自氰化钠、氰化钾、氰化亚铜或氰化锌中的一种或几种，优选氰化亚铜；反应溶剂选自NMP、DMF或DMA，优选NMP；反应温度为120～200℃，优选140～160℃；在步骤(5)中，脱甲基化试剂选自BBr 3、乙硫醇钠或溴化锂，脱甲基化反应的温度为-50～150℃；溴化反应的溴源选自NBS、二溴海因或溴，溴化反应的温度为20～45℃；脱甲基化反应或溴化反应中的反应溶剂选自二氯甲烷、乙酸、DMF、NMP和水中的一种或几种。
  10. 一种3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成方法，其特征在于它包括如下步骤：
    (1)4-甲氧基苯乙酮与碘化试剂或溴化试剂反应得到化合物IV；
    (2)化合物IV与氰化物反应生成化合物9；
    (3)化合物9经过卤化反应得到化合物VIII；
    (4)化合物VIII与化合物1先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到化合物5；或者化合物VIII与化合物1和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到化 合物5；
    (5)化合物5先进行脱甲基化反应得到化合物6，再进行溴化反应，得到化合物7；
    Figure PCTCN2020072582-appb-100004
    其中，R 7为I或Br，R 8为Cl、Br或I。
  11. 根据权利要求10所述的合成方法，其特征在于在步骤(1)中，所述碘化试剂选自碘或NIS，所述溴化试剂选自NBS、溴或二溴海因；在步骤(2)中，所述氰化物选自氰化钠、氰化钾、氰化亚铜或氰化锌中的一种或几种，优选氰化亚铜；反应溶剂选自NMP、DMF或DMA，优选NMP；反应温度为120～200℃；在步骤(3)中，化合物9与卤化试剂进行卤化反应，所述卤化试剂选自氯气、NCS、氯化铵、氯化氢、磺酰氯、碘、NIS、碘化钠、碘化钾、NBS、溴或二溴海因。
  12. 根据权利要求10所述的合成方法，其特征在于在步骤(4)中，化合物VIII与化合物1的反应温度为75～150℃，优选77～100℃；所述继续反应的温度为50～100℃，优选60～100℃；所述有机溶剂选自甲苯、二甲苯、NMP、乙酸乙酯、乙酸异丙酯、异丙醇、乙醇、叔丁醇、乙腈或DMF；所述碱选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙基胺、氢氧化锂、氢氧化钠或氢氧化钾。
  13. 根据权利要求10所述的合成方法，其特征在于在步骤(5)中，脱甲基化反应中采用脱甲基化试剂，所述脱甲基化试剂选自BBr 3、乙硫醇钠或溴化锂，脱甲基化反应的温度为-50～150℃；溴化反应的溴源选自NBS、二溴海因或溴，溴化反应的温度为20～45℃；脱甲基化反应或溴化反应中的反应溶剂选自二氯甲烷、乙酸、DMF、NMP 和水中的一种或几种。
  14. 一种3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成方法，其特征在于它包括如下步骤：
    (1)化合物9进行脱甲基化反应，得到化合物11；
    (2)化合物11通过溴化反应得到化合物12，再通过卤化反应得到化合物IX；
    (3)化合物IX与化合物1先在有机溶剂中加热进行反应，所得反应产物与碱再在水存在的条件下加热继续反应，得到化合物7；或者化合物IX与化合物1和碱先在有机溶剂中加热进行反应，所得反应产物再在水存在的条件下加热继续反应，得到化合物7；
    Figure PCTCN2020072582-appb-100005
    其中，R 9为Cl、Br或I。
  15. 根据权利要求14所述的合成方法，其特征在于在步骤(1)中，脱甲基化反应中的脱甲基化试剂选自BBr 3、乙硫醇钠或溴化锂；在步骤(2)中，溴化反应的溴化试剂为NBS、二溴海因或溴；优选的，溴化反应中采用NBS，溶剂选自DMF；步骤(2)中的卤化反应在卤化试剂存在下进行，所述卤化试剂选自氯气、NCS、氯化铵、氯化氢、磺酰氯、碘、NIS、碘化钠、碘化钾、NBS、溴或二溴海因，卤化反应的溶剂选自乙腈、甲醇、乙酸、丙酸、氯仿或乙酸乙酯。
  16. 根据权利要求14所述的合成方法，其特征在于在步骤(3)中，化合物IX与化合物1的反应温度为75～150℃，优选77～100℃；所述继续反应的温度为50～100℃，优选60～100℃；所述有机溶剂选自甲苯、二甲苯、NMP、乙酸乙酯、乙酸异丙酯、异丙醇、乙醇、叔丁醇、乙腈或DMF；所述碱选自碳酸钠、碳酸钾、碳酸氢钠、碳酸 氢钾、三乙胺、二异丙基乙基胺、氢氧化锂、氢氧化钠或氢氧化钾。
PCT/CN2020/072582 2019-01-19 2020-01-17 3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成 WO2020147803A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US17/310,123 US20220041593A1 (en) 2019-01-19 2020-01-17 Synthesis for 3-bromo-5-(2-ethylimidazo[1, 2-alpha]pyridine- 3-carbonyl)-2-hydroxybenzonitrile
KR1020217026328A KR102674919B1 (ko) 2019-01-19 2020-01-17 3-브로모-5-(2-에틸이미다조[1,2-a]피리딘-3-카르보닐)-2-하이드록시벤조니트릴의 합성
JP2021541467A JP7237385B2 (ja) 2019-01-19 2020-01-17 ３－ブロモ－５－（２－エチルイミダゾ［１，２－ａ］ピリジン－３－カルボニル）－２－ヒドロキシベンゾニトリルの合成
EP20740931.9A EP3915984B1 (en) 2020-01-17 Synthesis of 3-bromo-5-(2-ethylimidazo[1,2-alpha]pyridine-3-carbonyl)-2-hydroxybenzonitrile

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201910057056 2019-01-19
CN201910057056.3 2019-01-19
CN202010037085.6A CN111410654B (zh) 2019-01-19 2020-01-14 3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成
CN202010037085.6 2020-01-14

Publications (1)

Publication Number Publication Date
WO2020147803A1 true WO2020147803A1 (zh) 2020-07-23

Family

ID=71489055

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/072582 WO2020147803A1 (zh) 2019-01-19 2020-01-17 3-溴-5-(2-乙基咪唑并[1,2-a]吡啶-3-羰基)-2-羟基苯甲腈的合成

Country Status (6)

Country Link
US (1) US20220041593A1 (zh)
JP (1) JP7237385B2 (zh)
KR (1) KR102674919B1 (zh)
CN (1) CN111410654B (zh)
TW (1) TWI725710B (zh)
WO (1) WO2020147803A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023221078A1 (en) * 2022-05-20 2023-11-23 Jiangsu Atom Bioscience And Pharmaceutical Co., Ltd. Solid forms of a compound for treating or preventing hyperuricemia or gout

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018090921A1 (zh) * 2016-11-16 2018-05-24 江苏新元素医药科技有限公司 Urat1抑制剂及其应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2647451B1 (fr) * 1989-05-26 1994-08-05 Sanofi Sa Derives d'imidazo(1,2-a)pyridine, procede de preparation, compositions pharmaceutiques les contenant
UA112425C2 (uk) * 2010-12-13 2016-09-12 Еррей Біофарма Інк. ЗАМІЩЕНІ N-(1H-ІНДАЗОЛ-4-ІЛ)ІМІДАЗО[1,2-a]ПІРИДИН-3-КАРБОКСАМІДНІ СПОЛУКИ ЯК ІНГІБІТОРИ РЕЦЕПТОРНОЇ ТИРОЗИНКІНАЗИ ІІІ ТИПУ
CA2998034C (en) * 2015-09-10 2021-05-04 Dongfang Shi A group of compounds used for the treatment or prevention of hyperuricemia or gout
CN106357000B (zh) * 2016-09-29 2019-07-23 北京东土科技股份有限公司 基于工业互联网架构的智能变电站保护控制系统
CN108484600B (zh) * 2017-05-26 2022-12-13 江苏新元素医药科技有限公司 促尿酸排泄的urat1抑制剂

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018090921A1 (zh) * 2016-11-16 2018-05-24 江苏新元素医药科技有限公司 Urat1抑制剂及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3915984A4

Also Published As

Publication number Publication date
CN111410654A (zh) 2020-07-14
KR102674919B1 (ko) 2024-06-12
EP3915984A1 (en) 2021-12-01
EP3915984A4 (en) 2022-12-14
CN111410654B (zh) 2022-05-17
KR20210126614A (ko) 2021-10-20
TWI725710B (zh) 2021-04-21
JP2022517643A (ja) 2022-03-09
US20220041593A1 (en) 2022-02-10
JP7237385B2 (ja) 2023-03-13
TW202035407A (zh) 2020-10-01

Similar Documents

Publication Publication Date Title
NO338558B1 (no) Metode for fremstilling av aminotiazolderivater
JP2008525363A (ja) プロスタグランジン媒介疾患治療のためのピリジン化合物
JP2018065832A (ja) ベンズイミダゾール誘導体の製造方法
CN105566237B (zh) 一种治疗痛风的三唑巯乙酸类化合物的制备方法
JP6143877B2 (ja) ２−アリールセレナゾール化合物及びその薬剤組成物
WO2023201802A1 (zh) 一种恩赛特韦的合成方法
JP2023103364A (ja) 化合物、その薬学的に許容される塩又は立体異性体、及びその使用
CN106146518A (zh) 一种布鲁顿酪氨酸激酶抑制剂中间体及其制备方法
TWI725710B (zh) 3-溴-5-(2-乙基咪唑並[1,2-a]吡啶-3-羰基)-2-羥基苯甲腈的合成
WO2012174685A1 (zh) 一种2-取代-2h-1，2，3-三氮唑衍生物的制备方法
KR20170129191A (ko) (4s)-4-[4-사이아노-2-(메틸설폰일)페닐]-3,6-다이메틸-2-옥소-1-[3-(트라이플루오로메틸)페닐]-1,2,3,4-테트라하이드로 피리미딘-5-카보나이트릴의 생성 방법
CZ293246B6 (cs) Způsob výroby 2-aryl-3-aryl-5-halogenpyridinů
TW202200546A (zh) 芳香醚類化合物的製備方法
US7109353B2 (en) Process for preparing 5,6-dihydro-4-(S)-(ethylamino)-6-(S) methyl-4H-thieno[2,3b]thiopyran-2-sulphonamide-7,7-dioxide HCl
EP3915984B1 (en) Synthesis of 3-bromo-5-(2-ethylimidazo[1,2-alpha]pyridine-3-carbonyl)-2-hydroxybenzonitrile
JP2005504770A (ja) ５−スルホンアミド−８−ヒドロキシ−１，６−ナフチリジン−７−カルボキサミドの製造方法
CA2085347C (en) Novel cyclic aminophenylacetic acid derivative, production therof, and immune response modulator containing the same as active ingredient
WO2011082623A1 (zh) 一种非布索坦的制备方法
WO2017004964A1 (zh) 一种3-[5-(2-氟苯基)-1，2，4-噁二唑-3-基]苯甲酸的制备方法
JPWO2019140095A5 (zh)
TW201534607A (zh) 製備經取代的［１，２，４］三唑并［１，５－ａ］吡啶化物之方法
CN118026948A (zh) 三联芳环类化合物及其制备方法、药物组合物和应用
JPH0128013B2 (zh)
KR20110129622A (ko) 아조세미드 제조방법
JP2003160557A (ja) Ｎ−アルキルマレイミドの精製方法およびｎ−アルキルマレイミド組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20740931

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021541467

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020740931

Country of ref document: EP

Effective date: 20210819