CN116354983A - Phenyl substituted compound, preparation method and application thereof - Google Patents

Phenyl substituted compound, preparation method and application thereof Download PDF

Info

Publication number
CN116354983A
CN116354983A CN202111618495.0A CN202111618495A CN116354983A CN 116354983 A CN116354983 A CN 116354983A CN 202111618495 A CN202111618495 A CN 202111618495A CN 116354983 A CN116354983 A CN 116354983A
Authority
CN
China
Prior art keywords
compound
formula
added
methyl
ethyl
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
Application number
CN202111618495.0A
Other languages
Chinese (zh)
Inventor
储刚
金建淋
陈志金
符伟
刘强
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Huicheng Pharmaceutical Co ltd
Original Assignee
Nanjing Huicheng Pharmaceutical Co ltd
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 Nanjing Huicheng Pharmaceutical Co ltd filed Critical Nanjing Huicheng Pharmaceutical Co ltd
Priority to CN202111618495.0A priority Critical patent/CN116354983A/en
Publication of CN116354983A publication Critical patent/CN116354983A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a phenyl substituted compound, a preparation method thereof and application of the phenyl substituted compound serving as a reference substance in qualitative and/or quantitative analysis of related impurities in quality research of (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidine-3 (4H) -yl) benzoic acid bulk drug.

Description

Phenyl substituted compound, preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and in particular relates to a phenyl substituted compound, a preparation method thereof and application of the phenyl substituted compound serving as a reference substance in quality research of (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidine-3 (4H) -yl) benzoic acid (also known as (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-3 (2H) -yl) benzoic acid) raw material medicine.
Background
Acetyl-coa carboxylase (ACC) is a biotin enzyme that catalyzes the acetyl-coa reaction to malonyl-coa, which is the rate limiting step in restricting the first stage of fatty acid synthesis. In mammals, ACC exists in the form of two tissue-specific isozymes, with ACC1 being present primarily in lipid-producing tissues such as liver and fat, and ACC2 being present primarily in oxidized tissues such as liver, heart and skeletal muscle. ACC1 and ACC2 are encoded by separate genes, sharing 75% overall amino acid sequence identity, although exhibiting different cellular distributions. In the liver, fatty Acid (FA) synthesis and elongation is malonyl-coa, which catalyzes the production of acetyl-coa by ACC1, contributing to triglyceride formation and Very Low Density Lipoprotein (VLDL) production. Malonyl-coa formed by ACC2 functions to regulate FA oxidation in hearts and skeletal muscles with limited ability to synthesize fatty acids [ Tong L, harwood HJ jr.j Cell biochem.2006,99 (6): 1476-1788 ].
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are considered to be two manifestations of abnormal liver metabolism, the most common chronic liver disease at present, and their incidence is rising year by year. NASH may further progress to cirrhosis and liver cancer, possibly causing death due to liver disease. At present, the diseases lack effective treatment strategies, the existing treatment medicines are insulin sensitizers and antioxidants (such as vitamin E) represented by thiazolidinediones, and the treatment effects of the existing treatment medicines comprise lipid-lowering medicines, angiotensin receptor antagonists, polyunsaturated fatty acids and the like are very limited. In many studies today, ACC1 and ACC2 are considered promising drug action targets for the treatment of NAFLD and NASH [ Geraldine Harriman, jerey Greenwood, sathesh Bhat, et al Proc Natl Acad Sci U.S. A.2016,113 (13): E1796-E1805 ]. There has been some progress and research basis for drug studies targeting the ACC pathway that can inhibit de novo (de novo) synthesis of intracellular fat in the liver by inhibiting ACC1 and ACC2, a treatment regimen that can significantly reduce liver fat content and cirrhosis, while earlier reducing liver fibrosis marker levels. Additional studies have shown that simultaneous inhibition of ACC1 and ACC2 reduces the ability of FA to regenerate in tumor tissue, with the effect of inhibiting tumor cell growth [ Svensson RU, parker SJ, eichner LJ, et al Nat Med.2016,22 (10): 1108-1119 ]. CN201910071777.X discloses that the compound of formula (I) has good inhibitory activity on ACC1 and ACC2, and is expected to be a more effective and safer medicament for treating metabolic liver diseases such as fatty liver, nonalcoholic fatty liver hepatitis (NASH) and the like.
Figure BDA0003437171580000021
Disclosure of Invention
The compounds of formula (I) and their derivatives, such as pharmaceutically acceptable salts, isomers, crystalline forms or solvates of the compounds of formula (I), may contain impurities of various origins as bulk drugs, which may be detrimental to their potency, safety and efficacy. Therefore, research on the impurity or the property of the impurity of the compound of the formula (I) and the derivative thereof is of great significance for detection and control of the impurity or the impurity.
In one aspect, the present invention provides a compound of formula (C):
Figure BDA0003437171580000022
preferably, the purity of the compound of formula (C) prepared is at least 90% isolated (area normalization according to HPLC judgment). In some embodiments, the compound of formula (C) is isolated to have a purity of at least 93%. In some embodiments, the compound of formula (C) is isolated and prepared at a purity of at least 95%. In some embodiments, the compound of formula (C) is isolated to a purity of at least 97%. In other embodiments, the compound of formula (C) is isolated and prepared at a purity of at least 98%.
In another aspect, the present invention provides a process for the preparation of a compound of formula (C), comprising the reaction steps of:
Figure BDA0003437171580000023
1) reacting a compound of formula (C-1), a compound of formula (C-2) and triphosgene under the action of an alkaline reagent to produce a compound of formula (C-3);
2) Reacting the compound of formula (C-3) with an alkaline reagent to form a compound of formula (C-4);
3) The compound of formula (C-4) is reacted with N, N' -carbonyldiimidazole to produce a compound of formula (C-5)
4) Reacting the compound of formula (C-5) with a brominating reagent to produce a compound of formula (C-6);
5) Reacting a compound of formula (C-6) with a compound of formula (C-7) under the action of an alkaline reagent to produce a compound of formula (C-8);
6) Reacting a compound of formula (C-8) with a compound of formula (C-9) to produce a compound of formula (C);
wherein the basic reagent of step 1) includes, but is not limited to, triethylamine; the alkaline reagent of step 2) includes, but is not limited to, sodium metal reagent; the brominating reagent in step 4) includes, but is not limited to, N-bromosuccinimide; the alkaline reagent of step 5) includes, but is not limited to, potassium carbonate, potassium bicarbonate, sodium carbonate, cesium carbonate or cesium bicarbonate.
In another aspect, the present invention also provides a method for determining the purity of a compound of formula (C), characterized in that:
the chromatographic conditions are as follows: chromatographic column: octadecylsilane chemically bonded silica as packing (Agilent Eclipse Plus C, 4.6X105 mm,3.5 μm or equivalent performance column); mobile phase a:0.01mol/L ammonium acetate solution (pH 5.0); mobile phase B: acetonitrile; column temperature: 25 ℃; flow rate: 1.1mL per minute; detection wavelength: 240nm; dilution liquid: methanol-water (60:40);
the gradient elution procedure was as follows:
Figure BDA0003437171580000031
the measuring method comprises the following steps:
test solution: taking a proper amount of the compound, precisely weighing, adding methanol for ultrasonic dissolution and quantitatively diluting with methanol-water (60:40) to prepare a solution containing about 0.5mg of the compound in each 1mL;
sensitivity solution: precisely weighing a proper amount of corresponding sample solution, and quantitatively diluting 2000 times by adding methanol-water (60:40) to prepare a solution containing about 0.25 mug per 1mL;
precisely measuring the sensitivity solution and the sample solution, respectively injecting into a liquid chromatograph, and recording the chromatograms. The main peak S/N in the sensitivity solution is not less than 10, and the impurity chromatographic purity is calculated according to an area normalization method in the sample solution.
In another aspect, the present invention also provides the use of a compound of formula (C) as a reference control in the detection of impurities in a compound of formula (I).
In some specific embodiments, the use of a compound of formula (C) as a reference control in the detection of impurities in a compound of formula (I) is characterized in that it comprises the steps of:
chromatographic conditions:
chromatographic column: octadecylsilane chemically bonded silica as filler, (Agilent Eclipse Plus C, 4.6X105 mm,3.5 μm or equivalent performance chromatographic column)
Mobile phase a:0.01mol/L ammonium acetate solution (pH adjusted to 5.0.+ -. 0.1 with acetic acid)
Mobile phase B: acetonitrile
The gradient elution procedure was as follows:
Figure BDA0003437171580000041
column temperature: 25 ℃; flow rate: 1.1mL per minute; detection wavelength: 240nm; diluent: methanol-water (60:40)
System applicability test:
taking a proper amount of the compound reference substance of the formula (C), precisely weighing, placing into a measuring flask, adding methanol for ultrasonic dissolution, and diluting with methanol-water (60:40) to prepare a solution containing about 5.0 mug of the compound reference substance of the formula (C) per 1mL, wherein the solution is used as an impurity type compound reference substance positioning solution; taking a proper amount of a compound of formula (I) as a reference substance, precisely weighing, placing into a measuring flask, adding methanol to 50% of the volume of the measuring flask for ultrasonic dissolution, and quantitatively diluting with methanol-water (60:40) to prepare a solution containing about 2.5 mug of the compound as a reference substance solution per 1mL; a proper amount of the control solution was precisely measured, and diluted with methanol-water (60:40) to prepare a solution containing about 0.25. Mu.g per 1mL as a sensitivity solution. Precisely measuring impurity formula (C) compound reference substance positioning solution, sensitivity solution, and reference substance solution (10 μl), respectively, and injecting into liquid chromatograph, and recording chromatogram. The signal to noise ratio of the compound of formula (I) in the sensitivity solution is not less than 20; the RSD of the peak area of the control solution which is fed into 6 needles SH2442 is less than or equal to 5.0 percent.
Assay:
a proper amount of the compound of the formula (I) is taken, precisely weighed, added with methanol to 50% of the volume of a measuring flask for ultrasonic dissolution and quantitatively diluted with methanol-water (60:40) to prepare a solution containing about 0.5mg of the compound in each 1mL, and the solution is taken as a test sample solution. And precisely measuring 10 mu L of each of the blank diluent and the sample solution, respectively injecting into a liquid chromatograph, and recording a chromatogram. The chromatogram of the sample solution contains impurity formula (C) compound peaks, the impurity formula (C) compound correction factor is 1.0 calculated by the main component external standard method added with correction factors, and any impurity formula (C) compound less than 0.05% in the sample solution is negligible, and the calculation formula is as follows:
Figure BDA0003437171580000042
wherein:
W std : the weight of the compound of formula (I) as reference, mg;
W sam : weight, mg of the compound sample of formula (I);
A std : peak area of compound of formula (I) in control solution;
A sam : detecting the peak area of the impurity compound of formula (C) in the sample solution;
purity: content of compound of formula (I) control,%;
DF: dilution of the reference solution;
d: dilution of the sample solution;
f: correction factors.
In some embodiments of the invention, the impurity in the compound of formula (I) is less than or equal to 1.0% of the compound of formula (C).
The present invention provides a high purity compound of formula (C), which is an important impurity produced in the production process of the compound of formula (I). The high-purity compound of the formula (C) provided by the invention can effectively improve the scientificity and accuracy of detecting the impurity of the compound of the formula (I) and the preparation thereof, can effectively and conveniently monitor the impurity content of the compound of the formula (I), and is beneficial to optimizing the production process.
Description of the terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In the present invention, "purity" can be confirmed using conventional analytical methods, as can be easily calculated by area normalization by appropriate methods established and well known in the art, such as High Pressure Liquid Chromatography (HPLC), gas Chromatography (GC), etc., to completely separate the compound from other compounds.
The terms "hydrogen", "carbon", "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, isotopes of carbon include 13 C and C 14 Isotopes of C, oxygen include 16 O and 18 o, etc.
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples. The materials used in the examples below are commercially available unless otherwise specified.
Example 1 preparation of (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoic acid
Figure BDA0003437171580000051
Step 1: preparation of ethyl 2- (3- (3- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylate
Figure BDA0003437171580000061
Dichloromethane (79.5 kg) and ethyl 2-amino-4-methylthiophene-3-carboxylate (6.0 kg) were added to a 100L reactor, reacted with N, N' -carbonyldiimidazole (5.777 kg), under nitrogen protection, at 20-25℃overnight, after the reaction was completed, triethylamine (3.605 kg), ethyl 3-aminobenzoate methylsulfonate (9.309 kg) were added at 25℃overnight, after the reaction was completed, the reaction solution was slowly added to heptane in portions, the reaction solution was stirred for 0.5-1 h, centrifuged, rinsed with water, wet-product was beaten with water, beaten for 2h at 10-20℃and centrifuged, rinsed with water, and the solid was air-dried at 70.+ -. 5℃to obtain the title compound, 9.68kg in total, and 79.40% yield.
Step 2: preparation of 3- (5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoic acid
Figure BDA0003437171580000062
1, 4-dioxane (33.08 kg) and ethyl 2- (3- (3- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylate (3.2 kg) are added into a 100L reaction kettle, the temperature is raised and controlled to 50+/-5 ℃ until the 2- (3- (3- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylate is completely dissolved, potassium tert-butoxide (2.38 kg) is added after the complete dissolution, 50+/-5 ℃ is reacted for 0.5h, purified water is added after the reaction is finished, the reaction is stopped for 0.5h, hydrochloric acid is slowly added in batches, the pH is regulated to 2-3, the crystallization is carried out for more than 1h at 35+/-5 ℃, the crystallization is carried out for more than 8h at 15+/-5 ℃, the centrifugation and the water rinsing are repeated, the materials are added and the post-treatment are carried out at the other two 100L, and the solid is dried at 70 ℃ in an air blast for more than 8h, so that the title compound is obtained, which is 7.00kg and the yield is 90.90%.
Step 3: preparation of ethyl 3- (5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate
Figure BDA0003437171580000063
N, N-dimethylformamide (39.7 kg), 3- (5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidine-3 (4H) -yl) benzoic acid (6.98 kg) and N, N' -carbonyldiimidazole (5.62 kg) are added into a 100L reaction kettle, the reaction is carried out for 2 hours at 35+/-5 ℃ under the protection of nitrogen, absolute ethyl alcohol is added into the reaction liquid, the reaction is carried out overnight at 35+/-5 ℃, after the reaction is finished, the reverse liquid is slowly added into water in batches, the mixture is stirred for more than 3 hours at 15+/-5 ℃, centrifuged, rinsed with water, and dried by blast air at 70 ℃ for more than 8 hours. The title compound was obtained in a total of 6.62kg in 96.79% yield.
Step 4: preparation of ethyl 3- (6-bromo-5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate
Figure BDA0003437171580000064
N, N-dimethylacetamide (41.38 kg) and 3- (5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidine-3 (4H) -yl) ethyl benzoate (2.945 kg) are added into a 100 reaction kettle, the temperature is reduced to minus 20 ℃ after the solid is dissolved, N-dimethylacetamide (13.79 kg) solution of N-bromosuccinimide (1.587 kg) is dropwise added, the temperature is maintained to be no higher than minus 20 ℃ after the dropwise addition is completed, the stirring is maintained for 0.5H, the temperature is raised to be dissolved until the solid is dissolved after the reaction is completed, purified water is dropwise added, the temperature is controlled to be no higher than 30 ℃, the dropwise addition is completed, the crystallization is carried out at 10-15 ℃ for 3H, the centrifugation and the water rinsing are repeated, the material adding and the post-treatment are carried out at the other 100L, the temperature is 70 ℃ and the air drying is carried out for 8H to obtain the crude product of the title compound, the total 6.105kg, and the yield is 83.92%.
1, 4-dioxane (33.08 kg) and 3- (6-bromo-5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidine-3 (4H) -yl) ethyl benzoate crude product (3.05 kg) are added into a 100L reaction kettle, the temperature is raised to 85 ℃, purified water (13.70 kg) is added dropwise after the solid is dissolved, the temperature is maintained for stirring for 15-30 min after the dripping is finished, the filtration is carried out while the filtrate is hot, crystallization is carried out for 1H at 15+/-5 ℃, centrifugation is carried out, rinsing with water, refluxing and pulping wet methanol for 1H, crystallization is carried out for 1H at 15+/-5 ℃, centrifugation is carried out, rinsing with methanol is carried out, feeding and post treatment are repeated for more than 100L, and blast drying is carried out at 70 ℃ for more than 8H, so as to obtain the title compound, the total yield is 5.05kg, and 82.80%.
Step 5: preparation of ethyl (R) -3- (6-bromo-1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate
Figure BDA0003437171580000071
1-methyl-2-pyrrolidone (29.390 kg) and 3- (6-bromo-5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2, 3-d) were charged into a 50L vertical jacketed reaction vessel]Pyrimidine-3 (4H) -yl) benzoic acid ethyl ester (2.859 kg), (R) -4- (2-bromo-1- (2-methoxyphenyl) ethoxy) tetrahydro-2H-pyran (2.000 kg) and potassium carbonate (1.450 kg), stirring is started, nitrogen protection is started, heating is started, and the temperature is controlled to be 120-130 ℃. After the reaction was completed, the reaction mixture was cooled to 25.+ -. 5 ℃. Methyl tertiary butyl ether and water are added, and after stirring for 20-30min, the mixture is left to stand for delamination, the aqueous layer is removed, and the organic layer is retained. The organic layers were combined, water (28.600 kg) was added, stirred, allowed to stand for delamination, the aqueous layer was removed, the organic layer was retained, the above procedure was repeated, and the two organic layers were combined. Concentrating under reduced pressure, adding ethanol (3.945 kg) into a rotary steaming bottle, vacuum rotating until no solid adheres to the wall, transferring the suspension into a 50L reaction kettle, stirring, heating and refluxing for 30min, cooling to 20-30deg.C, filtering, and leaching the filter cake with ethanol (0.395 kg). The solid was air dried at 50.+ -. 5 ℃ to give the title compound in a total of 2.530kg in 61.87% yield. ESI-MS [ M+H ]] + m/z:643.1。
Step 6: preparation of ethyl (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate
Figure BDA0003437171580000081
Into a 10L four port reaction flask, ethyl 1, 4-dioxane (6.460 kg), (R) -3- (6-bromo-1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate (1.250 kg), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (0.557 kg), tris (dibenzylideneacetone) dipalladium (0.267 kg) and 2- (tri-n-butylstannyl) oxazole (0.769 kg) were charged, and the reaction was stopped by replacing 3-5 times with nitrogen gas, stirring with heating and refluxing for 30 min. The reaction solution was filtered at 60-100℃to remove solids, and the filtrate was collected. Repeating the above steps, combining the two filtrates, and concentrating under reduced pressure. Ethanol (3.945 kg) is added into a rotary steaming bottle, after the rotary steaming bottle rotates until no solid adheres to the wall, the suspension is transferred into a reaction kettle, the suspension is stirred for 0.5 to 1.0h at 15+/-5 ℃ and then n-heptane (11.790 kg) is added, after stirring for 3 to 5h, the solid is obtained after centrifugation; the solid was transferred to a 100L reactor, n-heptane (25.650 kg) was added, heated to 55±5 ℃, stirred for 0.5h, centrifuged to give a solid, and the solid was air-dried at 50±5 ℃ to give 2.090kg of crude title compound.
Methanol (4.100 kg), ethyl acetate (4.680 kg) and crude products of the title compounds (2.085 kg) are added into a 50L reaction kettle, heating, refluxing and stirring are carried out, when the temperature is 70+/-5 ℃, mercaptosilica gel (0.100 kg) is added, stirring is carried out for 30min, hot suction filtration is carried out, filtrate is transferred into the 50L reaction kettle, the temperature is reduced to 0-10 ℃, crystallization is carried out for more than 4 hours, filtration is carried out, a filter cake is leached by methanol (0.395 kg), solid is obtained, the solid is dried by blowing at 60+/-5 ℃ for more than 12 hours, and the title compound 1.310kg is obtained, and the yield is 53.30%. ESI-MS [ M+H ]] + m/z:632.2。
Step 7: preparation of (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoic acid
Figure BDA0003437171580000082
Methanol (4.27 kg) and tetrahydrofuran (14.4 kg) were added to a 100L reactor, ethyl (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate (2.156 kg) was added, and after stirring and dissolution, a solution of lithium hydroxide (131.2 g) in water (5.390 kg) was added, the temperature was controlled at 0 to 10℃and after completion of the dropwise addition, the reaction was stirred at room temperature. After the reaction was completed, the reaction mixture was cooled to 0 to 5℃and hydrochloric acid (1.08 kg) was added thereto to adjust the pH to 1 to 2, the precipitated solid was centrifugally filtered, and the cake was washed with water (5.000 kg) and air-dried at 60.+ -. 5℃for 12 hours or more. The title compound was obtained in a total amount of 2.025kg in 98.4%.
Example 2: preparation of methyl (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate
Figure BDA0003437171580000091
Step 1: preparation of methyl 2- (3- (3- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylate
Figure BDA0003437171580000092
Ethyl 2-amino-4-methylthiophene-3-carboxylate (10 g,54.05 mmol), triphosgene (6.4 g,21.60 mmol) was added to a two-necked flask, methylene chloride (200 mL) was added dropwise at-20℃under argon atmosphere, and after dissolution of the starting material, a methylene chloride solution of triethylamine (2.09 g,20.7 mmol) was slowly added dropwise to the reaction solution. After the reaction mixture was reacted at 0℃for 4 hours, methyl 3-aminobenzoate (8.93 g) was added thereto, and the reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with water (200 mL), the reaction was separated, the organic phase separated, the aqueous phase extracted twice with dichloromethane (200 mL), the organic phases combined, dried, and concentrated. Column chromatography purification afforded the title compound. ESI-MS [ M+H ]] + m/z: 363.
Step 2 preparation of 3- (5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoic acid
Figure BDA0003437171580000093
The procedure was analogous to the procedure of example 1, step 2, except that starting material 2- (3- (3- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylic acid ethyl ester was replaced with methyl 2- (3- (3- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylate to give the title compound.
Step 3 preparation of methyl 3- (5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate
Figure BDA0003437171580000094
The procedure was analogous to that of example 1, step 3, producing the title compound.
Step 4 preparation of methyl 3- (6-bromo-5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate
Figure BDA0003437171580000101
Methyl 3- (5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate (80 g, 0.803 mol,1.0 eq) was added to N, N-dimethylacetamide (1.2L), cooled to-10℃and a mixture of N-bromosuccinimide (NBS, 45.06g, 0.803 mol,1.0 eq) and N, N-dimethylacetamide (0.4L) was added dropwise thereto, the reaction was completed for 1.5 hours, 1.6L of water was added to the reaction solution, stirred for 2 hours, filtered and dried to obtain 90.0g of the title compound.
Step 5 preparation of (R) -methyl 3- (6-bromo-1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate
Figure BDA0003437171580000102
Methyl 3- (6-bromo-5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate (70 g,177.67mmol, 1.0 eq), (R) -4- (2-bromo-1- (2-methoxyphenyl) ethoxy) tetrahydro-2H-pyran (72.5 g,230.89mmol,1.3 eq) and potassium carbonate (49 g,355mmol,2.0 eq) were added to 1-methyl-2-pyrrolidone (700 mL), the reaction was warmed to 125℃and after completion, the reaction solution was added to 700mL of methyl tert-butyl ether, 700mL of water was added, stirred for 20min, and the solid was filtered to give the title compound.
Step 6: preparation of methyl (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate
Figure BDA0003437171580000103
(R) -3- (6-bromo-1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 2-dihydrothieno [2,3-d]Methyl pyrimidin-3 (4H) -yl) benzoate (45.18 g,71.77mmol,1.0 eq) 2- (tri-n-butylstannyl) oxazole (28.42 g, 79.44mmol,1.1 eq) and tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 1.1g,1.20mmol,0.02 eq), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (xphos, 20.61g,43.23mmol,0.60 eq) was added to 1, 4-dioxane (450 mL), the reaction was started, after completion of the reaction, the reaction solution was cooled to 60 ℃, filtered, the filtrate concentrated to dryness, 150mL ethyl acetate was added and stirred for 30min, and 350mL heptane was added and stirred for 2.5h, filtered, and air-dried. The solid was dissolved in 500mL of heptane, slurried for 30min, filtered, the wet product was dissolved in 150mL of methanol and 150mL of ethyl acetate, refluxed, 1.0g of mercaptosilica gel was added, hot filtered, and the filtrate was crystallized for 3h, and filtered to obtain the wet product. The wet product and filtrate were combined and purified by column chromatography to afford 28g of the title compound. 1 H NMR(500MHz,DMSO-d 6 ):δ8.21(s,1H),8.07(d, J＝8.0Hz,1H),7.90(s,1H),7.69(t,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),7.52(d,J＝7.5Hz,1H),7.39(s, 1H),7.32(t,J＝7.5Hz,1H),7.05(t,J＝7.5Hz,1H),7.01(d,J＝8.0Hz,1H),5.37(t,J＝7.0Hz,1H),4.14(d, J＝11.5Hz,1H),4.05(t,J＝7.0Hz,1H),3.90(s,3H),3.81(s,3H),3.64-3.62(m,2H),3.45(t,J＝3.5Hz,1H), 3.34-3.25(m,2H),2.79(s,3H),1.73-1.66(m,2H),1.39-1.31(m,2H).ESI-MS m/z:[M+H] + ＝640.2.
Example 3: preparation of the Compound of formula (I) (lithium bromide 10 equivalent)
Tetrahydrofuran (8.87 g) was added to a 100mL reaction flask, ethyl (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate (2.00 g), triethylamine (1.60 g) was added followed by methanol (3.96 g) and then a solution of lithium bromide (2.76 g) in water (5.00 g) was added dropwise after the dropwise addition was completed, and after the dropwise addition was completed, the mixture was heated to reflux, sampled (lot number: 1), and HPLC (above measurement method) was used to monitor the content of the compound of the impurity formula (C).
Example 4: preparation of the Compound of formula (I) (lithium bromide 20 equivalent)
Tetrahydrofuran (8.87 g) was added to a 100mL reaction flask, ethyl (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate (2.00 g), triethylamine (1.60 g) was added followed by methanol (3.96 g) and then a solution of lithium bromide (5.52 g) in water (5.00 g) was added dropwise after the dropwise addition was completed, and after the dropwise addition was completed, the mixture was heated to reflux, sampled (lot number: 2), and HPLC (above measurement method) was used to monitor the content of the compound of the impurity formula (C).
Example 5: preparation of the Compound of formula (I) (lithium bromide 30 equivalent)
Tetrahydrofuran (8.87 g) was added to a 100mL reaction flask, ethyl (R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) benzoate (2.00 g), triethylamine (1.60 g) was added followed by methanol (3.96 g) and then a solution of lithium bromide (8.28 g) in water (5.00 g) was added dropwise after the dropwise addition was completed, and after the dropwise addition was completed, the mixture was heated to reflux, sampled (lot number: 3), and HPLC (above measurement method) was used to monitor the content of the compound of the impurity formula (C).
The equivalents of lithium bromide were examined, and the progress of the reaction was monitored by HPLC using 10, 20, 30 equivalents of lithium bromide, respectively, with specific test data as shown in table 1 below:
TABLE 1
Figure BDA0003437171580000121
The test result shows that when the lithium bromide is 10 equivalents, the impurity of the formula (C) is larger, and the yield of the target compound of the formula (I) is lower; lithium bromide in the range of 20-30 equivalents can be reacted completely without significant differences in the progress of the reaction. In the established protocol, the amount of lithium bromide used is 20 equivalents.
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above, but rather is to be attributed to the claims.

Claims (6)

1. A compound represented by formula (C):
Figure FDA0003437171570000011
2. the compound of formula (C) according to claim 1, wherein the purity of the compound of formula (C) is at least 90%.
3. The compound of formula (C) according to claim 1, wherein the compound of formula (C) has a purity of at least 95%.
4. A process for preparing a compound of formula (C), comprising the reaction steps of:
Figure FDA0003437171570000012
1) reacting a compound of formula (C-1), a compound of formula (C-2) and triphosgene under the action of an alkaline reagent to produce a compound of formula (C-3);
2) Reacting the compound of formula (C-3) with an alkaline reagent to form a compound of formula (C-4);
3) Reacting a compound of formula (C-4) with N, N' -carbonyldiimidazole to form a compound of formula (C-5);
4) Reacting the formula (C-5) with a brominating reagent to produce a compound of formula (C-6);
5) Reacting a compound of formula (C-6) with a compound of formula (C-7) under the action of an alkaline reagent to produce a compound of formula (C-8);
6) The compound of formula (C-8) is reacted with a compound of formula (C-9) to produce a compound of formula (C).
5. The method for preparing a compound represented by formula (C) according to claim 4, wherein the alkaline agent in step 5) is selected from potassium carbonate, potassium bicarbonate, sodium carbonate, cesium carbonate or cesium bicarbonate.
6. The use of a compound of formula (C) according to claim 1 as a reference control.
CN202111618495.0A 2021-12-27 2021-12-27 Phenyl substituted compound, preparation method and application thereof Pending CN116354983A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111618495.0A CN116354983A (en) 2021-12-27 2021-12-27 Phenyl substituted compound, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111618495.0A CN116354983A (en) 2021-12-27 2021-12-27 Phenyl substituted compound, preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN116354983A true CN116354983A (en) 2023-06-30

Family

ID=86910325

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111618495.0A Pending CN116354983A (en) 2021-12-27 2021-12-27 Phenyl substituted compound, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN116354983A (en)

Similar Documents

Publication Publication Date Title
EP1251130B1 (en) Fused purine derivatives
US20230061083A1 (en) Kras g12c inhibitor compound and use thereof
CN115315427B (en) HPK1 inhibitor and preparation method and application thereof
CN107531678B (en) EGFR inhibitor and pharmaceutically acceptable salts and polymorphs thereof and uses thereof
CN113527335A (en) Macrocyclic compound as EGFR inhibitor and application thereof
JP2003522166A (en) Compound having antitumor activity: method for producing the same and pharmaceutical composition containing the same
CN113387957B (en) Spirocyclic indolone-pyrrolidine carbonate compound and composition, preparation method and application thereof
US20230095530A1 (en) Compound used as ret kinase inhibitor and application thereof
CN116354983A (en) Phenyl substituted compound, preparation method and application thereof
CN109809971B (en) Poly-benzyl derivative, pharmaceutical composition thereof, preparation method and application thereof
JP7301222B2 (en) Substituted tricyclic compounds as PRMT5 inhibitors and their applications
AU2009242219B2 (en) Benzocycloheptane and benzoxepine derivatives
CN115785088A (en) Compounds as SOS1 inhibitors and uses thereof
CN116354948A (en) Phenyl substituted compound, preparation method and application thereof
EP4159731A1 (en) New pyrazine compound
CN114746426B (en) Crystal forms as ACC1 and ACC2 inhibitors, and preparation method and application thereof
CN114133397B (en) Evodiamine compound and preparation method and application thereof
CN109400667B (en) Special isosteroid alkaloid and application of derivative thereof
RU2622386C2 (en) Derivatives of sitaxenthan
EP4071153B1 (en) Crystal form of thieno[2,3-c]pyridazine-4(1h)-one compound, preparation method therefor and use thereof
CN117384162A (en) Selective HER2 inhibitors
CN117100752A (en) Medical use of glucagon-like peptide-1 (GLP-1) receptor agonists
CN115335377A (en) Pyridopyrimidinones
CN117447460A (en) Heterocyclic compounds as RIPK1 inhibitors
CN113968871A (en) Crystalline forms of a phenyl-substituted ACC inhibitor

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication