CN114835641A - Synthetic method of 3-benzyl-6-bromo-2-methoxyquinoline - Google Patents
Synthetic method of 3-benzyl-6-bromo-2-methoxyquinoline Download PDFInfo
- Publication number
- CN114835641A CN114835641A CN202210490894.1A CN202210490894A CN114835641A CN 114835641 A CN114835641 A CN 114835641A CN 202210490894 A CN202210490894 A CN 202210490894A CN 114835641 A CN114835641 A CN 114835641A
- Authority
- CN
- China
- Prior art keywords
- compound
- bromo
- benzyl
- reacting
- steps
- 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.)
- Granted
Links
- WMFHVNYOCKTDMX-UHFFFAOYSA-N 3-benzyl-6-bromo-2-methoxyquinoline Chemical compound COC1=NC2=CC=C(Br)C=C2C=C1CC1=CC=CC=C1 WMFHVNYOCKTDMX-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title claims description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 23
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 20
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 16
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 14
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 claims abstract description 13
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000001308 synthesis method Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 4
- MFEILWXBDBCWKF-UHFFFAOYSA-N 3-phenylpropanoyl chloride Chemical compound ClC(=O)CCC1=CC=CC=C1 MFEILWXBDBCWKF-UHFFFAOYSA-N 0.000 claims abstract description 3
- -1 N- (4-bromo-2-formylphenyl) -3-phenylacrylamide Chemical compound 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 239000007787 solid Substances 0.000 claims description 34
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- 238000004537 pulping Methods 0.000 claims description 10
- 238000001514 detection method Methods 0.000 claims description 9
- XZBXAYCCBFTQHH-UHFFFAOYSA-N 3-chloropropylbenzene Chemical compound ClCCCC1=CC=CC=C1 XZBXAYCCBFTQHH-UHFFFAOYSA-N 0.000 claims description 8
- 238000002386 leaching Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- VBYZWJMZASVGNB-UHFFFAOYSA-N 2-amino-5-bromobenzaldehyde Chemical compound NC1=CC=C(Br)C=C1C=O VBYZWJMZASVGNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000007530 organic bases Chemical group 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 125000003172 aldehyde group Chemical group 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000007711 solidification Methods 0.000 abstract description 2
- 230000008023 solidification Effects 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 4
- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical compound C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 QUIJNHUBAXPXFS-XLJNKUFUSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229960000508 bedaquiline Drugs 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 3
- 230000002365 anti-tubercular Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- IMOLAGKJZFODRK-UHFFFAOYSA-N 2-phenylprop-2-enamide Chemical compound NC(=O)C(=C)C1=CC=CC=C1 IMOLAGKJZFODRK-UHFFFAOYSA-N 0.000 description 1
- UGXUDVNBDYIJHJ-UHFFFAOYSA-N 3-benzyl-6-bromo-2-chloroquinoline Chemical compound ClC1=NC2=CC=C(Br)C=C2C=C1CC1=CC=CC=C1 UGXUDVNBDYIJHJ-UHFFFAOYSA-N 0.000 description 1
- MOSDRQBDAXYTJC-UHFFFAOYSA-N C=C(C(NC(C=C1)=CC=C1Br)=O)C1=CC=CC=C1 Chemical compound C=C(C(NC(C=C1)=CC=C1Br)=O)C1=CC=CC=C1 MOSDRQBDAXYTJC-UHFFFAOYSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 208000015355 drug-resistant tuberculosis Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline; the synthesis method comprises the following steps: the method comprises the following steps: p-bromoaniline reacts with phosphorus oxychloride and N, N-dimethylformamide to generate a compound I; step two: reacting the compound I with phenylpropionyl chloride to generate N- (4-bromo-2-formylphenyl) -3-phenylacrylamide; step three: reacting the compound II with phosphorus oxychloride to generate a compound III; step four: reacting the compound III with sodium methoxide to generate a compound IV; the reaction process is clearer, and the yield is obviously improved compared with the original process; the Vilsmeier-Haake provided by the invention only needs one aldehyde group, and simultaneously increases the solvent to participate in the reaction process, thereby avoiding the problems of insufficient reaction, severe heat release and the like which are not beneficial to large-scale production operation caused by the solidification phenomenon in the early reaction of phosphorus oxychloride and N, N-dimethylformamide.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline.
Background
Bedaquiline was a drug developed by hadamard corporation and approved by the U.S. food and drug administration for the treatment of drug-resistant tuberculosis at 12/28 of 2012. The chemical name of the mycobacterium tuberculosis anti-tuberculosis compound is (1R,2S) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol, and the bedaquiline prevents the mycobacterium tuberculosis from utilizing ATP to generate energy by inhibiting a proton transfer chain of ATP synthetase of the mycobacterium, so that the mycobacterium tuberculosis anti-tuberculosis compound plays a role in tuberculosis resistance, and is a brand new action way for resisting the mycobacterium tuberculosis. Bedaquinoline is the first anti-tuberculosis drug with a new action mechanism approved for clinical use for more than 40 years, and is the only drug for treating multi-drug resistant tuberculosis at present. 3-benzyl-6-bromo-2-methoxyquinoline is an important intermediate for synthesizing bedaquiline, and original research US2005148581 reports that phenylpropionyl chloride is used as a raw material to react with p-bromoaniline to obtain N- (4-bromophenyl) phenylacrylamide, then the phenylacrylamide reacts with phosphorus oxychloride and N, N-dimethylformamide to generate Vilsmeier-Haake reaction to obtain 3-benzyl-6-bromo-2-chloroquinoline, and finally the 3-benzyl-6-bromo-2-methoxyquinoline is reacted with sodium methoxide. Although the method has short steps, the Vilsmeier-Haake reaction has violent heat release and is not beneficial to large-scale production operation. Meanwhile, the one-step reaction involves three reaction steps of aldehyde group addition, cyclization and chlorination, so that the reaction probability is high, the purity of a reaction system is low, and the yield is low.
Disclosure of Invention
The purpose of the invention is: overcomes the defects in the prior art, and provides a synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline which has high safety factor and convenient operation and is suitable for industrial production.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline, comprising the steps of:
the method comprises the following steps: p-bromoaniline reacts with phosphorus oxychloride and N, N-dimethylformamide to generate a compound I;
step two: reacting the compound I with phenylpropyl chloride to generate N- (4-bromo-2-formylphenyl) -3-phenylacrylamide;
step three: reacting the compound II with phosphorus oxychloride to generate a compound III;
step four: and reacting the compound III with sodium methoxide to generate a compound IV.
Further, in the first step, the molar ratio of p-bromoaniline to phosphorus oxychloride is 1: (1-2), wherein the molar ratio of the p-bromoaniline to the N, N-dimethylformamide is 1: (1-2).
Further, the specific steps of the first step are as follows: dropwise adding phosphorus oxychloride into an acetonitrile solution of N, N-dimethylformamide at a proper temperature, reacting for 0.5h at a proper temperature, adding p-bromoaniline at a proper temperature, reacting for 4-6 h at a proper temperature, stopping the reaction, cooling to 0-5 ℃, adding an alkali liquor, stirring for 0.5h, filtering out solids, leaching with water twice, and drying to obtain a compound I.
Further, the organic solvent in the first step is acetonitrile.
Further, the proper temperature in the first step is 10-80 ℃.
Further, the alkali liquor in the first step is inorganic alkali such as sodium hydroxide and potassium hydroxide.
Further, in the second step, the molar ratio of the compound I to the phenylpropyl chloride is 1: (1-1.2).
Further, the second step comprises the following specific steps: sequentially adding an acid-binding agent and 2-amino-5-bromobenzaldehyde into an organic solvent at a proper temperature, dropwise adding phenylpropyl chloride at the proper temperature, reacting for 6-12h, stopping the reaction when the content of the 2-amino-5-bromobenzaldehyde is less than 0.5% by HPLC (high performance liquid chromatography) detection, filtering out a solid, and drying to obtain a compound II.
Further, the proper temperature in the second step is 0-25 ℃, the acid-binding agent is organic base selected from triethylamine and pyridine, and the organic solvent is selected from dichloromethane and toluene.
Further, the third step comprises the following specific steps: adding the compound II into phosphorus oxychloride at a proper temperature for reacting for 2-12h, stopping the reaction when the content of the compound II is lower than 1% by HPLC detection, recovering the phosphorus oxychloride under reduced pressure, adding water to the remainder for quenching, filtering out the solid, washing with water twice, pulping and purifying with methanol to obtain a white-like solid, and drying to obtain a compound III.
Further, in the third step, the proper temperature is 20-100 ℃, and the molar ratio of the compound II to the phosphorus oxychloride is 1: (3-10).
Further, the fourth step comprises the following specific steps: adding the compound III into an organic solvent at a proper temperature, reacting in a methanol solution of sodium methoxide for 2-12h, stopping the reaction when the content of the compound III is lower than 0.1 percent by HPLC (high performance liquid chromatography) detection, adding water to quench the reaction, separating liquid, sequentially extracting a water phase with the organic solvent, desolventizing and recovering the organic solvent, pulping and purifying the residue with methanol to obtain a white solid, and drying to obtain a compound IV.
Further, in the third step, the molar ratio of the compound III to sodium methoxide is 1: (1-3), the proper temperature is 20-100 ℃, and the solvent is toluene.
The technical scheme adopted by the invention has the beneficial effects that:
1. the reaction process is clearer, and the yield is obviously improved compared with the original process.
2. The Vilsmeier-Haake provided by the invention only needs one aldehyde group, and simultaneously increases the solvent to participate in the reaction process, thereby avoiding the problems of insufficient reaction, severe heat release and the like which are not beneficial to large-scale production operation caused by the solidification phenomenon in the early reaction of phosphorus oxychloride and N, N-dimethylformamide.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. If the temperature is not particularly emphasized, the reaction is usually carried out at room temperature, and the room temperature in the present invention is 10 to 30 ℃.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
3-benzyl-6-bromo-2-methoxyquinoline comprising the following four steps:
synthesis of Compound (I)
Dropwise adding phosphorus oxychloride (169g,1.1mol) into acetonitrile (1000ml) solution of N, N-dimethylformamide (80g,1.1mol) at 10 ℃, stirring and reacting for 0.5h at 10-20 ℃, adding p-bromoaniline (172g, 1mol) at 10-20 ℃, heating to 80 ℃ after finishing the addition, reacting for 4-6 h, performing HPLC (high performance liquid chromatography) controlled reaction, cooling to 0-5 ℃, slowly adding sodium hydroxide aqueous solution, controlling the internal temperature to be lower than 20 ℃, stirring for 0.5h after finishing the addition, filtering out solids by a Buchner funnel, leaching twice, and drying to obtain 17.4g of off-white solids, wherein the purity is 97.3%, and the yield is 86.2%.
Synthesis of Compound (II)
Adding triethylamine (105g,1.1mol) and a compound I (200g,1.0mol) into dichloromethane (1000ml) in sequence at 25 ℃, cooling to 0-5 ℃ in an ice bath, slowly dropwise adding phenylpropyl chloride (168g,1.0mol), heating to 20-25 ℃ for reaction for 6-12h, stopping the reaction when the content of the compound I is less than 0.5% by HPLC (high performance liquid chromatography), filtering out a solid, and drying to obtain 313.3g of a white-like solid with the purity of 99.1% and the yield of 94.3%.
Synthesis of Compound (III)
Adding a compound II (33.2g,0.1mol) into phosphorus oxychloride (150ml) in batches at 10-20 ℃, heating to 90-100 ℃ after adding, reacting for 4-6 h, performing HPLC (high performance liquid chromatography) controlled reaction, cooling to 40-50 ℃, recovering part of phosphorus oxychloride under reduced pressure, adding ice water to quench residues, stirring for 0.5h, filtering out solids, leaching twice with water, pulping and purifying with 2W/W methanol at 20-25 ℃, and drying to obtain 26.9g of off-white solids, wherein the purity is 99.3% and the yield is 81.2%.
Synthesis of Compound (IV)
Compound III (50g,0.15mol) was added to toluene (150g) at 25 ℃ and sodium methoxide methanol solution (54.2g,0.3mol) was added with stirring. After the temperature is increased to 80-100 ℃, the reaction lasts for 4-10 hours, and the system is a white turbid liquid. And stopping the reaction when the content of the compound III is less than 0.1 percent through HPLC detection. Cooling to room temperature, adding 3W/W water into the reaction system, and stirring for 1 h. Separating liquid, extracting the water phase once by using 2W/W toluene, combining the toluene, recovering the toluene under reduced pressure to obtain a white solid, refluxing, pulping and purifying the wet product by using 1-2 times of methanol by weight, and drying by blowing at 60 ℃ to obtain 46.4g of the white solid, wherein the purity is 99.5% and the yield is 94.3%.
Example 2
3-benzyl-6-bromo-2-methoxyquinoline comprising the following four steps:
synthesis of Compound (I)
Dropwise adding 30.7g of phosphorus oxychloride (0.2 mol) into 100ml of acetonitrile (14.6g of N, N-dimethylformamide (0.2 mol) at 10 ℃, stirring and reacting at 10-20 ℃ for 0.5h, adding 17.2g of p-bromoaniline (0.1 mol) at 10-20 ℃, heating to 80 ℃ after adding, reacting for 4-6 h, performing HPLC (high performance liquid chromatography) controlled reaction, cooling to 0-5 ℃, slowly adding a sodium hydroxide aqueous solution, controlling the temperature to be lower than 20 ℃, stirring for 0.5h, filtering out solids by a Buchner funnel, leaching twice with water, and drying to obtain 15.9g of off-white solids with the purity of 98.2% and the yield of 79.6%.
Synthesis of Compound (II)
Adding pyridine (8.7g,0.11mol) and a compound I (20.0g,0.1mol) into dichloromethane (100ml) at 25 ℃, cooling to 0-5 ℃ in an ice bath, slowly adding phenylpropyl chloride (20.1g,0.12mol) dropwise, reacting for 6-12h after the temperature is increased to 20-25 ℃, stopping the reaction when the content of the compound I is less than 0.5% by HPLC (high performance liquid chromatography), filtering out a solid, and drying to obtain an off-white solid 30.3g, the purity is 99.3%, and the yield is 91.3%.
Synthesis of Compound (III)
Adding a compound II (33.2g,0.1mol) into phosphorus oxychloride (300ml) in batches at 10-20 ℃, heating to 90-100 ℃ after adding, reacting for 4-6 h, performing HPLC (high performance liquid chromatography) controlled reaction, cooling to 40-50 ℃, recovering part of phosphorus oxychloride under reduced pressure, adding ice water to quench residues, stirring for 0.5h, filtering out solids, leaching twice with water, pulping and purifying with 2W/W methanol at 20-25 ℃, and drying to obtain 27.8g of off-white solids, wherein the purity is 99.2% and the yield is 83.7%.
Synthesis of Compound (IV)
Compound III (50g,0.15mol) was added to toluene (150g) at 25 ℃ and sodium methoxide methanol solution (27g,0.15mol) was added with stirring. After the temperature is increased to 80-100 ℃, the reaction lasts for 4-10 hours, and the system is a white turbid liquid. And stopping the reaction when the content of the compound III is less than 0.1 percent through HPLC detection. Cooling to room temperature, adding 3W/W water into the reaction system, and stirring for 1 h. Separating liquid, extracting the water phase once by using 2W/W toluene, combining the toluene, recovering the toluene under reduced pressure to obtain a white solid, refluxing, pulping and purifying the wet product by using 1-2 times of methanol by weight, and drying by blowing at 60 ℃ to obtain 29.3g of the white solid, wherein the purity is 99.6% and the yield is 89.3%.
Example 3
3-benzyl-6-bromo-2-methoxyquinoline comprising the following four steps:
synthesis of Compound (I)
Dropwise adding 23.0g of phosphorus oxychloride (0.15 mol) into 100ml of acetonitrile (11.0g of N, N-dimethylformamide (0.15 mol) at 10 ℃, stirring and reacting for 0.5h at 10-20 ℃, adding 17.2g of p-bromoaniline (0.1 mol) at 10-20 ℃, heating to 80 ℃ after the addition, reacting for 4-6 h, performing HPLC (high performance liquid chromatography) controlled reaction, cooling to 0-5 ℃, slowly adding a sodium hydroxide aqueous solution, controlling the temperature to be lower than 20 ℃, stirring for 0.5h after the addition, pumping out a solid from a Buchner funnel, leaching twice with water, and drying to obtain 17.1g of off-white solid with purity of 98.5% and yield of 85.4%.
Synthesis of Compound (II)
Adding triethylamine (10.5g,0.11mol) and a compound I (20.0g,0.1mol) into dichloromethane (100ml) in sequence at 25 ℃, cooling to 0-5 ℃ in an ice bath, slowly dropwise adding phenylpropyl chloride (20.1g,0.12mol), heating to 20-25 ℃ completely, reacting for 6-12h, stopping the reaction when the content of the compound I is less than 0.5% by HPLC (high performance liquid chromatography), filtering out a solid, and drying to obtain 31.1g of a white-like solid with the purity of 99.1% and the yield of 93.6%.
Synthesis of Compound (III)
Adding a compound II (33.2g,0.1mol) into phosphorus oxychloride (100ml) in batches at 10-20 ℃, heating to 90-100 ℃ after adding, reacting for 4-6 h, performing HPLC (high performance liquid chromatography) controlled reaction, cooling to 40-50 ℃, recovering part of phosphorus oxychloride under reduced pressure, adding ice water to quench residues, stirring for 0.5h, filtering out solids, leaching twice with water, pulping and purifying with 2W/W methanol at 20-25 ℃, and drying to obtain 25.4g of off-white solids, wherein the purity is 99.2% and the yield is 76.6%.
Synthesis of Compound (IV)
Compound III (50g,0.15mol) was added to toluene (150g) at 25 ℃ and sodium methoxide methanol solution (73g,0.45mol) was added with stirring. After the temperature is increased to 80-100 ℃, the reaction lasts for 4-10 hours, and the system is a white turbid liquid. And stopping the reaction when the content of the compound III is less than 0.1 percent through HPLC detection. Cooling to room temperature, adding 3W/W water into the reaction system, and stirring for 1 h. Separating liquid, extracting the water phase once by using 2W/W toluene, combining the toluene, recovering the toluene under reduced pressure to obtain a white solid, refluxing, pulping and purifying the wet product by using 1-2 times of methanol by weight, and drying by blowing at 60 ℃ to obtain 31.9g of the white solid, wherein the purity is 99.8% and the yield is 97.4%.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.
Claims (10)
1. A synthetic method of 3-benzyl-6-bromo-2-methoxyquinoline is characterized by comprising the following steps: the synthesis method comprises the following steps:
the method comprises the following steps: p-bromoaniline reacts with phosphorus oxychloride and N, N-dimethylformamide to generate a compound I;
step two: reacting the compound I with phenylpropyl chloride to generate N- (4-bromo-2-formylphenyl) -3-phenylacrylamide;
step three: reacting the compound II with phosphorus oxychloride to generate a compound III;
step four: and reacting the compound III with sodium methoxide to generate a compound IV.
2. The method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline according to claim 1, wherein the method comprises the following steps: in the first step, the molar ratio of p-bromoaniline to phosphorus oxychloride is 1: (1-2), wherein the molar ratio of the p-bromoaniline to the N, N-dimethylformamide is 1: (1-2).
3. The method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline according to claim 1, wherein the method comprises the following steps: the specific steps of the first step are as follows: dropwise adding phosphorus oxychloride into an acetonitrile solution of N, N-dimethylformamide at a proper temperature, reacting for 0.5h at a proper temperature, adding p-bromoaniline at a proper temperature, reacting for 4-6 h at a proper temperature, stopping the reaction, cooling to 0-5 ℃, adding an alkali liquor, stirring for 0.5h, filtering out solids, leaching with water twice, and drying to obtain a compound I.
4. The method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline according to claim 1, wherein the method comprises the following steps: in the second step, the molar ratio of the compound I to the phenylpropionyl chloride is 1: (1-1.2).
5. The method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline according to claim 1, wherein the method comprises the following steps: the second step comprises the following specific steps: sequentially adding an acid-binding agent and 2-amino-5-bromobenzaldehyde into an organic solvent at a proper temperature, dropwise adding phenylpropyl chloride at the proper temperature, reacting for 6-12h, stopping the reaction when the content of the 2-amino-5-bromobenzaldehyde is less than 0.5% by HPLC (high performance liquid chromatography) detection, filtering out a solid, and drying to obtain a compound II.
6. The method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline according to claim 5, wherein: in the second step, the proper temperature is 0-25 ℃, the acid-binding agent is organic base selected from triethylamine and pyridine, and the organic solvent is selected from dichloromethane and toluene.
7. The method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline according to claim 1, wherein the method comprises the following steps: the third step comprises the following specific steps: adding the compound II into phosphorus oxychloride at a proper temperature for reacting for 2-12h, stopping the reaction when the content of the compound II is lower than 1% by HPLC detection, recovering the phosphorus oxychloride under reduced pressure, adding water to the remainder for quenching, filtering out the solid, washing with water twice, pulping and purifying with methanol to obtain a white-like solid, and drying to obtain a compound III.
8. The method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline according to claim 7, wherein: in the third step, the proper temperature is 20-100 ℃, and the molar ratio of the compound II to the phosphorus oxychloride is 1: (3-10).
9. The method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline according to claim 1, wherein the method comprises the following steps: the fourth step comprises the following specific steps: adding the compound III into an organic solvent at a proper temperature, reacting in a methanol solution of sodium methoxide for 2-12h, stopping the reaction when the content of the compound III is lower than 0.1 percent by HPLC (high performance liquid chromatography) detection, adding water to quench the reaction, separating liquid, sequentially extracting a water phase with the organic solvent, desolventizing and recovering the organic solvent, pulping and purifying the residue with methanol to obtain a white solid, and drying to obtain a compound IV.
10. The method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline according to claim 9, wherein: in the third step, the molar ratio of the compound III to sodium methoxide is 1: (1-3), the proper temperature is 20-100 ℃, and the solvent is toluene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210490894.1A CN114835641B (en) | 2022-05-07 | 2022-05-07 | Synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210490894.1A CN114835641B (en) | 2022-05-07 | 2022-05-07 | Synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114835641A true CN114835641A (en) | 2022-08-02 |
| CN114835641B CN114835641B (en) | 2024-03-15 |
Family
ID=82566904
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210490894.1A Active CN114835641B (en) | 2022-05-07 | 2022-05-07 | Synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114835641B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050148581A1 (en) * | 2002-07-25 | 2005-07-07 | Van Gestel Jozef F.E. | Novel mycobacterial inhibitors |
| CN102850269A (en) * | 2011-06-30 | 2013-01-02 | 梁泽西 | Synthesis process for 6-bromo-3-chlorophenyl-methyl-2-methoxy-quinoline |
| CN105175329A (en) * | 2014-06-10 | 2015-12-23 | 重庆圣华曦药业股份有限公司 | New synthesis route and method of bedaquiline racemate |
-
2022
- 2022-05-07 CN CN202210490894.1A patent/CN114835641B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050148581A1 (en) * | 2002-07-25 | 2005-07-07 | Van Gestel Jozef F.E. | Novel mycobacterial inhibitors |
| CN102850269A (en) * | 2011-06-30 | 2013-01-02 | 梁泽西 | Synthesis process for 6-bromo-3-chlorophenyl-methyl-2-methoxy-quinoline |
| CN105175329A (en) * | 2014-06-10 | 2015-12-23 | 重庆圣华曦药业股份有限公司 | New synthesis route and method of bedaquiline racemate |
Non-Patent Citations (2)
| Title |
|---|
| B.M. KIRAN 等: "REDISCOVERED SYNTHESIS OF 3-CYANOQUINOLINE DERIVATIVES", 《HETEROCYCLIC COMMUNICATIONS》, vol. 12, no. 6, pages 481 - 484, XP009120139 * |
| DE-LONG KONG 等: "A highly efficient way to recycle inactive stereoisomers of Bedaquiline into two previous intermediates via base-catalyzed Csp3–Csp3 bond cleavage", 《CHINESE CHEMICAL LETTERS》, vol. 26, pages 790 - 792 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114835641B (en) | 2024-03-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111153838B (en) | Synthetic method of florfenicol | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| CN114835641A (en) | Synthetic method of 3-benzyl-6-bromo-2-methoxyquinoline | |
| NO168821B (en) | PROCEDURE FOR THE PREPARATION OF BIS (3,5-DIOXOPIPERAZINYL) ALKANES OR ALKENES | |
| CN108424416B (en) | Method for synthesizing indole [1,2-c ] quinazoline compound | |
| CN115286514B (en) | Preparation method of 4' -chloro-2-aminobiphenyl sulfate | |
| CN107311946B (en) | Synthetic method of 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound | |
| CN114031511A (en) | Synthesis method of benzethonium chloride | |
| CN111848536B (en) | Preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole | |
| CN107311847B (en) | Preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane | |
| CN107501171B (en) | Synthetic method of 2-chloro-3-pyridylaldehyde | |
| CN110698381A (en) | Method for synthesizing N- (benzyloxycarbonyl) succinimide by one-pot two-phase method | |
| CN111303045A (en) | Production process of 2-ethoxy-4, 6-difluoropyrimidine | |
| CN109280049B (en) | Synthetic method of medical compound avanafil | |
| CN104193687B (en) | A kind of preparation method for treating pulmonary hypertension medicine | |
| US2714593A (en) | Dihydropyrrolo-(3.2-c) quinoline derivatives | |
| CN115850199B (en) | Preparation method of high-purity sodium sulfaisoxazole | |
| KR0163344B1 (en) | Process for the preparation of 3-nitro-9-ethyl carbazole | |
| CN110452139B (en) | Preparation method of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile | |
| CN113620877B (en) | Method for preparing 9-acridine formic acid by one-pot method | |
| WO1991016292A1 (en) | Process for preparation of resorcinol bis(dihydroxyethyl)ether | |
| CN111533699B (en) | Synthesis method of 2- (trifluoromethyl) pyrimidine-5-alcohol | |
| JPS5914469B2 (en) | Method for producing 5-methylfurfural | |
| CN115947675A (en) | Rasagiline intermediate and preparation method and application thereof | |
| CN106631827B (en) | The synthetic method of one kind (1- cyclopropyl -1- methyl) ethylamine and its hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |