CN114835641B - Synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline - Google Patents
Synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline Download PDFInfo
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- 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 12
- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- 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 48
- 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 29
- 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 19
- 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
- 239000002904 solvent Substances 0.000 claims abstract description 5
- MFEILWXBDBCWKF-UHFFFAOYSA-N 3-phenylpropanoyl chloride Chemical compound ClC(=O)CCC1=CC=CC=C1 MFEILWXBDBCWKF-UHFFFAOYSA-N 0.000 claims abstract description 4
- -1 N- (4-bromo-2-formylphenyl) -3-phenylpropionamide 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
- 239000007787 solid Substances 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 9
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 8
- 238000004537 pulping Methods 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000002386 leaching Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- 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
- 238000001514 detection method Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 150000007530 organic bases Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004064 recycling Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 4
- 125000003172 aldehyde group Chemical group 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000000034 method 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
- 239000000203 mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 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
- CCIVUDMVXNBUCY-UHFFFAOYSA-N 4-bromo-n-phenylaniline Chemical compound C1=CC(Br)=CC=C1NC1=CC=CC=C1 CCIVUDMVXNBUCY-UHFFFAOYSA-N 0.000 description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical group 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 2
- 238000007796 conventional method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 2
- 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
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229960000508 bedaquiline Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction 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
- 238000010438 heat treatment Methods 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
- 230000010534 mechanism of action Effects 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
- 238000000746 purification 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
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 201000008827 tuberculosis Diseases 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 medicine synthesis, in particular to a synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline; the synthesis method comprises the following steps: step one: reacting p-bromoaniline with phosphorus oxychloride and N, N-dimethylformamide to generate a compound I; step two: the compound I reacts with phenylpropionyl chloride to generate N- (4-bromo-2-formylphenyl) -3-phenylpropionamide; 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 prior process; the Vilsmeier-Hark related by the invention only needs to carry out one aldehyde group, and simultaneously increases the solvent to participate in the reaction process, so that the problems of insufficient reaction, severe heat release and the like which are unfavorable for mass production operation caused by solidification phenomenon in the early reaction of phosphorus oxychloride and N, N-dimethylformamide are avoided.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline.
Background
Bedaquinoline was developed by the United states Johnson pharmaceutical Co., ltd and approved by the United states food and drug administration at 28, 2012 for use in the treatment of drug resistant tuberculosis. The chemical name of the beta-quinoline is (1R, 2S) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol, and the beta-quinoline can inhibit energy generation of mycobacterium tuberculosis by using ATP through inhibiting a proton transfer chain of ATP synthetase of the mycobacterium, so that the beta-quinoline plays an anti-tuberculosis role, and is a brand-new action path for resisting the mycobacterium tuberculosis. Bedapquinoline is an antituberculosis drug with a new mechanism of action which has been approved for clinical use for over 40 years, and is the only drug for treating multi-drug resistant tuberculosis at present. The 3-benzyl-6-bromo-2-methoxyquinoline is an important intermediate for synthesizing the bedaquiline, and original research US2005148581 reports that the raw material is benzoyl chloride, the benzoyl chloride reacts with p-bromoaniline to obtain N- (4-bromophenyl) phenylamide, the N- (4-bromophenyl) phenylamide reacts with phosphorus oxychloride and N, N-dimethylformamide to generate Wilsmeier-hake reaction to obtain 3-benzyl-6-bromo-2-chloroquinoline, and finally the 3-benzyl-6-bromo-2-methoxyquinoline reacts with sodium methoxide. Although the steps of the method are shorter, the Vilsmeier-Hake reaction releases heat severely, which is unfavorable for mass production operation. Meanwhile, the one-step reaction involves three reaction steps of aldehyde group feeding, cyclization and chlorination, so that the reaction possibility is high, the purity of a reaction system is low, and the yield is low.
Disclosure of Invention
The purpose of the invention is that: overcomes the defects in the prior art, and provides a synthetic method of 3-benzyl-6-bromo-2-methoxyquinoline which has high safety coefficient and convenient operation and is suitable for industrial production.
In order to achieve the above object, the present invention adopts the following technical scheme:
a synthetic method of 3-benzyl-6-bromo-2-methoxyquinoline, comprising the following steps:
step one: reacting p-bromoaniline with phosphorus oxychloride and N, N-dimethylformamide to generate a compound I;
step two: the compound I reacts with phenylpropionyl chloride to generate N- (4-bromo-2-formylphenyl) -3-phenylpropionamide;
step three: reacting the compound II with phosphorus oxychloride to generate a compound III;
step four: and (3) reacting the compound III with sodium methoxide to generate a compound IV.
Further, in the first step, the molar ratio of the p-bromoaniline to the 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: dropping phosphorus oxychloride into 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 alkali liquor, stirring for 0.5h, filtering out solid, leaching with water twice, and drying to obtain the compound I.
Further, in the first step, the organic solvent is acetonitrile.
Further, the temperature in the first step is suitably 10-80 ℃.
Furthermore, the alkali liquor in the first step is inorganic alkali such as sodium hydroxide, potassium hydroxide and the like.
Further, in the second step, the molar ratio of the compound I to the phenylpropionyl chloride is 1: (1-1.2).
Further, the specific steps of the second step are as follows: adding an acid binding agent and 2-amino-5-bromobenzaldehyde into an organic solvent in sequence at a proper temperature, dropwise adding benzoyl chloride at a proper temperature, reacting for 6-12h, stopping reacting when HPLC (high performance liquid chromatography) detects that the content of the 2-amino-5-bromobenzaldehyde is less than 0.5%, filtering out solids, and drying to obtain a compound II.
Furthermore, the proper temperature in the second step is 0-25 ℃, the acid binding agent is organic base, selected from one of triethylamine and pyridine, and the organic solvent is selected from one of dichloromethane and toluene.
Further, the specific steps of the third step are as follows: and adding the compound II into phosphorus oxychloride at a proper temperature for reaction for 2-12h, stopping the reaction when HPLC detects that the content of the compound II is lower than 1%, recovering the phosphorus oxychloride under reduced pressure, adding water into the residue for quenching, filtering out the solid, washing the solid twice, pulping with methanol for purification to obtain an off-white solid, and drying to obtain the compound III.
Further, in the third step, the proper temperature is 20-100 ℃, and the molar ratio of the compound II to phosphorus oxychloride is 1: (3-10).
Further, the specific steps of the fourth step are as follows: adding the compound III into an organic solvent at a proper temperature, reacting for 2-12h in a methanol solution of sodium methoxide, stopping the reaction when the content of the compound III is lower than 0.1% by HPLC detection, adding water for quenching reaction, separating liquid, extracting the water phase by using the organic solvent, sequentially removing the solvent, recovering the organic solvent, pulping and purifying the residue by using methanol to obtain a white solid, and drying to obtain the 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 of the invention has the beneficial effects that:
1. the reaction process is clearer, and the yield is obviously improved compared with the prior process.
2. The Vilsmeier-Hark related by the invention only needs to carry out one aldehyde group, and simultaneously increases the solvent to participate in the reaction process, so that the problems of insufficient reaction, severe heat release and the like which are unfavorable for mass production operation caused by solidification phenomenon in the early reaction of phosphorus oxychloride and N, N-dimethylformamide are avoided.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications. Unless otherwise stated, the temperature is usually at room temperature, and in the present invention, the room temperature is 10 to 30 ℃.
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1
3-benzyl-6-bromo-2-methoxyquinoline comprising the following four steps:
synthesis of Compound (I)
Phosphorus oxychloride (169 g,1.1 mol) is added into acetonitrile (1000 ml) solution of N, N-dimethylformamide (80 g,1.1 mol) at 10 ℃ for reaction for 0.5h under stirring at 10-20 ℃, p-bromoaniline (172 g,1 mol) is added at 10-20 ℃, the temperature is raised to 80 ℃ for reaction for 4-6 h under stirring, HPLC (high performance liquid chromatography) is controlled for reaction, the temperature is reduced to 0-5 ℃, sodium hydroxide aqueous solution is slowly added, the internal temperature is controlled to be lower than 20 ℃ for 0.5h, the solid is filtered out by a Buchner funnel in a pumping way, and the solid is dried after leaching twice with water, thus obtaining 17.4g of off-white solid with the purity of 97.3% and the yield of 86.2%.
Synthesis of Compound (II)
Triethylamine (105 g,1.1 mol) and compound I (200 g,1.0 mol) were added to methylene chloride (1000 ml) in this order at 25℃and cooled to 0 to 5℃in an ice bath, and benzoyl chloride (168 g,1.0 mol) was slowly added dropwise, and the reaction was stopped when the temperature was raised to 20 to 25℃and the content of compound I was less than 0.5% by HPLC detection, and the solid was filtered off and dried to give an off-white solid 313.3g with a purity of 99.1% and a yield of 94.3%.
Synthesis of Compound (III)
Compound II (33.2 g,0.1 mol) is added into phosphorus oxychloride (150 ml) in batches at the temperature of 10-20 ℃, the mixture is heated to 90-100 ℃ for 4-6 h after the addition, the HPLC is performed for central control reaction, the temperature is reduced to 40-50 ℃ after the reaction is finished, part of phosphorus oxychloride is recovered under reduced pressure, the remainder is quenched by adding ice water, stirred for 0.5h, the solid is filtered out, the solid is leached twice with water, and is pulped and purified by 2W/W methanol at the temperature of 20-25 ℃, and the solid is dried, thus obtaining 26.9g of off-white solid with the purity of 99.3% and the yield of 81.2%.
Synthesis of Compound (IV)
To toluene (150 g) was added compound III (50 g,0.15 mol) at 25℃and sodium methoxide methanol solution (54.2 g,0.3 mol) was added with stirring. After the addition, the temperature is raised to 80-100 ℃ for reaction for 4-10 hours, and the system is white turbid liquid. The reaction can be stopped when the content of the compound III is detected by HPLC to be less than 0.1 percent. Cooling to room temperature, adding 3W/W water into the reaction system, and stirring for 1h. Separating, extracting the water phase once by using 2W/W toluene, merging the toluene, recovering the toluene under reduced pressure to obtain a white solid, refluxing and pulping wet products by using 1-2 times of methanol, purifying the wet products, and drying the wet products by blowing at 60 ℃ to obtain 46.4g of white solid with the purity of 99.5 percent and the yield of 94.3 percent.
Example 2
3-benzyl-6-bromo-2-methoxyquinoline comprising the following four steps:
synthesis of Compound (I)
Phosphorus oxychloride (30.7 g,0.2 mol) is added dropwise into an acetonitrile (100 ml) solution of N, N-dimethylformamide (14.6 g,0.2 mol) at 10 ℃, the mixture is stirred and reacted for 0.5h at 10-20 ℃, p-bromoaniline (17.2 g,0.1 mol) is added at 10-20 ℃, the mixture is heated to 80 ℃ for 4-6 h, the HPLC (high performance liquid chromatography) is performed for medium control reaction, the mixture is cooled to 0-5 ℃, sodium hydroxide aqueous solution is slowly added, the internal temperature is controlled to be lower than 20 ℃, the mixture is stirred for 0.5h, a buchner funnel is used for filtering out solids, and after leaching twice with water, the mixture is dried, the off-white solid is obtained, and the purity is 98.2%, and the yield is 79.6%.
Synthesis of Compound (II)
Pyridine (8.7 g,0.11 mol) and compound I (20.0 g,0.1 mol) are added into dichloromethane (100 ml) in sequence at 25 ℃, ice bath is cooled to 0-5 ℃, benzoyl chloride (20.1 g,0.12 mol) is slowly added dropwise, the reaction is stopped when the temperature is raised to 20-25 ℃ after the addition, the reaction is stopped when the content of the compound I is detected to be less than 0.5% by HPLC, solid is filtered out, and the solid is dried to obtain off-white solid with the purity of 30.3g and the yield of 91.3%.
Synthesis of Compound (III)
Compound II (33.2 g,0.1 mol) is added into phosphorus oxychloride (300 ml) in batches at the temperature of 10-20 ℃, the mixture is heated to 90-100 ℃ to react for 4-6 h, HPLC (high performance liquid chromatography) is performed to perform central control reaction, the temperature is reduced to 40-50 ℃, part of phosphorus oxychloride is recovered under reduced pressure, the remainder is quenched by adding ice water, stirred for 0.5h, the solid is filtered, the solid is leached twice by water, and is pulped and purified by 2W/W methanol at the temperature of 20-25 ℃, and the solid is dried to obtain 27.8g of off-white solid with the purity of 99.2% and the yield of 83.7%.
Synthesis of Compound (IV)
To toluene (150 g) was added compound III (50 g,0.15 mol) at 25℃and sodium methoxide methanol solution (27 g,0.15 mol) was added with stirring. After the addition, the temperature is raised to 80-100 ℃ for reaction for 4-10 hours, and the system is white turbid liquid. The reaction can be stopped when the content of the compound III is detected by HPLC to be less than 0.1 percent. Cooling to room temperature, adding 3W/W water into the reaction system, and stirring for 1h. Separating, extracting the water phase once by using 2W/W toluene, merging the toluene, recovering the toluene under reduced pressure to obtain a white solid, refluxing and pulping wet products by using 1-2 times of methanol, purifying the wet products, and drying the wet products by blowing at 60 ℃ to obtain 29.3g of white solid with the purity of 99.6 percent and the yield of 89.3 percent.
Example 3
3-benzyl-6-bromo-2-methoxyquinoline comprising the following four steps:
synthesis of Compound (I)
Phosphorus oxychloride (23.0 g,0.15 mol) is added dropwise into an acetonitrile (100 ml) solution of N, N-dimethylformamide (11.0 g,0.15 mol) at 10 ℃, the mixture is stirred and reacted for 0.5h at 10-20 ℃, p-bromoaniline (17.2 g,0.1 mol) is added at 10-20 ℃, the mixture is heated to 80 ℃ for 4-6 h, the HPLC (high performance liquid chromatography) is performed for medium control reaction, the mixture is cooled to 0-5 ℃, sodium hydroxide aqueous solution is slowly added, the internal temperature is controlled to be lower than 20 ℃, the mixture is stirred for 0.5h, a buchner funnel is used for filtering out solids, and after leaching twice with water, the mixture is dried to obtain 17.1g of off-white solids with the purity of 98.5% and the yield of 85.4%.
Synthesis of Compound (II)
Triethylamine (10.5 g,0.11 mol) and compound I (20.0 g,0.1 mol) are added into dichloromethane (100 ml) in sequence at 25 ℃, ice bath is cooled to 0-5 ℃, benzoyl chloride (20.1 g,0.12 mol) is slowly added dropwise, the reaction is stopped when the temperature is raised to 20-25 ℃ after the addition, the reaction is stopped when the content of the compound I is detected to be less than 0.5% by HPLC, solid is filtered out, and the solid is dried to obtain off-white solid 31.1g with the purity of 99.1% and the yield of 93.6%.
Synthesis of Compound (III)
Adding compound II (33.2 g,0.1 mol) into phosphorus oxychloride (100 ml) in batches at the temperature of 10-20 ℃, heating to 90-100 ℃ to react for 4-6 h, performing HPLC (high performance liquid chromatography) central control reaction, cooling to 40-50 ℃ after the reaction is finished, recovering part of phosphorus oxychloride under reduced pressure, quenching the residue by adding ice water, stirring for 0.5h, filtering out solid, leaching twice with water, pulping and purifying with 2W/W methanol at the temperature of 20-25 ℃, and drying to obtain 25.4g of off-white solid with the purity of 99.2% and the yield of 76.6%.
Synthesis of Compound (IV)
To toluene (150 g) was added compound III (50 g,0.15 mol) at 25℃and sodium methoxide methanol solution (73 g,0.45 mol) was added with stirring. After the addition, the temperature is raised to 80-100 ℃ for reaction for 4-10 hours, and the system is white turbid liquid. The reaction can be stopped when the content of the compound III is detected by HPLC to be less than 0.1 percent. Cooling to room temperature, adding 3W/W water into the reaction system, and stirring for 1h. Separating, extracting the water phase once by using 2W/W toluene, merging the toluene, recovering the toluene under reduced pressure to obtain a white solid, refluxing and pulping wet products by using 1-2 times of methanol, purifying the wet products, and drying the wet products by blowing at 60 ℃ to obtain 31.9g of white solid with the purity of 99.8 percent and the yield of 97.4 percent.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of the invention should be assessed as that of the appended claims.
Claims (1)
1. A synthetic method of 3-benzyl-6-bromo-2-methoxyquinoline is characterized in that: the synthesis method comprises the following steps:
step one: reacting p-bromoaniline with phosphorus oxychloride and N, N-dimethylformamide to generate a compound I;
step two: the compound I reacts with phenylpropionyl chloride to generate N- (4-bromo-2-formylphenyl) -3-phenylpropionamide;
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;
in the first step, the molar ratio of the p-bromoaniline to the phosphorus oxychloride is 1: (1-2), wherein the molar ratio of the p-bromoaniline to the N, N-dimethylformamide is 1: (1-2);
the specific steps of the second step are as follows: adding an acid binding agent and 2-amino-5-bromobenzaldehyde into an organic solvent in sequence at a proper temperature, dropwise adding benzoyl chloride at a proper temperature, reacting for 6-12h, stopping the reaction when HPLC (high performance liquid chromatography) detects that the content of the 2-amino-5-bromobenzaldehyde is less than 0.5%, filtering out solids, and drying to obtain a compound II;
the specific steps of the third step are as follows: adding the compound II into phosphorus oxychloride at a proper temperature for reaction for 2-12h, stopping the reaction when HPLC (high performance liquid chromatography) detects that the content of the compound II is lower than 1%, recovering phosphorus oxychloride under reduced pressure, adding water into the residue for quenching, filtering out solids, washing twice, pulping and purifying with methanol to obtain an off-white solid, and drying to obtain a compound III;
the specific steps of the fourth step are as follows: adding a compound III into an organic solvent at a proper temperature, reacting for 2-12 hours in a methanol solution of sodium methoxide, stopping the reaction when the content of the compound III is lower than 0.1 percent by HPLC detection, adding water for quenching reaction, separating liquid, extracting water phase by using the organic solvent, sequentially desolventizing and recycling the organic solvent, pulping and purifying residues by using methanol to obtain white solid, and drying to obtain a compound IV;
the specific steps of the first step are as follows: dropping phosphorus oxychloride into 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 alkali liquor, stirring for 0.5h, filtering out solid, leaching with water twice, and drying to obtain a compound I;
in the second step, the molar ratio of the compound I to the benzoyl chloride is 1: (1-1.2);
the proper temperature in the second step is 0-25 ℃, the acid binding agent is organic base, selected from one of triethylamine and pyridine, and the organic solvent is selected from one of dichloromethane and toluene;
in the third step, the proper temperature is 20-100 ℃, and the mol ratio of the compound II to phosphorus oxychloride is 1: (3-10); the molar ratio of the compound III to the sodium methoxide in the step three is 1: (1-3), the proper temperature is 20-100 ℃, and the solvent is toluene.
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| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| A highly efficient way to recycle inactive stereoisomers of Bedaquiline into two previous intermediates via base-catalyzed Csp3–Csp3 bond cleavage;De-Long Kong 等;《Chinese Chemical Letters》;第26卷;790-792 * |
| REDISCOVERED SYNTHESIS OF 3-CYANOQUINOLINE DERIVATIVES;B.M. Kiran 等;《Heterocyclic Communications》;第12卷(第6期);481-484 * |
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