CN111574444A - Preparation method of bedaquiline - Google Patents
Preparation method of bedaquiline Download PDFInfo
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- CN111574444A CN111574444A CN202010643159.0A CN202010643159A CN111574444A CN 111574444 A CN111574444 A CN 111574444A CN 202010643159 A CN202010643159 A CN 202010643159A CN 111574444 A CN111574444 A CN 111574444A
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- bedaquiline
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- 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 title claims abstract description 38
- 229960000508 bedaquiline Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 25
- 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 24
- 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 15
- 230000008569 process Effects 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 20
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 18
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 18
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 10
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
- QUIJNHUBAXPXFS-CDZUIXILSA-N (1s,2r)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-1-yl-1-phenylbutan-2-ol 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-CDZUIXILSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 239000004342 Benzoyl peroxide Substances 0.000 description 5
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 5
- 235000019400 benzoyl peroxide Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- -1 racemate Chemical compound 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- JZDLLTKMTDBCKZ-UHFFFAOYSA-N 3-[(2-bromo-5-chlorophenyl)methyl]-2-methoxyquinoline Chemical compound BrC1=CC=C(C=C1CC=1C(=NC2=CC=CC=C2C1)OC)Cl JZDLLTKMTDBCKZ-UHFFFAOYSA-N 0.000 description 1
- MFEILWXBDBCWKF-UHFFFAOYSA-N 3-phenylpropanoyl chloride Chemical compound ClC(=O)CCC1=CC=CC=C1 MFEILWXBDBCWKF-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229940126214 compound 3 Drugs 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
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for preparing bedaquiline shown as a formula IV, which comprises the step of reacting a compound II with a compound III. The method changes the ultralow temperature reaction of the prior process, and carries out the ultralow temperature reaction which is difficult to realize in the prior industry at the conventional temperature (heating condition), so that the large-scale industrial production becomes possible. In addition, the method shortens the reaction route, improves the conversion rate and the reaction yield of the reaction substrate, ensures that the product is easier to crystallize and purify, and simultaneously reduces the production cost.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of bedaquiline.
Background
The bedaquiline is a drug which is developed by the Jiansheng pharmaceutical Co., Ltd, approved to be on the market by the U.S. food and drug administration in 12-28 days 2012 and is clinically used for treating drug-resistant tuberculosis. The chemical name is (1R,2S) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol. The structure is as follows:
the bedaquiline inhibits the mycobacterium tuberculosis from utilizing ATP to generate energy by inhibiting the proton transfer chain of ATP synthetase of the mycobacterium tuberculosis, thereby playing an anti-tuberculosis role. The compound is a brand new action way for resisting mycobacterium tuberculosis, is a first approved antituberculosis drug with a new action mechanism for more than 40 years and is the only drug for treating multi-drug resistant tuberculosis at present.
European Journal of Organic Chemistry, (11), 2057-. The method has the defects of high yield, more synthesis steps, use of expensive reagents and catalysts and unsuitability for industrial production, and the specific synthetic route is as follows:
patent documents US2005148581 and CN101180302 report that 4-bromoaniline and phenylpropionyl chloride are used as starting materials, a racemate of bedaquiline is obtained through multi-step reaction, and then a target product is obtained through chiral column chromatography purification or induced recrystallization by introducing a chiral reagent, and the specific synthetic route is as follows:
the process route has low material cost and simple operation, but the compound 1 and the compound 3 need to react at-78 ℃ under the action of LDA, the reaction time is long, the yield is very low, the purity of the prepared bedaquiline is not high, and the total yield of the product is about 6%.
Patent document CN105085395A discloses that compound 1 and compound 4 are reacted and then reduced to obtain a bedaquiline racemate. The synthetic route is as follows:
patent document CN105175329A discloses that a bedaquiline racemate is obtained by reacting naphthalene formaldehyde with a grignard reagent, oxidizing the reaction product, and then reusing the grignard reagent. The specific synthetic route is as follows:
however, the above methods have problems of long reaction steps, expensive reagents, severe reaction conditions, and the like.
Disclosure of Invention
In order to improve the technical problem, the invention provides a method for preparing bedaquiline shown as a formula IV, which comprises the step of reacting a compound II with a compound III:
wherein X is halogen.
According to an embodiment of the invention, said X is chlorine or bromine.
According to an embodiment of the invention, the molar ratio of compound II to compound III may be 1 (1-2), for example 1 (1.2-1.8), such as 1: 1.5.
According to an embodiment of the invention, the reaction time may be 1 to 10 hours, for example 2 to 8 hours.
According to embodiments of the invention, the temperature of the reaction may be in the range of 0 to 100 deg.C, for example 10 to 90 deg.C, 20 to 80 deg.C, 30 to 70 deg.C, such as 40 to 60 deg.C.
According to an embodiment of the invention, the reaction may be carried out in the presence of metallic Zn, for example in the presence of zinc powder.
According to an embodiment of the present invention, the molar ratio of the compound II, the metal Zn (such as zinc powder) and the compound III may be 1 (1-3) to (1-2), such as 1 (1.5-2.5) to (1.2-1.8), such as 1:2: 1.5.
According to an embodiment of the invention, the reaction may be carried out in the presence of a catalyst selected from the group consisting of trimethylchlorosilane, 1, 2-dibromoethane and I2One, two or three of them. According to an embodiment of the invention, the catalyst is used in an amount of from 0.005 to 0.2mL of catalyst which is liquid at ordinary temperature or from 0.005 to 0.2g of catalyst which is solid at ordinary temperature, for example from 0.011mL, 0.01mL, 0.007mL of trimethylchlorosilane or 1, 2-dibromoethane are used for 1g of compound II.
According to an embodiment of the present invention, the solvent used for the reaction may be any suitable solvent that dissolves but does not react with the reactants, including but not limited to diethyl ether, n-butyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran, or a mixture of two or more thereof. The solvent is preferably an anhydrous reagent.
In one embodiment, the method for preparing bedaquiline comprises the following steps: in tetrahydrofuran, reacting a compound II and a compound III in the presence of zinc powder under the action of a catalyst of trimethylchlorosilane or 1, 2-dibromoethane to obtain the bedaquiline shown in a formula IV. For example, the reaction scheme may be as follows:
according to an embodiment of the invention, said compound II can be prepared by methods known in the literature or else by the following methods: reacting compound I with NCS (N-chlorosuccinimide) or NBS (N-bromosuccinimide) to give compound II:
wherein, X is chlorine or bromine.
According to an embodiment of the present invention, the reaction for preparing the compound II may be carried out in the presence of benzoyl peroxide.
According to an embodiment of the present invention, the molar ratio of the compound I, NCS or NBS to benzoyl peroxide in the preparation of the compound II can be 1 (1-2) to (0.01-0.6), for example, 1:1.1: 0.6.
According to an embodiment of the present invention, the reaction for preparing the compound II may be performed at 30 to 80 ℃, and the reaction time may be 1 to 10 hours, for example, 5 hours.
According to an embodiment of the present invention, the organic solvent used in the reaction for preparing the compound II is any suitable organic solvent capable of dissolving the reaction raw material but not participating in the reaction, including but not limited to: methylene chloride, chloroform, carbon tetrachloride, 1, 2-dichloroethane, tetrachloroethane, n-hexane, cyclohexane, THF, etc.
According to an embodiment of the invention, compound II may be prepared by: and (2) reacting the compound I, NCS or NBS in an organic solvent at the temperature of 10-100 ℃ under the initiation of benzoyl peroxide to obtain a compound II.
According to an embodiment of the present invention, the bedaquiline of formula IV may be prepared by:
step 1): reacting compound I with NCS (N-chlorosuccinimide) or NBS (N-bromosuccinimide) to give compound II:
wherein, in the compound II, X is chlorine or bromine;
step 2): and reacting the compound II with the compound III under the action of zinc powder and a catalyst to obtain the bedaquiline shown in the formula IV.
For example, the reaction scheme may be as follows:
according to an embodiment of the invention, wherein the catalyst in step 2) is trimethylchlorosilane or 1, 2-dibromoethane.
In the context of the present invention, the bedaquiline of formula IV is a mixture of (1S,2R) -1- (6-bromo-2-methoxy-3-quinolinyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol and (1R,2S) -1- (6-bromo-2-methoxy-3-quinolinyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol, for example, as racemates of the two.
Advantageous effects
The invention provides a novel method for preparing bedaquiline, such as racemate, which can synthesize bedaquiline more conveniently, efficiently and economically and can carry out industrial production. The advantages of the invention are embodied in:
1. the method changes the ultralow temperature reaction of the prior process, and carries out the ultralow temperature reaction which is difficult to realize in the prior industry at the conventional temperature (heating condition), so that the large-scale industrial production becomes possible;
2. the method greatly shortens the reaction route, improves the conversion rate and the reaction yield of the reaction substrate, ensures that the product is easier to crystallize and purify, and simultaneously reduces the production cost;
3. the synthesis method provided by the invention has the advantages of ingenious conception, realization of the control of reaction sites by utilizing the selectivity of zinc powder on the activities of benzyl and halogen on an aromatic ring (the halogen on the aromatic ring does not react with the zinc powder), avoidance of the harsh conditions of ultralow temperature reaction, realization of the synthesis of the bedaquiline racemate by one-step reaction, high product yield and simple operation of the synthesis method.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1: preparation of 6-bromo-3-chlorobenzyl-2-methoxyquinoline
3-benzyl-6-bromo-2-methoxyquinoline (32.7g, 0.01mol, 1eq) was dissolved in 200ml of 1, 2-dichloroethane, and NCS (14.7g, 1.1eq), benzoyl peroxide (1.5g, 0.006mol) and replaced with argon. The reaction was heated to 80 ℃ and the reaction was continued for 5 hours while maintaining the temperature. After completion of the reaction, it was cooled, added with water and extracted with dichloromethane, anhydrous Na2SO4Drying, concentration of the organic phase and recrystallization of the residue from methanol gave compound II-1(29.3g, 81% yield).1H NMR(400MHz,CDCl3)7.87(s,1H),7.84(d, J ═ 4.0Hz,1H),7.63-7.70(m,2H), 7.29-7.41 (m,5H),6.05(s,1H),4.04(s, 3H). Ms (+ C, ESI): M ═ 362, found: 363(M + 1).
Example 2: preparation of 6-bromo-3-bromobenzyl-2-methoxyquinoline
3-benzyl-6-bromo-2-methoxyquinoline (32.7g, 1eq) was dissolved in 200ml of methylene chloride, and NBS (18.7g, 1.05eq), benzoyl peroxide (1.5g) and argon gas were added for substitution. The reaction was heated to reflux and maintained at this temperature for a further 5 hours. After completion of the reaction, it was cooled, added with water and extracted with dichloromethane, anhydrous Na2SO4Drying, concentrating the organic phase and recrystallizing the residue from methanol gave Compound II-2(34.6g, 85% yield).1H NMR(400MHz,CDCl3)8.10(s,1H), 7.87(d, J ═ 4.0Hz,1H), 7.44-7.69 (m,4H), 7.26-7.38 (m,3H), 6.56(s,1H),4.06(s, 3H); ms (+ C, ESI): M406, found: (407, M + 1).
Example 3: preparation of bedaquiline (racemate)
Zinc powder (6.5g, 2eq) was suspended in 20ml of anhydrous tetrahydrofuran, and trimethylchlorosilane (0.2ml) was slowly added dropwise at room temperature, followed by stirring for 5min after the addition. Then, the temperature was raised to 60 ℃ and 90ml of an anhydrous THF mixed solution prepared from Compound II-1(18.2g, 1eq) and Compound III (17g, 1.5eq) was slowly added dropwise thereto over 1 hour. After the addition, stirring was continued for 4 h. Stopping heating, cooling to room temperature, extracting with ethyl acetate, and collecting anhydrous Na2SO4Drying, concentrating the organic phase to 50ml, stirring in ice water bath to precipitate diastereomer B, i.e. (S, S) -bedaquiline and (R, R) -bedaquiline diastereomer mixture, suction filtering, washing with small amount of ethyl acetate, discarding solid, combining mother liquor, and concentrating to dryness. 50ml of ethanol was added thereto and stirred at 0 ℃ to precipitate bedaquiline racemate IV which is racemate of (1S,2R) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol and (1R,2S) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol (9.7g, yield 35%).1H NMR(400MHz,CDCl3)8.89(s,1H),8.61(d, J ═ 8Hz,1H),8.30(s, br,1H),7.96(s,1H),7.91(d, J ═ 8Hz,1H),7.87(d, J ═ 8Hz,1H),7.71(d, J ═ 8Hz,1H),7.58-7.66(m,3H),7.46-7.49(m,1H),7.30(t, J ═ 8Hz,1H),7.13-7.14(m,2H),6.87-6.88(m,3H),5.89(s,1H),4.21(s,3H),2.51-2.55(m,1H),1.91-2.10(m, 9H). Ms (+ C, ESI): M554, found: (555, M + 1).
Example 4: preparation of bedaquiline (racemate)
Zinc powder (6.5g, 2eq) was suspended in 20ml of anhydrous tetrahydrofuran, and trimethylchlorosilane (0.2ml) was slowly added dropwise at room temperature, followed by stirring for 5min after the addition. Then, the temperature was raised to 60 ℃ and 100ml of an anhydrous THF mixed solution prepared from Compound II-2(20.4g, 1eq) and Compound III (17g, 1.5eq) was slowly added dropwise thereto over 1 hour. After the addition, stirring was continued for 4 h. Stopping heating, cooling to room temperature, and adding ethyl acetateEster extraction, anhydrous Na2SO4Drying, concentrating the organic phase to 50ml, stirring in ice water bath to precipitate diastereomer B, i.e. (S, S) -bedaquiline and (R, R) -bedaquiline diastereomer mixture, suction filtering, washing with small amount of ethyl acetate, discarding solid, combining the washing liquid with mother liquid, and concentrating under reduced pressure to dryness. 50ml of ethanol was added thereto and stirred at 0 ℃ to precipitate bedaquiline racemate IV which is the racemate of (1S,2R) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol and (1R,2S) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol (7.8g, yield 28%).1H NMR(400MHz,CDCl3)8.89(s,1H),8.61(d, J ═ 8Hz,1H),8.30(s, br,1H),7.96(s,1H),7.91(d, J ═ 8Hz,1H),7.87(d, J ═ 8Hz,1H),7.71(d, J ═ 8Hz,1H),7.58-7.66(m,3H),7.46-7.49(m,1H),7.30(t, J ═ 8Hz,1H),7.13-7.14(m,2H),6.87-6.88(m,3H),5.89(s,1H),4.21(s,3H),2.51-2.55(m,1H),1.91-2.10(m, 9H). Ms (+ C, ESI): M554, found (555, M + 1).
Example 5: preparation of bedaquiline (racemate)
Zinc powder (6.5g, 2eq) was suspended in 20ml of anhydrous tetrahydrofuran, and trimethylchlorosilane (0.2ml) was slowly added dropwise at room temperature, followed by stirring for 5min after the addition. Then, the temperature was raised to 60 ℃ and a solution of compound II-1(18.2g, 1eq) in anhydrous THF was slowly added dropwise thereto over a period of 0.5 hour, and the mixture was then incubated for 0.5 hour. Then, a solution of Compound III (17g, 1.5eq) in anhydrous THF was added dropwise over 15 minutes. After the addition, stirring was continued for 4 h. Stopping heating, cooling to room temperature, extracting with ethyl acetate, and collecting anhydrous Na2SO4Drying, concentrating the organic phase to 50ml, stirring in ice water bath to precipitate diastereomer B, i.e. (S, S) -bedaquiline and (R, R) -bedaquiline diastereomer mixture, suction filtering, washing with small amount of ethyl acetate, discarding solid, combining the washing liquid with mother liquid, and concentrating under reduced pressure to dryness. Adding 50ml ethanol, stirring at 0 deg.C to precipitate bedaquiline racemate IV,it was the racemate of (1S,2R) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol and (1R,2S) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol (4.7g, yield 17%).1H NMR(400MHz,CDCl3)8.89(s,1H),8.61(d, J ═ 8Hz,1H),8.30(s, br,1H),7.96(s,1H),7.91(d, J ═ 8Hz,1H),7.87(d, J ═ 8Hz,1H),7.71(d, J ═ 8Hz,1H),7.58-7.66(m,3H),7.46-7.49(m,1H),7.30(t, J ═ 8Hz,1H),7.13-7.14(m,2H),6.87-6.88(m,3H),5.89(s,1H),4.21(s,3H),2.51-2.55(m,1H),1.91-2.10(m, 9H). Ms (+ C, ESI): M554, found (555, M + 1).
Example 6: preparation of bedaquiline (racemate)
Zinc powder (6.5g, 2eq) was suspended in 20ml of anhydrous tetrahydrofuran, and 1, 2-dibromoethane (0.15ml) was slowly added dropwise at room temperature, followed by stirring for 5min after completion of the addition. Then, the temperature was raised to 60 ℃ and a solution of compound II-2(20.4g, 1eq) in anhydrous THF was slowly added dropwise thereto over a period of 0.5 hour, and the mixture was then incubated for 0.5 hour. Then, a solution of Compound III (17g, 1.5eq) in anhydrous THF was added dropwise over 15 minutes. After the addition, stirring was continued for 4 h. Stopping heating, cooling to room temperature, extracting with ethyl acetate, and collecting anhydrous Na2SO4Drying, concentrating the organic phase to 50ml, stirring in ice water bath to precipitate diastereomer B, i.e. (S, S) -bedaquiline and (R, R) -bedaquiline diastereomer mixture, suction filtering, washing with small amount of ethyl acetate, discarding solid, combining the washing liquid with mother liquid, and concentrating under reduced pressure to dryness. 50ml of ethanol was added thereto and stirred at 0 ℃ to precipitate bedaquiline racemate IV which is the racemate of (1S,2R) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol and (1R,2S) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol (3.3g, yield 12%).1H NMR(400MHz,CDCl3)8.89(s,1H),8.61(d,J＝8Hz,1H),8.30(s,br,1H),7.96(s,1H),7.91(d,J＝8Hz,1H),7.87(d,J＝8Hz,1H),7.71(d,J＝8Hz,1H),7.58-7.66(m,3H),7.46-749(m,1H),7.30(t, J ═ 8Hz,1H),7.13-7.14(m,2H),6.87-6.88(m,3H),5.89(s,1H),4.21(s,3H),2.51-2.55(m,1H),1.91-2.10(m, 9H). Ms (+ C, ESI): M554, found (555, M + 1).
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A process for preparing bedaquiline of formula IV comprising the step of reacting compound II with compound III:
wherein X is halogen, preferably chlorine or bromine.
2. The process according to claim 1, wherein the reaction is carried out in the presence of metallic Zn, such as zinc powder.
3. The method of claim 2, wherein the molar ratio of the compound II, the metal Zn (such as zinc powder) and the compound III is 1 (1-3) to (1-2), such as 1 (1.5-2.5) to (1.2-1.8), such as 1:2: 1.5.
4. A process according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of a catalyst selected from trimethylchlorosilane, 1, 2-dibromoethane and I2One, two or three of them.
5. The process according to any one of claims 1 to 4, wherein the reaction is carried out in a solvent selected from one or a mixture of two or more of diethyl ether, n-butyl ether, dioxane, tetrahydrofuran and 2-methyltetrahydrofuran; preferably, the solvent is an anhydrous reagent.
6. The method according to any one of claims 1-5, comprising the steps of: and (2) reacting the compound II with the compound III in tetrahydrofuran in the presence of zinc powder under the action of a catalyst of trimethylchlorosilane or 1, 2-dibromoethane to obtain the bedaquiline shown in the formula IV.
7. The method according to any one of claims 1-5, comprising the steps of:
step 1): reacting the compound I with NCS (N-chlorosuccinimide) or NBS (N-bromosuccinimide) to obtain a compound II;
in compound II, X is chloro or bromo;
step 2): and reacting the compound II with the compound III under the action of zinc powder and a catalyst to obtain the bedaquiline shown in the formula IV.
8. The process of claim 7 wherein the catalyst in step 2) is trimethylchlorosilane or 1, 2-dibromoethane.
9. The process according to any one of claims 1 to 8, wherein the temperature at which compound II is reacted with compound III is from 0 to 100 ℃.
10. The method according to any one of claims 1 to 9, wherein the bedaquiline of formula IV is a mixture of (1S,2R) -1- (6-bromo-2-methoxy-3-quinolinyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol and (1R,2S) -1- (6-bromo-2-methoxy-3-quinolinyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol, e.g. as the racemate of both.
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| CN112645935A (en) * | 2020-12-15 | 2021-04-13 | 植恩生物技术股份有限公司 | Preparation method of voriconazole key intermediate |
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