CN111747975B - Preparation method of bedaquiline racemate and intermediate thereof - Google Patents
Preparation method of bedaquiline racemate and intermediate thereof Download PDFInfo
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- CN111747975B CN111747975B CN202010613085.6A CN202010613085A CN111747975B CN 111747975 B CN111747975 B CN 111747975B CN 202010613085 A CN202010613085 A CN 202010613085A CN 111747975 B CN111747975 B CN 111747975B
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- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical class 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 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- 238000000034 method Methods 0.000 claims abstract description 54
- 229960000508 bedaquiline Drugs 0.000 claims abstract description 12
- 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 8
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 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 description 25
- 230000008569 process Effects 0.000 claims description 22
- 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 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 10
- -1 borate compound Chemical class 0.000 claims description 9
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 8
- 239000003999 initiator Substances 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000007818 Grignard reagent Substances 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 6
- 150000004795 grignard reagents Chemical class 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- HAUKUGBTJXWQMF-UHFFFAOYSA-N lithium;propan-2-olate Chemical compound [Li+].CC(C)[O-] HAUKUGBTJXWQMF-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052738 indium Inorganic materials 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007514 bases Chemical class 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims description 2
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 2
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims description 2
- LTEHWCSSIHAVOQ-UHFFFAOYSA-N tripropyl borate Chemical compound CCCOB(OCCC)OCCC LTEHWCSSIHAVOQ-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 2
- 229910052740 iodine Inorganic materials 0.000 claims 2
- 239000011630 iodine Substances 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 21
- 239000002904 solvent Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000001953 recrystallisation Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000002365 anti-tubercular Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 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
- SHULJILYSSQUBG-UHFFFAOYSA-N B(O)(O)OC(C)(C)C(C)(C)O.CO Chemical compound B(O)(O)OC(C)(C)C(C)(C)O.CO SHULJILYSSQUBG-UHFFFAOYSA-N 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 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
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000015355 drug-resistant tuberculosis Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory 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
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a bedaquiline racemate and an intermediate thereof. The method of the invention realizes the convenient, efficient and economical synthesis and industrial production of the bedaquiline and the intermediate thereof. In particular, the method of the invention has the following advantages: the method thoroughly changes the ultralow temperature reaction required by the preparation of the bedaquiline from the compound I and the compound II, changes the ultralow temperature reaction which is not easy to realize in the prior industry into the ultralow temperature reaction which is carried out at the conventional temperature, and enables the large-scale industrialized production to be possible; the method greatly improves the conversion rate of the reaction substrate, improves the reaction yield, ensures that the product is easier to crystallize and purify (the recrystallization of the intermediate can be realized by using the conventional solvent of ethyl acetate or methanol), and simultaneously reduces the production cost.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a bedaquiline racemate and an intermediate thereof.
Background
Bedaquinoline was developed by the United states Johnson pharmaceutical Co., ltd, approved by the United states food and drug administration for sale at 12/28 of 2012, and is clinically used for the treatment of drug-resistant tuberculosis, and its chemical name is (1R, 2S) -1- (6-bromo-2-methoxy-3-quinolinyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol, the structure is as follows:
bedapsone inhibits the energy production of mycobacterium tuberculosis by ATP by inhibiting the proton transfer chain of ATP synthase of mycobacterium, thereby exerting an antitubercular effect. The medicine is a brand new action way against mycobacterium tuberculosis, is a first approved antitubercular medicine for clinic over 40 years, has a new action mechanism, and is the only medicine for treating multi-drug-resistant tuberculosis at present.
To date, few synthetic routes have been reported for bedaquiline. The currently reported synthetic routes mainly comprise two routes, european Journal ofOrganic Chemistry, (11), 2057-2061,2011 report that the method is used for preparing the bedaquiline through chiral catalysis and asymmetric synthesis, and has the defects of higher yield, more steps, expensive reagents and catalysts, and inapplicability to industrial production. Patent documents WO 2006125796 and WO2004011436 disclose that a racemate of Bedaquinoline is obtained by multi-step reaction by taking 4-bromoaniline and phenylpropionyl chloride as starting materials, and then a target product is obtained by chiral column chromatography purification or chiral reagent induction recrystallization. The specific synthetic route is as follows:
although the process has low material cost and simple operation, a plurality of problems still exist: compound 1 and compound 3 react under the action of LDA at-78 ℃ for long reaction time (about 30 hours), the raw materials cannot be completely converted, the side reactions are more, and the yield is very low (26 percent); and the purity of the obtained product Bedapsone is low, and the total yield is about 6% after purification.
Chinese patent document CN105085395a discloses a method for obtaining bedaquiline racemate V by reacting compound I with compound VI and then reducing, the synthetic route is as follows:
however, the reaction of the compound I and the compound VI is inevitably carried out under ultralow temperature conditions, and the main reason is that the compound I has two reaction sites under the action of LDA, one is the benzyl position of the quinoline ring, which is a desired reaction site and relatively active, and the other is bromine on the quinoline ring can also react under the action of LDA to generate a debrominated byproduct. In order to allow the reaction to proceed at the desired site, a relatively good selectivity can be obtained only under ultra-low temperature conditions. Furthermore, the reaction will produce two chiral centers, four chiral isomers, plus four chiral isomers of the debrominated product, which is almost impossible to obtain by crystallization purification the desired configuration. In addition, the reaction steric hindrance of the two substrates (the compound I and the compound VI) is large, the required reaction temperature is low, the time is long, and the energy consumption is huge. In addition, many domestic medical enterprises at present do not have large-scale ultralow-temperature reaction kettles, and the low reaction temperature is easy to realize in a laboratory or a reaction kettle of 100L-200L, but is very difficult to implement in a large reaction kettle of thousands of liters, so that the current technology limits the mass production of the beraoquinoline to a certain extent.
Disclosure of Invention
In order to solve the above problems, the present invention provides a compound represented by the following formula III,
wherein R is 1 And R is 2 Identical or different, independently of one another, from H or C 1-6 An alkyl group;
when R is 1 And R is 2 Are all selected from C 1-6 When alkyl, optionally both may form, together with the O atom to which they are attached and the B atom, a 5-10 membered ring, said 5-10 membered ring optionally being substituted with 1-4C atoms 1-6 Alkyl substitution.
According to an embodiment of the invention, in compound III, R 1 And R is 2 The same or different, independently of one another, from H, methyl, ethyl, or isopropyl;
or R is 1 And R is 2 Together with the O atom and the B atom to which they are attached formA 5-10 membered ring, for example forming a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring or a 10-membered ring, said 5-10 membered ring being optionally substituted with 1-4 of the following groups: methyl, ethyl, propyl or butyl; more specifically, R 1 And R is 2 Together with the O atoms to which they are attached, the B atoms may form the structure:wherein->The position represents the site of attachment to the quinoline ring.
As an example, compound III is selected from the following structures:
the invention also provides a preparation method of the compound III, which comprises the following steps:
a-1) when R in the compound III 1 And R is 2 Are all C 1-6 In the case of alkyl groups, the method comprises the steps of:
reacting the compound I with a compound B-1 to obtain a compound III:
wherein, in the compound B-1, R 3 Selected from the group consisting ofor-OC 1-6 Alkyl, R 1 And R is 2 Are all C 1-6 Alkyl, optionally both, may form a 5-10 membered ring together with the O atom and B atom to which they are attached;
or alternatively, the process may be performed,
a-2) when R in Compound III 1 And R is 2 When both are H, the method comprises the following steps:
the compound I reacts with a borate compound B-2 to obtain a compound III:
wherein, in the compound B-2, R 1 、R 2 And R is 4 Identical or different, independently C 1-6 Alkyl, and any two of which do not form a ring.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting ofIn this case, the reaction time may be 4 to 10 hours.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting ofWhen the temperature of the reaction may be from 80 ℃ to 120 ℃, for example from 90 ℃ to 110 ℃.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting ofWhen the reaction is carried out in the presence of a metal Pd catalyst, the metal Pd catalyst can be tetra-triphenylphosphine palladium, palladium acetate, di (triphenylphosphine) palladium dichloride, [1,1' -bis (diphenylphosphino) ferrocene]One, two or more of palladium dichloride and the like.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting ofWhen the reaction is carried out, the reaction may be carried out in the presence of a promoter selected from at least one of basic compounds such as sodium acetate, potassium carbonate and the like.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting ofWhen the reaction is carried out in an organic solvent, the organic solvent may be selected from one, two or more of toluene, dioxane, acetonitrile, THF, DMF, DMSO, N, N-dimethylacetamide, N-methylpyrrolidone, or the like.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting ofIn this case, the molar ratio of the compound I to the compound B-1 may be 1 (1-3), for example 1 (1-2), for example 1 (1-1.5).
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting ofWhen the compound III-1 was prepared, the following procedure was adopted:
according to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting of-OC 1-6 In the process of alkyl, in the reaction, the compound I and metal Mg react in an inert gas atmosphere to generate a Grignard reagent, then an initiator is used for initiating, and then the Grignard reagent reacts with the compound B-1 to obtain the compound III.
According to an embodiment of the invention, the gas inert to the reaction in step a-1) is selected from argon or nitrogen.
According to an embodiment of the present invention, the initiator in step a-1) is selected from one or both of 1, 2-dibromoethane or elemental iodine, etc.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting of-OC 1-6 When alkyl, the molar ratio of compound I to compound B-1 is 1 (1-3), e.g., 1 (1-2), e.g., 1 (1-1.5).
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting of-OC 1-6 In the case of alkyl groups, the reaction time may be 2 to 10 hours.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting of-OC 1-6 In the case of alkyl groups, the reaction temperature may be from 0℃to 80℃and, for example, from 50℃to 70 ℃.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting of-OC 1-6 In the case of alkyl groups, the molar ratio of the compound I to magnesium powder may be 1 (1-3), for example 1 (1-2), for example 1:1.5.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting of-OC 1-6 In the case of alkyl group, the reaction may be carried out in a suitable organic solvent selected from at least one of diethyl ether, n-butyl ether, THF, methyltetrahydrofuran, etc.
According to an embodiment of the invention, in step a-1) when R 3 Selected from the group consisting of-OC 1-6 In the case of alkyl, compound III-1 is prepared by the following method,
according to an embodiment of the present invention, in the step a-2), the borate compound B-2 is selected from one, two or more of trimethyl borate, triethyl borate, tripropyl borate, triisopropyl borate, tributyl borate.
According to an embodiment of the invention, compound I in step a-2) is reacted with metal Mg in a gaseous atmosphere inert to the reaction to form a Grignard reagent, which is then initiated with an initiator and reacted with a borate compound B-2 to obtain compound III.
According to an embodiment of the invention, the gas inert to the reaction in step a-2) is selected from argon or nitrogen.
According to an embodiment of the present invention, the initiator in step a-2) is selected from one or both of 1, 2-dibromoethane or elemental iodine, etc.
According to an embodiment of the invention, the molar ratio of compound I to borate compound B-2 in step a-2) may be 1 (1-3), for example 1 (1-2), such as 1 (1-1.5).
According to an embodiment of the present invention, the time of the reaction in step a-2) may be 2 to 10 hours.
According to an embodiment of the present invention, the temperature of the reaction in step a-2) may be from 0℃to 80℃such as from 0℃to 70 ℃.
According to an embodiment of the invention, the molar ratio of compound I to magnesium powder in step a-2) may be 1 (1-3), for example 1 (1-2), such as 1:1.5.
According to an embodiment of the present invention, the reaction in step a-2) may be carried out in a suitable organic solvent selected from one, two or more of diethyl ether, n-butyl ether, THF, methyltetrahydrofuran and the like.
According to an embodiment of the present invention, compound III-2) can be prepared in step a-2) by the following method:
the invention also provides the use of compound III for the preparation of compound IV,
in the compound IV, R 1 And R is 2 Has the same definition as in compound III.
The invention also provides a preparation method of the compound IV, which comprises the following steps:
b) Reacting the compound III with a compound II to obtain a compound IV:
according to an embodiment of the invention, in step b), the reaction time may be 1 to 5 hours.
According to an embodiment of the invention, in step b), the temperature of the reaction may be from-20 ℃ to 30 ℃, for example from 0 ℃ to 30 ℃.
According to an embodiment of the invention, in step b), the reaction may be performed in the presence of lithium isopropoxide and LDA.
According to an embodiment of the present invention, in step b), the reaction may be carried out in a suitable organic solvent including, but not limited to, one or both of tetrahydrofuran, 2-methyltetrahydrofuran.
According to an embodiment of the invention, compound IV-1 is prepared in step b) using the following method:
the invention also provides the use of compound IV in the preparation of bedaquiline.
The invention also provides a method for preparing the bedaquiline by the compound IV, which comprises the following steps:
c) The compound IV reacts with copper bromide and/or cuprous bromide to obtain the bedaquiline racemate:
according to an embodiment of the invention, in step c), the reaction time may be from 1 to 10 hours.
According to an embodiment of the invention, in step c), the temperature of the reaction may be between 50 ℃ and 90 ℃, for example 70 ℃.
According to an embodiment of the invention, in step c), the molar ratio of compound IV to copper bromide may be from 1:1 to 10, for example from 1:1 to 5, such as 1:2.
According to an embodiment of the present invention, in step c), the solvent may be any suitable solvent that dissolves but does not react with the reactants, including but not limited to DMF, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, water, methanol, ethanol, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture of two, three, or more thereof.
According to an embodiment of the invention, in step c), bedaquiline is prepared by a method,
or alternatively, the process may be performed,
as an example, the bedaquiline racemate was prepared using the following method:
a) The compound I reacts with a compound B-1 or a compound B-2 to obtain a compound III;
b) Reacting the compound III with a compound II to obtain a compound IV;
c) The compound IV reacts with copper bromide and/or cuprous bromide to obtain a bedaquiline racemate;
advantageous effects
The invention provides a preparation method of a key intermediate of bedaquiline, namely compounds III and IV and two intermediates. The invention also provides a method for preparing the bedaquiline racemate by using the intermediate. The method of the invention realizes the convenient, efficient and economical synthesis and industrial production of the bedaquiline and the intermediate thereof. In particular, the method of the invention has the following advantages:
1. the method thoroughly changes the ultralow temperature reaction required by the preparation of the bedaquiline from the compound I and the compound II, changes the ultralow temperature reaction which is not easy to realize in the prior industry into the ultralow temperature reaction which is carried out at the conventional temperature, and enables the large-scale industrialized production to be possible.
2. The method greatly improves the conversion rate of the reaction substrate, improves the reaction yield, ensures that the product is easier to crystallize and purify (the recrystallization of the intermediate can be realized by using the conventional solvent of ethyl acetate or methanol), and simultaneously reduces the production cost.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Example 1: preparation of Compound III-1 (3-benzyl-2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) quinoline)
Compound I (65.6 g,1 eq), bis (pinacolato) diboron (53 g,1.05 eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (7.3 g,0.05 eq), anhydrous sodium acetate (33 g,2 eq) was suspended in 500ml dioxane and replaced with argon. The system was warmed to 100℃and kept at that temperature for 8 hours. After completion of the reaction, the extract was extracted with ethyl acetate and concentrated to about 200ml, followed by crystallization with stirring (ethyl acetate as a solvent) to give compound III-1 (66.8 g, yield 89%). 1 H NMR(400MHz,CDCl 3 ) δ8.10 (s, 1H), 7.94 (dd, j=8.0 hz, j=4 hz, 1H), 7.81 (d, j=4 hz, 1H), 7.57 (s, 1H), 7.30-7.31 (m, 2H), 7.22-7.26 (m, 3H), 4.11 (s, 3H), 4.02 (s, 2H), 1.36 (s, 12H); ms (+c, ESI): m=375, found: 376 (M+1).
Example 2: preparation of Compound III-1 (3-benzyl-2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) quinoline)
Mg powder (7.2 g,1.5 eq) was added to a 1L three-necked flask, and 50ml of anhydrous THF and 30ml of compound I solution (65.6 g of compound I in 300ml of anhydrous THF,1 eq) were added under argon. Heated to reflux temperature and 1, 2-dibromoethane (0.5 ml) was added dropwise to initiate the reaction. After the completion of the addition, the mixture was stirred for 2 minutes, and the remaining solution (270 ml) of Compound I was slowly added dropwise while keeping a slight boiling condition. After the addition, the reaction is continued for 1 hour in a micro-boiling state, and the reaction is cooled to room temperature, so as to prepare the Grignard solution. The prepared grignard solution was slowly added dropwise to methanol pinacol borate (47.4 g,1.5 eq) anhydrous THF (50 ml) cooled at 0 ℃ and the temperature was maintained for reaction for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the extract was concentrated to about 200 ml. Crystallization with stirring (using ethyl acetate as solvent) gives compound III-1 (51.8 g, 69% yield). 1 H NMR(400MHz,CDCl 3 ) δ8.10 (s, 1H), 7.94 (dd, j=8.0 hz, j=4 hz, 1H), 7.81 (d, j=4 hz, 1H), 7.57 (s, 1H), 7.30-7.31 (m, 2H), 7.22-7.26 (m, 3H), 4.11 (s, 3H), 4.02 (s, 2H), 1.36 (s, 12H); ms (+c, ESI): m=375, found: 376 (M+1).
Example 3: preparation of Compound III-2 (3-benzyl-2-methoxy-6-quinolineboronic acid)
Mg powder (7.2 g,1.5 eq) was added to a 1L three-necked flask, and 50ml of anhydrous THF, and 30ml of compound I solution (65.6 g in 300ml of anhydrous THF,1 eq) were added under argon. Heated to reflux temperature and 1, 2-dibromoethane (0.5 ml) was added dropwise to initiate the reaction. After the completion of the addition, the mixture was stirred for 2 minutes, and the remaining solution (270 ml) of Compound I was slowly added dropwise while keeping a slight boiling condition. After the addition, the reaction is continued for 1 hour in a micro-boiling state, and the reaction is cooled to room temperature, so as to prepare the Grignard solution. The prepared grignard solution was slowly added dropwise to trimethyl borate (31.2 g,1.5 eq) anhydrous THF (50 ml) cooled at 0 ℃ and the temperature was maintained for reaction for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the extract was concentrated to about 200 ml. Crystallization with stirring (using ethyl acetate as solvent) gives compound III-2 (42.8 g, 73% yield). 1 H NMR(400MHz,CDCl 3 )δ8.37 (s, 1H), 8.17 (d, j=8.0 hz,1H, arh), 8.11 (s, 1H), 7.79 (d, j=8.0 hz, 1H), 7.29-7.31 (m, 4H), 7.21-7.23 (m, 1H), 4.04 (s, 2H), 4.03 (s, 3H); ms (+c, ESI): m=293, found: 294 (M+1).
Example 4: preparation of Compound IV-1 (4-dimethylamino-1- (2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-quinolinyl) -2- (1-naphthyl) -1-phenyl-2-butanol)
Compound III-1 (12 g,0.032 mol) was dissolved in 20mL of anhydrous tetrahydrofuran, lithium isopropoxide (35 mL, 1M) was added dropwise at room temperature, and stirring was continued at room temperature for 1 hour after the addition was completed. LDA (17.6 ml, 2M) was then slowly added dropwise, cooled to 0℃with an ice-salt bath, and stirring was continued at this temperature for 0.5 hours after the addition. A solution of Compound II (8 g,0.035 mol) in THF (8 ml) was slowly added dropwise, and the reaction was continued for 1 hour after completion of the addition. After the reaction is completed, NH is added dropwise 4 The reaction was quenched with 50ml of saturated aqueous Cl solution. Extraction with ethyl acetate, drying over anhydrous magnesium sulfate, and concentrating under reduced pressure. After concentration, compound IV-1 (8.1 g, 42% yield) was obtained by crystallization from methanol. 1 H NMR(400MHz,CDCl 3 ) Delta 8.98 (s, 1H), 8.65 (d, j=8.0 hz, 1H), 8.34 (s, 1H), 8.12 (s, br, 1H), 7.81-7.96 (m, 3H), 7.59-7.64 (m, 2H), 7.48 (t, j=8 hz, 1H), 7.30 (t, j=8 hz, 1H), 7.17 (s, br, 2H), 6.86-6.87 (m, 3H), 5.89 (s, 1H), 4.24 (s, 3H), 2.51-2.55 (m, 1H), 2.08-2.14 (m, 1H), 1.95-2.02 (m, 7H), 1.54 (s, 1H), 1.40 (s, 12H), 1.24-1.33 (m, 1H); ms (+c, ESI): m=602, found: 603 (M) + +1).
Example 5: preparation of Compound IV-2 (4-dimethylamino-1- (2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-quinolinyl) -2- (1-naphthyl) -1-phenyl-2-butanol)
Compound III-2 (3 g,0.01 mol) was dissolved in 15mL of anhydrous tetrahydrofuran, LDA (10 mL, 2M) was slowly added dropwise at 0deg.C, and stirred after the additionAfter stirring for 10 minutes, lithium isopropoxide (11 ml, 1M) was added dropwise. Stirring was continued at room temperature for 1 hour after the addition was completed. Then, LDA (5.5 ml, 2M) was slowly added dropwise, cooled to 0℃with an ice-salt bath, and stirring was continued at that temperature for 0.5 hours after the addition was completed. Then a solution of compound II (2.5 g,0.01 mol) in THF (3 ml) was slowly added dropwise, and the reaction was continued for 1 hour after the addition was completed. After the reaction is completed, NH is added dropwise 4 The reaction was quenched with 50ml of saturated aqueous Cl solution. Then extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After concentrating the extract, the compound IV-2 (1.9 g, yield 37%) was obtained by crystallization from methanol. 1 H NMR(400MHz,CDCl 3 ) Delta 8.78 (s, 1H), 8.51 (d, j=8 hz, 1H), 7.94 (s, 1H), 7.92 (d, j=8 hz, 1H), 7.88 (d, j=8 hz, 1H), 7.73 (d, j=8 hz, 1H), 7.55-7.62 (m, 3H), 7.45-7.49 (m, 2H), 7.29 (t, j=8 hz, 1H), 7.13-7.15 (m, 2H), 6.89-6.90 (m, 3H), 5.88 (s, 1H), 4.25 (s, 3H), 2.52-2.55 (m, 1H), 2.01-2.10 (m, 2H), 1.97 (s, 6H), 1.91-1.94 (m, 1H). Ms (+c, ESI): m=520, found: (521, M+1).
Example 6: preparation of Beda quinoline (racemate)
Compound IV-1 (6 g,0.01 mol) was suspended in methanol at a volume ratio of 1:1: to a solvent (90 ml) made up of water, copper bromide (4.4 g,0.02mol,2 eq) was then added to the solvent at room temperature. After the addition, the temperature was raised to the reflux temperature, and stirring was continued for 8 hours in the reflux state. Heating was stopped, cooled to room temperature, and solid was precipitated, suction-filtered and washed with water to give compound V (4.85 g, yield 88%) as a pale yellow solid. 1 H NMR(400MHz,CDCl 3 ) Delta 8.89 (s, 1H), 8.61 (d, j=8 hz, 1H), 8.30 (s, br, 1H), 7.96 (s, 1H), 7.91 (d, j=8 hz, 1H), 7.87 (d, j=8 hz, 1H), 7.71 (d, j=8 hz, 1H), 7.58-7.66 (m, 3H), 7.46-7.49 (m, 1H), 7.30 (t, j=8 hz, 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): m=554, found: (555, M+1).
Example 7: preparation of Beda quinoline (racemate)
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Compound IV-2 (5.2 g,0.01 mol) was suspended in a volume ratio of 1:1 methanol: to the solution was added copper bromide (4.4 g,0.02mol,2 eq) at room temperature to a solvent (80 ml) composed of water=water. After the addition, the temperature was raised to the reflux temperature, and stirring was continued for 6 hours in the reflux state. Heating was stopped, cooled to room temperature, and solid was precipitated, suction-filtered and washed with water to give compound V (4.2 g, 76% yield) as a pale yellow solid. 1 H NMR(400MHz,CDCl 3 ) Delta 8.89 (s, 1H), 8.61 (d, j=8 hz, 1H), 8.30 (s, br, 1H), 7.96 (s, 1H), 7.91 (d, j=8 hz, 1H), 7.87 (d, j=8 hz, 1H), 7.71 (d, j=8 hz, 1H), 7.58-7.66 (m, 3H), 7.46-7.49 (m, 1H), 7.30 (t, j=8 hz, 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): m=554, 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, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (26)
1. A compound represented by the following formula III,
wherein R is 1 And R is 2 Identical or different, independently of one another, from H or C 1-6 An alkyl group;
when R is 1 And R is 2 Are all selected from C 1-6 When alkyl, optionally both may form, together with the O atom to which they are attached and the B atom, a 5-10 membered ring, said 5-10 membered ring optionally being substituted with 1-4C atoms 1-6 Alkyl substitution.
2. A compound represented by the following formula III,
in the compound III, R 1 And R is 2 The same or different, independently of one another, from H, methyl, ethyl or isopropyl;
or R is 1 And R is 2 Together with the O atom and B atom to which they are attached, form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with 1-4 of the following groups: methyl, ethyl, propyl or butyl.
3. A compound according to claim 2, wherein R 1 And R is 2 Together with the O atom and B atom to which they are attached, form the structure:wherein->The position represents the site of attachment to the quinoline ring.
4. The following compounds:
5. a process for the preparation of a compound according to any one of claims 1 to 3, comprising the steps of:
a-1) when R in the compound III 1 And R is 2 Are all C 1-6 In the case of alkyl groups, the method comprises the steps of:
reacting the compound I with a compound B-1 to obtain a compound III:
wherein, in the compound B-1, R 3 Selected from the group consisting ofor-OC 1-6 Alkyl, R 1 And R is 2 Are all C 1-6 Alkyl, optionally both, may form a 5-10 membered ring together with the O atom and B atom to which they are attached;
or alternatively, the process may be performed,
a-2) when R in Compound III 1 And R is 2 When both are H, the method comprises the following steps:
the compound I reacts with a borate compound B-2 to obtain a compound III:
wherein, in the compound B-2, R 1 、R 2 And R is 4 Identical or different, independently of one another, C 1-6 An alkyl group.
6. The process according to claim 5, wherein R in step a-1) 3 Selected from the group consisting ofWhen the reaction temperature is 80-120 ℃.
7. The process according to claim 5, wherein R in step a-1) 3 Selected from the group consisting ofWhen the reaction is carried out in the presence of a metallic Pd catalyst, the metallic Pd catalyst is tetra-triphenylphosphine palladium, palladium acetate, di (triphenylphosphine) palladium dichloride and [1,1' -bis (diphenylphosphino) ferrocene]One, two or more of palladium dichloride.
8. The process according to claim 5, wherein R in step a-1) 3 Selected from the group consisting ofWhen the reaction is carried out in the presence of a promoter selected from basic compounds.
9. The process according to claim 5, wherein R in step a-1) 3 Selected from the group consisting ofIn the case of the compound I and the compound B-1, the molar ratio is 1 (1-3).
10. The process according to claim 5, wherein R in step a-1) 3 Selected from the group consisting ofWhen the compound III-1 was prepared, the following procedure was adopted:
11. the process according to claim 5, wherein R in step a-1) 3 Selected from the group consisting of-OC 1-6 When alkyl is carried out, in the reaction, a compound I and metal Mg react in an inert gas atmosphere to generate a Grignard reagent, then an initiator is used for initiating, and then the Grignard reagent reacts with a compound B-1 to obtain a compound III; the inert gas for reaction in step a-1) is selected from argon or nitrogen;
the initiator in the step a-1) is selected from one or two of 1, 2-dibromoethane or elemental iodine.
12. The method of claim 11, whereinWhen R in step a-1) 3 Selected from the group consisting of-OC 1-6 When alkyl, the mol ratio of the compound I to the compound B-1 is 1 (1-3);
when R in step a-1) 3 Selected from the group consisting of-OC 1-6 When alkyl is used, the reaction temperature is 0-80 ℃;
when R in step a-1) 3 Selected from the group consisting of-OC 1-6 In the case of alkyl, the molar ratio of the compound I to the magnesium powder is 1 (1-3).
13. The process according to any one of claims 5 to 11, wherein in step a-1) when R 3 Selected from the group consisting of-OC 1-6 In the case of alkyl, compound III-1 is prepared by the following method,
14. the method according to claim 5, wherein in the step a-2), the borate compound B-2 is one, two or more selected from the group consisting of trimethyl borate, triethyl borate, tripropyl borate, triisopropyl borate and tributyl borate.
15. The preparation method according to claim 5, wherein in the step a-2), the compound I and the metal Mg are reacted in an inert gas atmosphere to generate a Grignard reagent, and then initiated by an initiator and then reacted with the borate compound B-2 to obtain a compound III;
the initiator in the step a-2) is selected from one or two of 1, 2-dibromoethane or elemental iodine.
16. The process according to claim 5, wherein the molar ratio of the compound I to the borate compound B-2 in the step a-2) is 1 (1-3);
the temperature of the reaction in the step a-2) is 0 ℃ to 80 ℃;
the molar ratio of the compound I to the magnesium powder in the step a-2) is 1 (1-3).
17. The process according to claim 5, wherein compound III-2 is prepared in step a-2) by:
18. the use of a compound III according to any of claims 1 to 3 for the preparation of a compound IV,
in the compound IV, R 1 And R is 2 Having the definition given in any one of claims 1 to 3.
19. A process for the preparation of compound IV as shown below,
in the compound IV, R 1 And R is 2 Having the definition given in any one of claims 1 to 3;
the method is characterized by comprising the following steps of:
b) A reaction of compound III according to any one of claims 1 to 3 with compound II to give compound IV:
wherein R is 1 And R is 2 Having the definition given in any one of claims 1 to 3.
20. The method of claim 19, wherein the reaction temperature is-20 ℃ to 30 ℃;
in step b), the reaction is carried out in the presence of lithium isopropoxide and LDA.
21. The process according to claim 19, wherein compound IV-1 is prepared in step b) by the following method:
22. the use of compound IV as claimed in claim 18 for the preparation of bedaquiline.
23. A process for the preparation of bedaquiline comprising the steps of:
c) The compound IV reacts with copper bromide and/or cuprous bromide to obtain the bedaquiline racemate:
24. the process according to claim 23, wherein in step c) the temperature of the reaction is 50 ℃ to 90 ℃;
in step c), the molar ratio of the compound IV to the copper bromide is 1:1-10.
25. The process according to claim 23, wherein in step c) bellaquine is prepared by a process,
or alternatively, the process may be performed,
26. the method of claim 23, wherein the bedaquiline racemate is prepared by:
a) The compound I reacts with a compound B-1 or a compound B-2 to obtain a compound III;
b) Reacting the compound III with a compound II to obtain a compound IV;
c) The compound IV reacts with copper bromide and/or cuprous bromide to obtain a bedaquiline racemate;
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