CN109762007B - Process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester - Google Patents
Process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 18
- 239000004327 boric acid Substances 0.000 title claims description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000005859 coupling reaction Methods 0.000 claims abstract description 26
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims abstract description 11
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940112669 cuprous oxide Drugs 0.000 claims abstract description 11
- 150000004820 halides Chemical class 0.000 claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- -1 N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester Chemical class 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 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 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000007865 diluting Methods 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- SMTJVGKZVGURTO-UHFFFAOYSA-N B(O)(O)OB(O)O.OCC(C)(CO)C Chemical compound B(O)(O)OB(O)O.OCC(C)(CO)C SMTJVGKZVGURTO-UHFFFAOYSA-N 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- FRLHQRHJAUNBJX-UHFFFAOYSA-N B(O)(O)OB(O)O.C=1(O)C(O)=CC=CC1 Chemical compound B(O)(O)OB(O)O.C=1(O)C(O)=CC=CC1 FRLHQRHJAUNBJX-UHFFFAOYSA-N 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 230000008878 coupling Effects 0.000 abstract description 3
- 238000010168 coupling process Methods 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 229910052763 palladium Inorganic materials 0.000 abstract description 3
- 239000007818 Grignard reagent Substances 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 230000003321 amplification Effects 0.000 abstract 1
- 150000004795 grignard reagents Chemical class 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 150000002894 organic compounds Chemical class 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- SBZWAVVCJBBNSM-UHFFFAOYSA-N 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C(CC1)=CCN1CC1=CC=CC=C1 SBZWAVVCJBBNSM-UHFFFAOYSA-N 0.000 description 2
- WXJBZPDYIKQTBZ-UHFFFAOYSA-L [Li+].[Cl-].[Br-].CC(C)[Mg+] Chemical compound [Li+].[Cl-].[Br-].CC(C)[Mg+] WXJBZPDYIKQTBZ-UHFFFAOYSA-L 0.000 description 2
- QDSFHRPYZPQWEJ-UHFFFAOYSA-N benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound O1C(C)(C)C(C)(C)OB1C1=CCN(C(=O)OCC=2C=CC=CC=2)CC1 QDSFHRPYZPQWEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 2
- 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 description 1
- 229940122746 Fatty acid amide hydrolase inhibitor Drugs 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003940 fatty acid amidase inhibitor Substances 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a method for synthesizing organic compounds. A process for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate includes such steps as reaction of N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide with diborate, cuprous halide or cuprous oxide, ligand and organic alkali in solvent to obtain N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate. The method has the advantages of originality, simple and convenient operation, short process route, low cost, high product purity and mild reaction conditions, avoids the adoption of metal palladium coupling or high-activity Grignard reagent and low-temperature conditions in the traditional method, has potential cost advantage and is suitable for industrial amplification production.
Description
Technical Field
The invention relates to a process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester, belonging to the field of synthesis of pharmaceutical intermediates.
Background
The N-substituted-1, 2,5, 6-tetrahydropyridine structure is often introduced into a drug molecule as an important structural unit or used to perform a coupling reaction to obtain a compound having pharmaceutical activity. Such as opioid receptor 1(OGL1) antagonist 1 and fatty acid amide hydrolase inhibitor 2. The synthesis of the compounds usually adopts palladium-catalyzed coupling of N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate ester, and then reduction is carried out to obtain the required compounds.
Currently, two methods are mainly used for synthesizing the N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate ester: method 1[1]The N-substituted-1, 2,5, 6-tetrahydropyridine-4-trifluoromethanesulfonate with high price is taken as a raw material and is synthesized by coupling reaction with diborate ester under the catalysis of metal palladium; method two[2]The method adopts N-substituted-4-piperidone as a raw material, reacts with triaryl phosphite, halogen and organic base to convert carbonyl into alkenyl halide, and then reacts with isopropyl magnesium chloride-lithium chloride and alkoxy borate to obtain N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate. Its main advantage is easily available raw material. But the synthesis is carried out by a two-step method, high-activity isopropyl magnesium bromide-lithium chloride is used, the low-temperature condition is adopted, the process is complicated, and the yield and the purity are not high.
Reference documents: gerfaud, T.; martin, c.; bouquet, k.; talano, s.;Millois-Barbuis, C.；Musicki,B.；Boiteau,J.；Cardinaud,I.Organic Process Research and Development.2017,21,631-640.
2. chinese patent CN201610014644.5, publication No. CN 105566367.
The above method has the following disadvantages: in the first method, an expensive metal palladium catalyst is used, so that the cost is high; the second method needs two steps of reaction, uses high-activity isopropyl magnesium bromide-lithium chloride and low-temperature conditions, and has the disadvantages of complex operation and low yield and purity.
Disclosure of Invention
The invention aims to solve the problems of the defects and provides a process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate, wherein an N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide is used as a raw material and reacts with diborate, cuprous halide or cuprous oxide, a ligand and an organic base in a reaction solvent to obtain the N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate, and the HPLC and nuclear magnetic purity is more than 99%. The one-step synthesis method has the advantages of short process route, low cost, high product purity, mild reaction conditions, easy operation and suitability for industrial application.
The technical scheme adopted by the invention for solving the problems is as follows: a process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester is characterized by comprising the following steps: the method comprises the following steps:
coupling reaction: dissolving N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate ester, cuprous halide or cuprous oxide, ligand and organic base in a reaction solvent, and stirring for reaction at 30-60 ℃; after the reaction is finished, filtering the reaction solution by using kieselguhr, diluting the filtrate by using a diluting solvent, washing the filtrate by using water, washing the filtrate by using saturated salt solution, evaporating the filtrate to dryness, adding a mixed solvent, pulping and filtering to obtain the pure N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester, wherein the purity of HPLC (high performance liquid chromatography) and nuclear magnetism is more than 99%, and the yield is 65-75%.
In the coupling reaction, in an N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, a substituent on N is selected from Boc, Cbz, methyl, ethyl, isopropyl and benzyl; the halogen is selected from chlorine, bromine and iodine.
In the coupling reaction, the diborate is selected from one of pinacol diborate, neopentyl glycol diborate and phthalic acid diphenol diborate.
In the coupling reaction, cuprous halide is selected from one of cuprous iodide, cuprous bromide and cuprous chloride.
In the coupling reaction, the ligand is selected from one of triphenylphosphine, ferrocene and 1, 3-bis (diphenylphosphino) propane.
In the coupling reaction, the organic base adopts lithium methoxide or lithium tert-butoxide.
In the coupling reaction, the reaction solvent is selected from one of N, N-dimethylformamide, dimethyl sulfoxide and 1, 4-dioxane.
In the coupling reaction, N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate, cuprous halide or cuprous oxide, and the equivalent ratio of the ligand to the organic base are 1:1-1.2:0.05-0.1:0.1-0.2: 2-2.2.
In the coupling reaction, the diluting solvent is selected from one of ethyl acetate, dichloromethane and toluene.
In the coupling reaction, the mixed solvent comprises n-heptane or n-hexane and ethanol, and the mass ratio of the n-heptane or the n-hexane to the ethanol is 3-6: 1.
The method adopts a one-step synthesis method, has short process route, adopts N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate, cuprous halide or cuprous oxide, ligand and organic base as raw materials, has easily obtained reaction raw materials and low cost, usually adopts palladium chloride dppf as a catalyst in the diborate coupling reaction, and has the selling price of 4 ten thousand yuan/kg, but the method adopts cuprous oxide or cuprous halide as a coupling reagent, the selling price is lower than 1 thousand yuan/kg, the reaction conditions are mild, such as temperature, pollution in the reaction process and the like, the method is friendly and easy to operate, the prepared product has high purity which is more than 99 percent, the industrial yield of the product is high and can reach 65-75 percent, and the method is suitable for industrial application.
Detailed description of the preferred embodiments
Example 1
Synthesis of N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester:
under the protection of nitrogen, dissolving N-Boc-1,2,5, 6-tetrahydropyridine-4-bromine (26.3g, 0.1mol), pinacol diboron (25.4g, 0.1mol), cuprous oxide (1.43g, 0.01mol), triphenylphosphine (5.24g, 0.02mol) and lithium methoxide (7.2g, 0.2mol) in N, N-dimethylformamide (130g) in a reaction bottle, and controlling the temperature to be 45-55 ℃ to stir for reaction; after the reaction was completed by GC assay, the reaction solution was filtered through celite, the filter cake was rinsed with toluene (50g), the filtrate was diluted with toluene (50g), the filtrate was washed with water (100g), the layers were separated, the organic layer was checked by GC for the absence of N, N-dimethylformamide and was washed with saturated brine (100g), the solvent was evaporated, heptane/ethanol 5:1 was added and slurried, 20.1g of white solid N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was obtained after filtration, HPLC: 99.2%, yield 65%.
Example 2
Synthesis of N-Cbz-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester:
under the protection of nitrogen, dissolving N-Cbz-1,2,5, 6-tetrahydropyridine-4-iodine (34.3g, 0.1mol), pinacol diboron (30.5g, 0.12mol), cuprous iodide (2.5g, 0.008mol), triphenylphosphine (4.2g, 0.016mol) and lithium methoxide (8.4g, 0.22mol) in dimethyl sulfoxide (130g) in a reaction bottle, and controlling the temperature to be 40-50 ℃ to stir for reaction; after the reaction was completed by GC assay, the reaction solution was filtered through celite, the filter cake was rinsed with dichloromethane (50g), the filtrate was diluted with dichloromethane (50g), the filtrate was washed with water (100g), the layers were separated, the organic layer was checked by GC for no dimethylsulfoxide, the organic layer was washed with saturated brine (100g), the solvent was evaporated, N-hexane/ethanol (6: 1) was added and slurried, and after filtration, 25.7g of white solid N-Cbz-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was obtained, with HPLC: 99.5% and yield of 75%.
Example 3
Synthesis of N-benzyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester:
under the protection of nitrogen, dissolving N-benzyl-1, 2,5, 6-tetrahydropyridine-4-bromine (25.2g, 0.1mol), pinacol diboron (30.5g, 0.12mol), cuprous oxide (1.43g, 0.01mol), 1, 3-bis (diphenylphosphino) propane (8.25g, 0.02mol) and lithium tert-butoxide (17.6g, 0.22mol) in N, N-dimethylformamide (130g) in a reaction bottle, and stirring to react at the temperature of 45-55 ℃; after the reaction was completed by GC assay, the reaction solution was filtered through celite, the filter cake was rinsed with toluene (50g), the filtrate was diluted with toluene (50g), the filtrate was washed with water (100g), the layers were separated, the organic layer was checked by GC for the absence of N, N-dimethylformamide and was washed with saturated brine (100g), the solvent was evaporated, heptane/ethanol 3:1 was added and slurried, 20.3g of white-like solid N-benzyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was obtained after filtration, HPLC: 99.6%, yield 68%.
Example 4
Synthesis of N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid neopentyl glycol ester:
under the protection of nitrogen, dissolving N-Boc-1,2,5, 6-tetrahydropyridine-4-bromine (26.3g, 0.1mol), neopentyl glycol diborate (22.6g, 0.1mol), cuprous oxide (1.43g, 0.01mol), triphenylphosphine (5.24g, 0.02mol) and lithium methoxide (7.2g, 0.2mol) in N, N-dimethylformamide (130g) in a reaction bottle, and stirring to react at the temperature of 45-55 ℃; after the reaction was completed by GC assay, the reaction solution was filtered through celite, the filter cake was rinsed with toluene (50g), the filtrate was diluted with toluene (50g), the filtrate was washed with water (100g), and the layers were separated, and GC assay showed that the organic layer had no N, N-dimethylformamide, and the organic layer was washed with saturated brine (100g), the solvent was evaporated, heptane/ethanol 5:1 was added and the mixture was slurried, and after filtration, 21.2g of white solid N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid neopentyl glycol ester was obtained, with HPLC 99.8%, and the yield 72%.
Claims (10)
1. A process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester is characterized by comprising the following steps: the method comprises the following steps: coupling reaction: dissolving N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate ester, cuprous halide or cuprous oxide, ligand and organic base in a reaction solvent, and stirring for reaction at 30-60 ℃; after the reaction is finished, filtering the reaction solution by using kieselguhr, diluting the filtrate by using a diluting solvent, washing the filtrate by using water, washing the filtrate by using saturated salt solution, evaporating the filtrate to dryness, adding a mixed solvent, pulping and filtering to obtain the pure N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester.
2. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, in the N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, a substituent on N is selected from Boc, Cbz, methyl, ethyl, isopropyl and benzyl; the halogen is selected from chlorine, bromine and iodine.
3. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the diborate is selected from one of pinacol diborate, neopentyl glycol diborate and catechol diborate.
4. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the cuprous halide is selected from one of cuprous iodide, cuprous bromide and cuprous chloride.
5. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the ligand is selected from one of triphenylphosphine, ferrocene and 1, 3-bis (diphenylphosphino) propane.
6. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the organic base adopts lithium methoxide or lithium tert-butoxide.
7. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the reaction solvent is selected from one of N, N-dimethylformamide, dimethyl sulfoxide and 1, 4-dioxane.
8. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate, cuprous halide or cuprous oxide, and the equivalent ratio of the ligand to the organic base are 1:1-1.2:0.05-0.1:0.1-0.2: 2-2.2.
9. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the diluting solvent is selected from one of ethyl acetate, dichloromethane and toluene.
10. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the mixed solvent comprises n-heptane or n-hexane and ethanol, and the mass ratio of the n-heptane or the n-hexane to the ethanol is 3-6: 1.
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