CN107573278A - A kind of preparation method of the piperidones of pharmaceutical intermediate N BOC 3 - Google Patents
A kind of preparation method of the piperidones of pharmaceutical intermediate N BOC 3 Download PDFInfo
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- CN107573278A CN107573278A CN201710830877.7A CN201710830877A CN107573278A CN 107573278 A CN107573278 A CN 107573278A CN 201710830877 A CN201710830877 A CN 201710830877A CN 107573278 A CN107573278 A CN 107573278A
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- China
- Prior art keywords
- boc
- preparation
- piperidones
- catalyst
- hydroxy piperidines
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000012450 pharmaceutical intermediate Substances 0.000 title claims abstract description 7
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 title abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 239000004793 Polystyrene Substances 0.000 claims abstract description 19
- 229920002223 polystyrene Polymers 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 12
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 6
- 239000005708 Sodium hypochlorite Substances 0.000 claims abstract description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 4
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical class ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 claims abstract 4
- 238000006243 chemical reaction Methods 0.000 claims description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 238000003756 stirring Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- RIFXIGDBUBXKEI-UHFFFAOYSA-N tert-butyl 3-oxopiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCCC(=O)C1 RIFXIGDBUBXKEI-UHFFFAOYSA-N 0.000 claims description 20
- UIJXHKXIOCDSEB-UHFFFAOYSA-N tert-butyl 3-hydroxypiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCCC(O)C1 UIJXHKXIOCDSEB-UHFFFAOYSA-N 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical class OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
- -1 tetramethyl piperidine nitrogen oxygen free radical Chemical class 0.000 abstract description 14
- 239000004005 microsphere Substances 0.000 abstract description 8
- 238000011084 recovery Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 28
- 239000007787 solid Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- IZUZIVIUDTZPFE-UHFFFAOYSA-N tert-butyl decanoate Chemical class CCCCCCCCCC(=O)OC(C)(C)C IZUZIVIUDTZPFE-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000007800 oxidant agent Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 150000002978 peroxides Chemical class 0.000 description 3
- OXTNCQMOKLOUAM-UHFFFAOYSA-N 3-Oxoglutaric acid Chemical compound OC(=O)CC(=O)CC(O)=O OXTNCQMOKLOUAM-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tertiry butyl alcohol Natural products CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 1
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical compound CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 description 1
- 229910020350 Na2WO4 Inorganic materials 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical class CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to technical field of organic synthesis, and in particular to a kind of preparation method of the piperidones of pharmaceutical intermediate N BOC 3.The problem of solving tetramethyl piperidine nitrogen oxygen free radical of used catalyst 2,2,6,6 or derivatives thereof in the existing piperidones preparation methods of N BOC 3 catalytic capability and catalytic activity be low, catalyst is difficult to recovery.The preparation method includes：3 hydroxy piperidines are placed in solvent with sodium carbonate, di-tert-butyl dicarbonate and reacted, the hydroxy piperidines of N BOC 3 are prepared；The hydroxy piperidines of N BOC 3 are placed in solvent with KBr, catalyst, sodium hypochlorite under weak basic condition and reacted, obtain the piperidones of N BOC 3.The preparation method of the present invention has used immobilized 9 azabicyclic [3 of crosslinked polystyrene microsphere, 3,1] oxygen radical of nonyl 9 is catalyst, aoxidized using liquor natrii hypochloritis, in the method, catalyst is easy to recovery, and the yield of product is prepared with energy raising, the production cost of the piperidones of N BOC 3 is reduced, and the pollution to environment can be reduced.
Description
Technical field
The invention belongs to organic chemical synthesis field, and in particular to a kind of preparation of pharmaceutical intermediate N-BOC-3- piperidones
Method.
Background technology
The structure of one or more piperidine rings can be usually included in many natural or synthetic medical compounds, particularly
The piperidine ring of 3- positions substitution is especially common.When synthesizing this kind of compound, N-BOC-3- piperidones is often used as its conjunction
Into intermediate and critical materials.
At present, it is by aoxidizing N-BOC-3- hydroxy piperidines to obtain, being somebody's turn to do to prepare N-BOC-3- piperidones the best ways
Method synthesis step number is few, high income, is to use most commonly seen method.But in existing method for oxidation, oxidant used is held high
Expensive, the catalytic capability of oxidation catalyst is inadequate, and catalytic effect is poor, and post catalyst reaction is difficult to reclaim, and easily causes environment dirt
Dye.
Such as in patent document 1, N-BOC-3- hydroxy piperidines are oxidized to N-BOC-3- piperazines using Dai Si-Martin's oxidant
Pyridine ketone, the oxidizer molecule amount is big, and molecule utilization rate is not high, and expensive, rarely has and is used in large-scale production.
In patent document 2, use with TEMPO (referred to as " TEMPO ") as catalyst,
The method aoxidized using liquor natrii hypochloritis prepares N-BOC-3- piperidones, and after this method reaction, catalyst can not be from
Separated in system, can only be disposed as waste, easily cause environmental pollution.
In non-patent literature 1, N-BOC-3- piperidones is prepared using the method for Swern oxidations, the preparation method needs
Ultralow temperature, and a large amount of gases are had during side reaction and are produced, it is unfavorable for production safety, manufacturing cost is also higher.
Therefore, required product effectively can not be inexpensively made in existing N-BOC-3- piperidones preparation method, limit it
Application and popularization in pharmaceuticals industry field of fine chemical.
Prior art literature
Patent document
Patent document 1：US 2011/105520
Patent document 2：WO 2009/82134
Non-patent literature
Non-patent literature 1：Bioorg.Med.Chem.Lett., 13,2155-2158 (2003)
The content of the invention
The technical problem to be solved by the invention is to provide a kind of preparation side of pharmaceutical intermediate N-BOC-3- piperidones
Method, this method use the immobilized 9- azabicyclics [3,3,1] of crosslinked polystyrene microsphere-nonyl- 9- oxygen radicals (referred to as " PS-
ABNO ") it is catalyst, the method aoxidized using liquor natrii hypochloritis prepares N-BOC-3- piperidones, urging in this method
Agent PS-ABNO can be separated and recovered easily by filtering, and can recycled, significantly reduce N-BOC-3-
The production cost of piperidones, while reduce environmental pollution.
In order to solve the above-mentioned technical problem, the invention discloses following scheme：
A kind of preparation method of pharmaceutical intermediate N-BOC-3- piperidones compounds, including：
Step 1,3- hydroxy piperidines and sodium carbonate, di-tert-butyl dicarbonate (abbreviation " BoC2O ") are placed in solvent and reacted,
N-BOC-3- hydroxy piperidines are prepared；
Step 2, by the N-BOC-3- hydroxy piperidines obtained in step 1 and KBr, catalyst, sodium hypochlorite in alkaline bar
Part is put down to react in solvent, and N-BOC-3- piperidones is prepared.
Catalyst described in step 2 is that the immobilized 9- azabicyclics [3,3,1] of crosslinked polystyrene microsphere-nonyl- 9- oxygen is free
Base, its structural formula are as follows：
Wherein, PS represents crosslinked polystyrene microsphere.
Further, the step 1 specifically includes：Added in reaction vessel 1 equivalent 3- hydroxy piperidines, 0.5~1.2 work as
Sodium carbonate, water and the organic solvent of amount, are stirred, and the two of 0.8~1.5 equivalent is slowly added at a temperature of 0 DEG C~25 DEG C
Dimethyl dicarbonate butyl ester is reacted, and N-BOC-3- hydroxy piperidines are prepared.
Further, the step 2 specifically includes：Added in reaction vessel 1 equivalent N-BOC-3- hydroxy piperidines, 0.01
The catalyst and chlorinated hydrocarbon solvent of the KBr of~0.2 equivalent, 0.005~0.1 equivalent, it is added dropwise at a temperature of 0 DEG C~25 DEG C
The liquor natrii hypochloritis of 1.0~4.5 equivalents is reacted, and the liquor natrii hypochloritis is adjusted with alkalescent material or acidic materials
Its pH value is 7.5~8.5；After reaction terminates, catalyst is removed by filtration, separates organic phase, is concentrated to give target product N-BOC-
3- piperidones.
Further, the envelope-bulk to weight ratio of 3- hydroxy piperidines and water is 2-5ml/g in step 1.
Further, the envelope-bulk to weight ratio of 3- hydroxy piperidines and organic solvent is 2-5ml/g in step 1.
Further, organic solvent described in step 1 is methanol or ethanol.
Further, in step 2, the envelope-bulk to weight ratio of N-BOC-3- hydroxy piperidines and chlorinated hydrocarbon solvent is 3-8ml/g.
Further, chlorohydrocarbon described in step 2 is dichloromethane or 1,2- dichloroethanes.
Further, alkalescent material described in step 2 is sodium acid carbonate；The acidic materials be hydrochloric acid, sulfuric acid, acetic acid or
Person's niter cake.
Further, the chemical combination of the immobilized 9- azabicyclics [3,3,1] of the crosslinked polystyrene microsphere-nonyl- 9- oxygen radicals
Thing is prepared by lower noodle producing method, including：
Step (1), by the ammonium chloride of the glutaraldehyde of 1 equivalent, the acetone dicarboxylic acid of 0.7~2 equivalent and 0.7~1.5 equivalent
Be placed in the hydrophosphate aqueous solution of 0.4~2 equivalent, be maintained at the concentration of the hydrophosphate aqueous solution for 0.20~0.80g/ml,
Reaction temperature is -10 DEG C~70 DEG C, pH value is reacted under conditions of being 4~6, adds two carbonic acid two of 0.9~2.0 equivalent afterwards
Tert-butyl alcohol ester, 3- oxo -9- azabicyclos [3,3,1] nonane -9- carboxylic acid tert-butyl esters are prepared；
Step (2), 3- oxo -9- azabicyclos [3,3,1] nonane -9- carboxylic acid tert-butyl esters of 1 equivalent are added and its body
Product weight is than in the alcohols solvent for 2~15ml/g, after carrying out reduction reaction with the sodium borohydride of 0.5~1.5 equivalent, being prepared into
To 3- hydroxyl -9- azabicyclos [3,3,1] nonane -9- carboxylic acid tert-butyl esters；
Step (3), by the N, N- that the crosslinked polystyrene chlorine ball of 1 equivalent adds with its envelope-bulk to weight ratio is 3~15ml/g
In solvent dimethylformamide, swelling is stirred at room temperature, and the 3- hydroxyl -9- azepines for subsequently adding 0.8~2.0 equivalent are double
Ring [3,3,1] nonane -9- carboxylic acid tert-butyl esters, the sodium hydrogen of 1.0~2.5 equivalents is complete in 20 DEG C~100 DEG C reactions, and crosslinking is made
Polystyrene-supported 3- hydroxyls -9- azabicyclos [3,3,1] nonane -9- carboxylic acid tert-butyl esters；
Step (4), by immobilized 3- hydroxyls -9- azabicyclos [3,3, the 1] nonane -9- carboxylic acids of the crosslinked polystyrene of 1 equivalent
In the dichloromethane solvent that it is 2~7ml/g with its envelope-bulk to weight ratio that the tert-butyl ester, which adds, 0.2~1 times of body of methylene chloride volume is added
Long-pending trifluoroacetic acid, it is complete in 0 DEG C~40 DEG C reactions, immobilized 9- azabicyclos [3,3, the 1] nonyl- of crosslinked polystyrene microsphere is made
3- alcohol；
Step (5), immobilized 9- azabicyclos [3,3,1] the nonyl- 3- alcohol of the crosslinked polystyrene of 1 equivalent is added and its volume
Weight is than for 2~15ml/g alcohols solvent, acetonitrile or its in the mixed solvent, under conditions of reaction temperature is 0 DEG C~80 DEG C
Oxidation reaction is carried out with the peroxide oxidant of 0.8~5 equivalent, obtains the immobilized 9- azabicyclics of crosslinked polystyrene microsphere
[3,3,1]-nonyl- 9- oxygen radicals；
During specific implementation, the hydrophosphate may include disodium hydrogen phosphate, dibastic sodium phosphate, dipotassium hydrogen phosphate, potassium hydrogen phosphate
And its any at least one in hydrate；
During specific implementation, the alcohols solvent may include methanol, ethanol, propyl alcohol, isopropanol or butanol etc.；
During specific implementation, the chlorinated hydrocarbon solvent can be dichloromethane or 1,2- dichloroethanes etc.；
During specific implementation, the peroxide oxidant can be hydrogen peroxide, metachloroperbenzoic acid, Peracetic acid, peroxide
Change any at least one in urea hydrogen, a carboxyl benzoyl hydroperoxide or sodium tungstate.
The beneficial effects of the invention are as follows：
The preparation method of the present invention by using recyclable immobilized 9- azabicyclics of crosslinked polystyrene microsphere [3,3,
1] as catalyst in high yield, N-BOC-3- piperidones has been prepared to high-quality in-nonyl- 9- oxygen radicals.In the preparation side
In method, catalyst can directly be recovered by filtration after the completion of reaction, and the catalyst property after recovery keeps stable, can be complete
Beauteously reuse, significantly reduce the production cost of N-BOC-3- piperidones, reduce the discharge of discarded object, avoid environment
Pollution.
Embodiment
The following example is only used for that the present invention is described in detail, it will be appreciated that the scope of the present invention is not limited to
These embodiments.
PS-ABNO preparation embodiment
Prepare embodiment 1
The good reaction unit of frame, 215g disodium hydrogen phosphate dodecahydrate, 600ml water are added into reaction bulb, and stirring is molten
Solution, less than 10 DEG C are cooled to frozen water, add 35.3g ammonium chloride, 109.6g acetone dicarboxylic acid, it is clear that stirring is dissolved to it
Clearly.At 5 DEG C, 120.1g glutaraldehyde and 120g water are added into reaction bulb, stirring makes its reaction complete, measures reaction solution
PH is 4.5；Ice bath is removed, room temperature is allowed to warm to 35 DEG C of warm water, is stirred overnight, there is gas releasing.The next morning sees
Reaction solution is faint yellow, is released substantially without gas, and the pH for measuring reaction solution is 6.0；With 40% NaOH adjust reaction solution pH to
8.5~9.5, about with 30g NaOH；After adding NaOH, 250ml methanol is added, is stirred, and is cooled with ice-water bath；So
144g di-tert-butyl dicarbonate is added in backward reaction bulb, about 10min is added, and stirring makes its reaction complete；Removed after 5min
Water-bath, it is set to react complete at room temperature；The pH that reaction solution is measured at 25 DEG C is 7.0~7.5；800ml is added into reaction bulb
EA, stir, reaction solution depressurized and filtered, filtrate is added to stratification in separatory funnel, and has in reaction bulb a large amount of
White solid separate out, dissolved after adding water, have that a small amount of yellow substance is not soluble in water and EA in；Aqueous phase is extracted with 800ml EA
Once, merge organic phase, respectively washed once with 600ml 1N hydrochloric acid and 500ml water, organic phase anhydrous Na2SO4Dry,
And stood overnight, filter, after solvent is recovered under reduced pressure, residue is placed in refrigerator and refrigerated, separate out a large amount of white solid productions
Product, suction filtration obtain white solid product；Mother liquor is placed in refrigerator after partial solvent is recovered under reduced pressure, and separates out white solid again, will
It depressurizes suction filtration and obtains white solid, and the white solid obtained for the first time merges, and dries at room temperature, white solid is obtained
102g, yield 71.3%.1H-NMR (400MHz, CDCl3)：δ=4.73 (1H, br), 4.60 (1H, br), 2.54-2.66 (2H,
M), 2.38 (1H, s), 2.34 (1H, s), 1.75-1.79 (2H, m), 1.63-1.70 (2H, m), 1.51-1.59 (2H, m), 1.49
(9H, s).
Prepare embodiment 2
The good reaction unit of frame, 23.9g 3- oxo -9- azabicyclos [3,3,1] nonyl is added in 500ml there-necked flask
Alkane -9- carboxylic acid tert-butyl esters, 239ml methanol, are stirred to reaction solution clear, and are cooled to 0 DEG C with ice salt bath, in batches and are delayed
Slowly 4.5g NaBH is added into reaction solution4, there is in adition process a small amount of gas to release；NaBH4After addition, make it in ice
Stirring is complete to reaction under salt bath；Reaction solution clear when 10 DEG C.Reaction solution is poured into what is be made into by 12ml concentrated hydrochloric acids
In 400ml frozen water, stir, extracted three times with dichloromethane 400ml × 3, merge organic phase and simultaneously washed with 300ml, it is organic
Mutually it is concentrated under reduced pressure, light yellow viscous liquid 25g, crude yield about 100% is obtained after concentration, gained liquid curing is pale yellow colored solid
Body, it is pale white solid powder after smashing to pieces.1H-NMR (400MHz, CDCl3)：δ=4.47 (1H, m), 4.36 (1H, m), 3.67
(1H, m), 2.26-2.35 (2H, m), 2.06-2.11 (1H, m), 1.73-1.75 (1H, m), 1.63-1.66 (2H, m), 1.30-
1.59 (14H, m).
Prepare embodiment 3
The good device of frame, dry DMF 240ml, crosslinked polystyrene chlorine ball 24.0g, nitrogen are added into 500ml there-necked flasks
Under protection, it is stirred at room temperature, it is fully swelled；Again at 35 DEG C, stirred under nitrogen atmosphere makes it be swelled in DMF；It is anti-after swelling
It is faint yellow muddiness to answer liquid, adds 3- hydroxyl -9- azabicyclos [3,3,1] nonane -9- carboxylic acid tert-butyl esters 24.1g stirrings thereto
Solution is glassy yellow after uniformly；5g sodium hydrogen is added into solution, makes solution stirring reaction 30min at the temperature (35 DEG C)；Will
Reaction bulb is put into 60 DEG C of oil bath, makes its reaction complete, and solution is that yellow is muddy, stops heating, Temperature fall is simultaneously stirred
Night；At 32 DEG C, reaction solution outward appearance adds 200ml water, stirred, decompression is filtered, and filter cake is used thereto without obvious change
The clear water washing of 500ml × 2, drains, it is double to obtain the immobilized 3- hydroxyls -9- azepines of khaki solid crosslinked polystyrene microsphere as far as possible
Ring [3.3.1] nonane -9- carboxylic acid tert-butyl ester 55.0g, it is directly used in and reacts in next step.
Prepare embodiment 4
The good reaction unit of frame, it is double that the immobilized 3- hydroxyls -9- azepines of crosslinked polystyrene microsphere are added into 500ml reaction bulb
Ring [3.3.1] nonane -9- carboxylic acid tert-butyl esters 55.0g, dichloromethane 200ml stir and cooled with ice-water bath；After 50min
(now 6 DEG C of reacting liquid temperature) start that TFA50ml is added dropwise into bottle, and stirring makes its reaction complete；After 10min, reaction solution (temperature
12 DEG C) it is lark, continue to stir；Reaction solution (9 DEG C of temperature) is yellowish-brown after 10min, continues to stir；Reaction solution after 45min
(10 DEG C of temperature) is lark, stops reaction, decompression filters, by filter cake 50%K2CO3The aqueous solution, which stirs, to be washed, and is then drained, filter cake
Washed twice with the clear water of 50ml × 2, drain to obtain the immobilized 9- azabicyclos [3,3,1] of yellow solid crosslinked polystyrene microsphere
Nonyl- 3- alcohol 44.3g, it is directly used in and reacts in next step.
Prepare embodiment 5
The good device of frame, to reaction bulb in add and PS-ABNH 44.1g and methanol 200ml and stir, then add
Na2WO4·2H2O 8.25g, and start to be cooled with frozen water；UHP36.8g is added at 5 DEG C, about 5min is added, and stirring makes its reaction
Completely；Reaction solution outward appearance is warmed to room temperature and is stirred overnight without significant change after 25min.34 DEG C of reaction solution outward appearances of room temperature are without obvious
Change, stop reaction, pour into 200ml water, stir, filter, the NaHCO of filter cake saturation3Solution, which stirs, to be washed, and is filtered, filter cake
Washed twice with clear water 50ml × 2, drain to obtain faint yellow solid (wet product) 49.0g, be put into (75 DEG C) drying of hot-air oven, obtain
To the immobilized 9- azabicyclics [3,3,1] of 30.0g khaki solid crosslinked polystyrene microspheres-nonyl- 9- oxygen radical products.Gained
The immobilized 9- azabicyclics [3,3,1] of crosslinked polystyrene microsphere-nonyl- 9- oxygen radicals are used for the system of following N-BOC-3- piperidones
It is standby.
The preparation of N-BOC-3- piperidones
Embodiment 1
In the step 1, according to below scheme prepare compound N-BOC-3- hydroxy piperidines：
820ml water, 206.4g sodium carbonate is added in reaction bulb, stirring makes its dissolving, and solution becomes after adding methanol
White opacity, then adds 328g 3- hydroxy piperidines, stirs, cooled with ice bath, is slowly added to 250g's at 9 DEG C
BoC2O, temperature rise, and continuously add 200g BoC2O into reaction bulb when cooling to 20 DEG C, temperature rises, then waits to cool
Remaining 550g BoC2O is slowly added at 20 DEG C, common 2h is added, and reaction is overnight；Reaction stands 0.5h at room temperature after terminating,
Add 1500ml water, stir, add 1500ml dichloromethane to extract once, aqueous phase extracts two with 1000ml dichloromethane
It is secondary, merge organic phase, 100g anhydrous Na is used after 1000ml water washing2SO4Dry, filtering, obtained after concentration and recovery solvent
675g weak yellow liquid, it is put into after refrigerator cold-storage and obtains that for white solid, N-BOC-3- hydroxy piperidines are prepared,1H-NMR
(400MHz, CDCl3)：δ=3.78-3.82 (2H, m), 3.68-3.73 (1H, m), 3.56-3.61 (1H, m), 2.98 (2H,
M), 2.99-3.06 (1H, m), 1.89-1.93 (1H, m), 1.72-1.77 (1H, m), 1.38-1.54 (11H, m).
Embodiment 2
In the step 2, according to below scheme prepare compound N-BOC-3- piperidones：
Added into reaction bulb 20.1g N-BOC-3- hydroxy piperidines, 703.5mg PS-ABNO, 100ml dichloromethane
Alkane, 1g KBr are added to reaction system after being dissolved in water, 5 DEG C are cooled to ice bath, by 8.4g NaHCO3It is dissolved in 100ml's
In liquor natrii hypochloritis, its pH=8.5 or so is adjusted, is slowly added to, control drop speed makes reaction temperature be not higher than 10 DEG C, drips
Bi Hou, TLC are detected, and after reaction completely, PS-ABNO are recovered by filtration, reaction solution stands liquid separation, aqueous phase 100ml dichloromethane
Extraction, merge organic phase, with 100ml washing once, organic phase anhydrous Na2SO4Dry, filtering, be concentrated to give the light of 19.8g
Yellow oily product, obtains target product N-BOC-3- piperidones, yield 99.4%,1H-NMR (400MHz, CDCl3)：δ=
4.03 (2H, m), 3.58-3.61 (2H, m), 2.47-2.51 (2H, m), 1.97-2.03 (2H, m), 1.48 (9H, s).
Embodiment 3
PS-ABNO, the 100ml's reclaimed into reaction bulb in addition 20.1g N-BOC-3- hydroxy piperidines, embodiment 2
Dichloromethane, 1g KBr are added to reaction system after being dissolved in water, 5 DEG C are cooled to ice bath, by 8.4g NaHCO3It is dissolved in
In 100ml liquor natrii hypochloritises, its pH=8.5 or so is adjusted, is slowly added to, control drop speed makes reaction temperature be not higher than 10 DEG C,
After being added dropwise, TLC detections, after reaction completely, PS-ABNO is recovered by filtration, reaction solution stands liquid separation, and aqueous phase is with the two of 100ml
Chloromethanes extracts, and merges organic phase, with 100ml washing once, organic phase anhydrous Na2SO4Dry, filtering, be concentrated to give
19.5g faint yellow oily product, yield 97.9%.
Embodiment 4
Using the PS-ABNO of recovery in embodiment 3, with reference to the operation in above-described embodiment 3, continue to repeat experiment behaviour
Make, obtain compound N-BOC-3- piperidones.
Embodiment 5
Using the PS-ABNO of recovery in embodiment 4, with reference to the operation in above-described embodiment 3, continue to repeat experiment behaviour
Make, obtain compound N-BOC-3- piperidones.
Embodiment 6
Using the PS-ABNO of recovery in embodiment 5, with reference to the operation in above-described embodiment 3, continue to repeat experiment behaviour
Make, obtain compound N-BOC-3- piperidones.
Embodiment 7
Using the PS-ABNO of recovery in embodiment 6, with reference to the operation in above-described embodiment 3, continue to repeat experiment behaviour
Make, obtain compound N-BOC-3- piperidones.
Experimental data in 4-7 of the embodiment of the present invention is referring to following table：
Embodiment 8
Added into reaction bulb 20.1g N-BOC-3- hydroxy piperidines, 70.4mg PS-ABNO, 100ml dichloromethane
Alkane, 0.5g KBr are added to reaction system after being dissolved in water, 5 DEG C are cooled to ice bath, by 8.4g NaHCO3It is dissolved in 100ml
Liquor natrii hypochloritis in, adjust its pH=8.5 or so, be slowly added to, control drop speed make reaction temperature be not higher than 10 DEG C, be added dropwise
After, TLC detections, after reaction completely, PS-ABNO is recovered by filtration, reaction solution stands liquid separation, aqueous phase 100ml dichloromethane
Alkane extracts, and merges organic phase, with 100ml washing once, organic phase anhydrous Na2SO4Dry, filtering, be concentrated to give faint yellow oil
Shape product 19.3g, yield 96.9%.
Comparative example 1
20.1g N-BOC-3- hydroxy piperidines, 703.5mg TEMPO, 100ml dichloromethane is added into reaction bulb,
1g KBr is added to reaction system after being dissolved in water, and 5 DEG C are cooled to ice bath, by 8.4g NaHCO3It is dissolved in 100ml time
In sodium chlorate solution, its pH=8.5 or so is adjusted, is slowly added to, control drop speed makes reaction temperature be not higher than 10 DEG C, is added dropwise
Afterwards, TLC is detected, and after reaction completely, reaction solution stands liquid separation, and aqueous phase is extracted with 100ml dichloromethane, is merged organic phase, is used
100ml washing once, organic phase anhydrous Na2SO4Dry, filtering, be concentrated to give 17.4g faint yellow oily product, yield
87.3%.
Comparative example 2
Added into reaction bulb 20.1g N-BOC-3- hydroxy piperidines, 70.4mg TEMPO, 100ml dichloromethane,
0.5g KBr is added to reaction system after being dissolved in water, and 5 DEG C are cooled to ice bath, by 8.4g NaHCO3It is dissolved in 100ml's
In liquor natrii hypochloritis, its pH=8.5 or so is adjusted, is slowly added to, control drop speed makes reaction temperature be not higher than 10 DEG C, drips
Bi Hou, TLC are detected, and after reaction carries out 6 hours, raw material is still complete without conversion.
Above content is to combine specific preferred embodiment further description made for the present invention, it is impossible to is assert
The specific implementation of the present invention is confined to these explanations.For general technical staff of the technical field of the invention,
On the premise of not departing from present inventive concept, some simple deduction or replace can also be made, should all be considered as belonging to the present invention's
Protection domain.
Claims (10)
- A kind of 1. preparation method of pharmaceutical intermediate N-BOC-3- piperidones compounds, it is characterised in that including：Step 1,3- hydroxy piperidines are placed in solvent with sodium carbonate, di-tert-butyl dicarbonate and reacted, N-BOC-3- is prepared Hydroxy piperidine；Step 2, by the N-BOC-3- hydroxy piperidines obtained in step 1 and KBr, catalyst, sodium hypochlorite in weak basic condition Under be placed in solvent and react, N-BOC-3- piperidones is prepared.
- 2. preparation method as claimed in claim 1, it is characterised in that catalyst described in step 2 is that crosslinked polystyrene is micro- The immobilized 9- azabicyclics [3,3,1] of ball-nonyl- 9- oxygen radicals.
- 3. the preparation method as described in claim 1-2, it is characterised in that the step 1 specifically includes：Add in reaction vessel Enter the 3- hydroxy piperidines of 1 equivalent, the sodium carbonate of 0.5~1.2 equivalent, water and organic solvent, stir, at 0 DEG C~25 DEG C At a temperature of be slowly added to the di-tert-butyl dicarbonate of 0.8~1.5 equivalent and reacted, N-BOC-3- hydroxy piperidines are prepared.
- 4. the preparation method as described in claim 1-2, it is characterised in that the step 2 specifically includes：Add in reaction vessel Enter the catalyst and chloro of the N-BOC-3- hydroxy piperidines of 1 equivalent, the KBr of 0.01~0.2 equivalent, 0.005~0.1 equivalent Hydrocarbon solvent, the liquor natrii hypochloritis that 1.0~4.5 equivalents are added dropwise at a temperature of 0 DEG C~25 DEG C are reacted, the sodium hypochlorite Solution adjusts its pH value as 7.5~8.5 with alkalescent material or acidic materials；After reaction terminates, catalyst is recovered by filtration, separates Organic phase, it is concentrated to give target product N-BOC-3- piperidones.
- 5. preparation method as claimed in claim 3, it is characterised in that the envelope-bulk to weight ratio of 3- hydroxy piperidines and water in step 1 For 2-5ml/g.
- 6. preparation method as claimed in claim 3, it is characterised in that the volume of 3- hydroxy piperidines and organic solvent in step 1 Weight ratio is 2-5ml/g.
- 7. preparation method as claimed in claim 3, it is characterised in that organic solvent described in step 1 is methanol or ethanol.
- 8. preparation method as claimed in claim 4, it is characterised in that N-BOC-3- hydroxy piperidines and chlorohydrocarbon are molten in step 2 The envelope-bulk to weight ratio of agent is 3-8ml/g.
- 9. preparation method as claimed in claim 4, it is characterised in that chlorohydrocarbon described in step 2 is dichloromethane or 1, 2- dichloroethanes.
- 10. preparation method as claimed in claim 4, it is characterised in that alkalescent material described in step 2 is sodium acid carbonate； The acidic materials are hydrochloric acid, sulfuric acid, acetic acid or niter cake.
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