CN106631989A - Preparation method of donepezil hydrochloride related substance E - Google Patents
Preparation method of donepezil hydrochloride related substance E Download PDFInfo
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- CN106631989A CN106631989A CN201611056290.7A CN201611056290A CN106631989A CN 106631989 A CN106631989 A CN 106631989A CN 201611056290 A CN201611056290 A CN 201611056290A CN 106631989 A CN106631989 A CN 106631989A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000000126 substance Substances 0.000 title abstract description 6
- 229960003135 donepezil hydrochloride Drugs 0.000 title abstract 2
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 46
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 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 description 14
- 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 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- SGIBOXBBPQRZDM-UHFFFAOYSA-N 1-benzylpiperidine-4-carbaldehyde Chemical class C1CC(C=O)CCN1CC1=CC=CC=C1 SGIBOXBBPQRZDM-UHFFFAOYSA-N 0.000 claims description 7
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 7
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 5
- 239000003999 initiator Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- -1 bromo succinyl Imines Chemical class 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 238000005286 illumination Methods 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- NNYBQONXHNTVIJ-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 NNYBQONXHNTVIJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 229940063718 lodine Drugs 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 2
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 claims 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims 1
- 239000001095 magnesium carbonate Substances 0.000 claims 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims 1
- 229910003445 palladium oxide Inorganic materials 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 2
- IHMQOBPGHZFGLC-UHFFFAOYSA-N 5,6-dimethoxy-2,3-dihydroinden-1-one Chemical compound C1=C(OC)C(OC)=CC2=C1C(=O)CC2 IHMQOBPGHZFGLC-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 100
- 238000010792 warming Methods 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 19
- 238000000926 separation method Methods 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- WXQDFOGZIYLEGP-UHFFFAOYSA-N C(C(C)C)#N.C(C(C)C)#N.[N] Chemical compound C(C(C)C)#N.C(C(C)C)#N.[N] WXQDFOGZIYLEGP-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 101000671814 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 38 Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102100040108 Ubiquitin carboxyl-terminal hydrolase 38 Human genes 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
Abstract
The invention relates to a preparation method of a donepezil hydrochloride related substance E. The high-yield and high-purity related substance E is obtained by taking 5,6-dimethoxy-1-indanone as a starting material through four-step reaction.
Description
Technical field
The present invention relates to a kind of preparation method of Doneppezil Hydrochloride about material E, belongs to pharmaceutical technology field.
Background technology
Doneppezil Hydrochloride be by Japanese Wei Cai Pharmaceutical Co., Ltd research and develop anti-acetylcholinesterase inhibitor, 1997
January lists in the U.S., and in October, 1999 is listed in China, has become and has treated the one of slight or moderate Alzheimer's disease
Line medication, its structural formula is shown below：
Newest American Pharmacopeia has described nine kinds of relevant materials of following A, B, C, D, E, F, G, H, I, and it is relevant to define each
The limit standard of material, its structural formula is as follows：
The newest American Pharmacopeia of contrast（USP38）With a upper pharmacopeia, it can be seen that newly increased about substance B and relevant material
E, wherein, relevant substance B is easily prepared due to its simple structure, and passes through Literature Consult, is found also without the system about material E
Preparation Method.
The content of the invention
It is an object of the invention to provide a kind of preparation method of Doneppezil Hydrochloride about material E.
A kind of preparation method of Doneppezil Hydrochloride about material E is the technical scheme is that, is obtained through the following steps
：
Wherein, substituent X is selected from halogen, preferred chlorine, bromine or iodine in compound I.
The first step, substrate 5,6- dimethoxy -1- indones and halide reagent are prepared under radical initiator effect to be changed
Compound I；
Second step, compound I Jing Basic fluxing ractions obtain compound II；
3rd step, compound II reacts prepare compound III with N- benzyl-4-piperidinealdehydes；
4th step, the hydrogenated reduction of compound III obtains relevant material E；
According to the present invention, the solvent of first step reaction is selected from non-protonic solvent, and preferred carbon tetrachloride, acetonitrile or chloroform are more excellent
Select carbon tetrachloride；The halide reagent selected from bromine, bromo-succinimide, chlorosuccinimide, N-iodosuccinimide,
One kind in bromine chloride or lodine chloride, preferred bromo-succinimide；The radical initiator is selected from benzoyl peroxide, idol
Nitrogen bis-isobutyronitrile or illumination, preferred benzoyl peroxide.
According to the present invention, in more detail, the first step adds 5,6- dimethoxy -1- indones and halide reagent to non-matter
In sub- property solvent, radical initiator or illumination, back flow reaction to reaction was added to finish, isolated compound I, substituent
X is defined as above.
According to the present invention, the preferred water of the solvent used by second step hydrolysis-tetrahydrofuran mixed solvent, water：Tetrahydrochysene furan
Volume ratio of muttering is（0.1-1）：1；
According to the present invention, second step hydrolysis needs to use alkali, alkali used to be selected from lithium carbonate, cesium carbonate, calcium carbonate, carbonic acid
One kind in magnesium, sodium acid carbonate, NaOH, potassium hydroxide, lithium hydroxide, preferred potassium carbonate.
According to the present invention, the solvent of three-step reaction is selected from organic solvent miscible with water, preferred methyl alcohol, ethanol, isopropyl
Alcohol, acetone, acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, DMF, more preferably DMA, first
Alcohol；Reaction temperature is preferred 50-90 DEG C, more preferably 60-70 DEG C.
According to the present invention, three-step reaction needs to use alkali, alkali used to be selected from sodium carbonate, potassium carbonate, sodium acid carbonate, hydrogen-oxygen
Change sodium or potassium hydroxide, preferred potassium carbonate.
According to the present invention, the solvent of four-step reaction hydrogenation process selected from alcohol or chlorohydrocarbon, the preferred methyl alcohol of the alcohol, second
Alcohol, isopropanol, more preferably methyl alcohol；The preferred dichloromethane of the chlorohydrocarbon, more preferably chloroform, dichloromethane.
According to the present invention, the catalyst of four-step reaction hydrogenation process reaction is palladium carbon, palladium dydroxide, palladium, dioxy
Change platinum, preferred palladium carbon；The hydrogen source of catalytic hydrogenation is selected from ammonium acetate, ammonium formate, formic acid, hydrogen, preferred hydrogen.
According to the present invention, carry out isolating and purifying the relevant thing that can be obtained high-purity, meet pharmacopoeial requirements by column chromatography
Matter E.
The invention has the beneficial effects as follows with 5,6- dimethoxy -1- indones for starting material, through four-step reaction, with high receipts
Rate, high-purity obtain relevant material E.
Specific embodiment：
For a better understanding of the present invention content, is described further with reference to specific embodiment, but the present invention is not only limited to
This.
Embodiment 1
Under room temperature condition, by 5,6- dimethoxy -1- indones（15.0g, 78mmol）Add into 150ml carbon tetrachloride, heat up
To 50 DEG C it is molten it is clear after, addN-Bromo-succinimide（15.3g, 86mmol）, benzoyl peroxide（0.1g, 0.4mmol）, rise
Temperature closes heating to the h of back flow reaction 4, is cooled to after room temperature and filters, 300ml eluent methylene chlorides, vacuum rotary steam organic phase, post
Chromatography（Dichloromethane：Acetone=100：8）Obtain compound I（17.0g, 80.4%）.
Under room temperature condition, by compound I（10.0g, 37mmol）Add into 300ml water, add tetrahydrofuran 100ml,
Add potassium carbonate（25.5g, 184mmol）, back flow reaction 2h is warming up to, heating is closed, it is cooled to room temperature, dichloromethane
（150ml*3）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying, vacuum rotary steam organic phase, column chromatography
Separate（Dichloromethane：Acetone=100：15）Obtain compound II（6.1g, 79.2%）.
Under room temperature condition, by compound II（4.0g, 19mmol）Add into 40ml methyl alcohol, be warming up to 40-50 DEG C, be added dropwise
Wet chemical（18.0g potassium carbonate is dissolved in 180ml water）, after completion of dropping, the methyl alcohol of 1- benzyl-4-piperidinealdehydes is added dropwise
Solution（4.3g is dissolved in 40ml methyl alcohol）, completion of dropping is warming up to 60-70 DEG C of reaction 4h, TLC detections, and reaction finishes, close plus
Heat, is cooled to room temperature, dichloromethane（200ml*2）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying,
Vacuum rotary steam organic phase, column chromatography for separation（Dichloromethane：Acetone：Methyl alcohol=100：100：1）Obtain compound III（4.5g,
60.2%）.
Under room temperature condition, by compound III（3.4g, 8.6mmol）Add mixed to 68ml methyl alcohol and 68ml dichloromethane
In bonding solvent, palladium carbon is added（0.68g）, hydrogen is poured, the h of room temperature reaction 2.5, TLC detection, reaction is finished, filtered, decompression rotation
Steam organic phase, column chromatography for separation（Dichloromethane：Acetone：Methyl alcohol=100：100：1）Obtain impurity E（2.8g, 82.4%）.
Embodiment 2
Under room temperature condition, by 5,6- dimethoxy -1- indones（15.0g, 78mmol）Add into 150ml carbon tetrachloride, heat up
To 50 DEG C it is molten it is clear after, addN- bromo-succinimide（15.3g, 86mmol）, benzoyl peroxide（0.1g, 0. 4mmol）,
Back flow reaction 4h is warming up to, heating is closed, is cooled to after room temperature and is filtered, 300ml eluent methylene chlorides, vacuum rotary steam organic phase,
Column chromatography for separation（Dichloromethane：Acetone=100：8）Obtain compound I（17.0g, 80.4%）.
Under room temperature condition, by compound I（10.0g, 37mmol）Add into 300ml water, add tetrahydrofuran 30ml, plus
Enter sodium carbonate（19.5g, 184mmol）, back flow reaction 2h is warming up to, heating is closed, it is cooled to room temperature, dichloromethane（150ml*
3）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying, vacuum rotary steam organic phase, column chromatography for separation（Two
Chloromethanes：Acetone=100：15）Obtain compound II（6.0g, 77.9 %）.
Under room temperature condition, by compound II（4.0g, 19mmol）Add into 40ml methyl alcohol, be warming up to 40-50 DEG C, be added dropwise
Wet chemical（18.0g potassium carbonate is dissolved in 180ml water）, after completion of dropping, the methyl alcohol of 1- benzyl-4-piperidinealdehydes is added dropwise
Solution（4.3g is dissolved in 40ml methyl alcohol）, completion of dropping is warming up to 60-70 DEG C of reaction 4h, TLC detections, and reaction finishes, close plus
Heat, is cooled to room temperature, dichloromethane（200ml*2）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying,
Vacuum rotary steam organic phase, column chromatography for separation（Dichloromethane：Acetone：Methyl alcohol=100：100：1）Obtain compound III（4.5g,
60.2%）.
Under room temperature condition, by compound III（3.4g, 8.6mmol）Add mixed to 68ml methyl alcohol and 68ml dichloromethane
In bonding solvent, palladium carbon is added（0.68g）, hydrogen is filled with, the h of room temperature reaction 2.5, TLC detection, reaction is finished, filtered, decompression rotation
Steam organic phase, column chromatography for separation（Dichloromethane：Acetone：Methyl alcohol=100：100：1）Obtain impurity E（2.8g, 82.4%）.
Embodiment 3
Under room temperature condition, by 5,6- dimethoxy -1- indones（15.0g, 78mmol）Add into 150ml chloroforms, be warming up to 50
It is DEG C molten it is clear after, add bromine（13.8g, 86mmol）, azodiisobutyronitrile（0.1g, 0. 6mmol）, back flow reaction 6h is warming up to,
Heating is closed, is cooled to after room temperature and is filtered, vacuum rotary steam organic phase, column chromatography for separation（Dichloromethane：Acetone=100：8）Must change
Compound I（14.9.0g, 70.5%）.
Under room temperature condition, by compound I（10.0g, 37mmol）Add into 300ml water, add tetrahydrofuran 60ml, plus
Enter cesium carbonate（60.0 g, 184mmol）, back flow reaction 2h is warming up to, heating is closed, it is cooled to room temperature, dichloromethane（150ml*
3）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying, column chromatography for separation after vacuum rotary steam（Dichloromethane
Alkane：Acetone=100：15）Obtain compound II（5.7g, 73.4 %）.
Under room temperature condition, by compound II（4.0g, 19mmol）Add into 40ml ethanol, be warming up to 40-50 DEG C, hydrogen-oxygen
Change sodium water solution（5.2g NaOH is dissolved in 52ml water）, after completion of dropping, the ethanol that 1- benzyl-4-piperidinealdehydes are added dropwise is molten
Liquid（4.3g is dissolved in 40ml ethanol）, completion of dropping is warming up to 70-80 DEG C of reaction 6h, TLC detections, and reaction finishes, close plus
Heat, is cooled to room temperature, dichloromethane（200ml*2）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying,
After vacuum rotary steam, column chromatography for separation（Dichloromethane：Acetone：Methyl alcohol=100：100：1）Obtain compound III（3.7g, 50.0%）.
Under room temperature condition, by compound III（3.4g, 8.6mmol）Add the mixing to 68ml ethanol and 68ml chloroforms molten
In agent, palladium carbon is added（0.68g）, hydrogen is poured, the h of room temperature reaction 2.5, TLC detection, reaction is finished, filtered, and vacuum rotary steam has
After machine phase, column chromatography for separation（Dichloromethane：Acetone：Methyl alcohol=100：100：1）Obtain impurity E（2.2g, 64.9%）.
Example IV
Under room temperature condition, by 5,6- dimethoxy -1- indones（15.0g, 78mmol）Add into 150ml acetonitriles, be warming up to 50
It is DEG C molten it is clear after, addN- chlorosuccinimide（11.5g, 86mmol）, azodiisobutyronitrile（0.1g, 0. 6mmol）, heat up
To back flow reaction 8h, heating is closed, be cooled to after room temperature and filter, vacuum rotary steam organic phase, column chromatography for separation（Dichloromethane：Third
Ketone=100：8）Obtain compound I（9.0g, 50.8%）.
Under room temperature condition, by compound I（8.4g, 37mmol）Add into 300ml water, add tetrahydrofuran 60ml, plus
Enter sodium acid carbonate（15.5g, 185mmol）, back flow reaction 3h is warming up to, heating is closed, it is cooled to room temperature, dichloromethane
（150ml*3）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying, column chromatography for separation after vacuum rotary steam
（Dichloromethane：Acetone=100：15）Obtain compound II（4.8g, 62.3 %）.
Under room temperature condition, by compound II（4.0g, 19mmol）Add into 40ml acetone, be warming up to 40-50 DEG C, be added dropwise
Aqueous sodium carbonate（13.0g sodium carbonate is dissolved in 130ml water）, after completion of dropping, the acetone of 1- benzyl-4-piperidinealdehydes is added dropwise
Solution（4.3g is dissolved in 40ml acetone）, completion of dropping is warming up to 50-60 DEG C of reaction 6h, TLC detections, and reaction finishes, close plus
Heat, is cooled to room temperature, dichloromethane（200ml*2）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying,
After vacuum rotary steam, column chromatography for separation（Dichloromethane：Acetone：Methyl alcohol=100：100：1）Obtain compound III（3.2g, 43.2%）.
Under room temperature condition, by compound III（3.2g, 8.1mmol）Add mixed to 68ml ethanol and 68ml dichloromethane
In bonding solvent, palladium carbon is added（0.64g）, add ammonium formate（5.0g）, back flow reaction 2h is warming up to, TLC detections, reaction is finished,
Filter, after vacuum rotary steam organic phase, column chromatography for separation（Dichloromethane：Acetone：Methyl alcohol=100：100：1）Obtain impurity E（2.0g,
62.5%）.
Embodiment five
Under room temperature condition, by 5,6- dimethoxy -1- indones（15.0g, 78mmol）Add into 150ml chloroforms, be warming up to 50
It is DEG C molten it is clear after, addN- chlorosuccinimide（11.5g, 86mmol）, benzoyl peroxide（0.1g, 0. 4mmol）, heat up
To back flow reaction 8h, heating is closed, be cooled to after room temperature and filter, vacuum rotary steam organic phase, column chromatography for separation（Dichloromethane：Third
Ketone=100：8）Obtain compound I（10.3g, 58.1%）.
Under room temperature condition, by compound I（8.4g, 37mmol）Add into 300ml water, add tetrahydrofuran 80ml, plus
Enter NaOH（7.4g, 185mmol）, back flow reaction 0.5h is warming up to, heating is closed, it is cooled to room temperature, dichloromethane
（150ml*3）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying, column chromatography for separation after vacuum rotary steam
（Dichloromethane：Acetone=100：15）Obtain compound II（4.1g, 53.2%）.
Under room temperature condition, by compound II（4.0g, 19mmol）Add into 40ml acetonitriles, be warming up to 40-50 DEG C, be added dropwise
Wet chemical（18.0g potassium carbonate is dissolved in 180ml water）, after completion of dropping, the acetonitrile of 1- benzyl-4-piperidinealdehydes is added dropwise
Solution（4.3g is dissolved in 40ml acetonitriles）, completion of dropping is warming up to 80-90 DEG C of reaction 6h, TLC detections, and reaction finishes, close plus
Heat, is cooled to room temperature, dichloromethane（200ml*2）Extraction, saturated nacl aqueous solution（200ml）Washing, anhydrous sodium sulfate drying,
After vacuum rotary steam, column chromatography for separation（Dichloromethane：Acetone：Methyl alcohol=100：100：1）Obtain compound III（3.4g, 45.3%）.
Claims (8)
1. preparation method of a kind of Doneppezil Hydrochloride about material E, it is characterised in that
The first step, substrate 5,6- dimethoxy -1- indones and halide reagent prepare compound I under radical initiator effect；
Second step, compound I Jing alkaline hydrolysis obtains compound II；
3rd step, compound II reacts prepare compound III with N- benzyl-4-piperidinealdehydes；
4th step, the hydrogenated reduction of compound III obtains relevant material E；
Wherein, the substituent X in compound I be halogen, preferred chlorine, bromine or iodine.
2. preparation method according to claim 1, it is characterised in that the reaction dissolvent of the first step is molten selected from aprotic
Agent, more preferably preferred carbon tetrachloride, acetonitrile or chloroform, carbon tetrachloride.
3. preparation method according to claim 1, it is characterised in that the described halide reagent of first step reaction is selected from bromine
Element, bromo-succinimide, chlorosuccinimide, N-iodosuccinimide, bromine chloride or lodine chloride, preferred bromo succinyl
Imines；Described radical initiator is selected from benzoyl peroxide, azodiisobutyronitrile or illumination, preferred benzoyl peroxide.
4. preparation method according to claim 1, it is characterised in that the described alkaline hydrolysis reagent of second step reaction is selected from carbonic acid
Sodium, potassium carbonate, lithium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, sodium acid carbonate, NaOH, potassium hydroxide or lithium hydroxide, it is excellent
Select potassium carbonate.
5. preparation method according to claim 1, it is characterised in that the second step reaction preferred water-tetrahydrochysene of solvent used
Furans mixed solvent, water：Tetrahydrofuran volume ratio is（0.1-1）：1.
6. preparation method according to claim 1, it is characterised in that the reaction dissolvent of the 3rd step has selected from miscible with water
Machine solvent, preferred methyl alcohol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, DMF
Or DMA, more preferably methyl alcohol；Reaction temperature is preferred 50-90 DEG C, more preferably 60-70 DEG C.
7. preparation method according to claim 1, it is characterised in that three-step reaction needs to use alkali selected from sodium carbonate,
Potassium carbonate, sodium acid carbonate, NaOH or potassium hydroxide, preferred potassium carbonate.
8. preparation method according to claim 1, it is characterised in that the catalyst of the four-step reaction is palladium carbon, hydrogen
Palladium oxide, palladium or platinum dioxide, preferred palladium carbon；The hydrogen source of catalytic hydrogenation is selected from ammonium acetate, ammonium formate, formic acid or hydrogen,
It is preferred that hydrogen.
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| CN1041720C (en) * | 1993-05-11 | 1999-01-20 | 惠尔康基金会集团公司 | Bicyclic amide derivatives, preparation method thereof, pharmaceutical composition and pharmaceutical application thereof |
| WO2007108011A2 (en) * | 2006-03-20 | 2007-09-27 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure donepezil |
| CN101516372A (en) * | 2004-07-29 | 2009-08-26 | 阿特西斯公司 | Tricyclic indeno-pyrrole derivatives as serotonin receptor modulators |
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| CN1041720C (en) * | 1993-05-11 | 1999-01-20 | 惠尔康基金会集团公司 | Bicyclic amide derivatives, preparation method thereof, pharmaceutical composition and pharmaceutical application thereof |
| CN101516372A (en) * | 2004-07-29 | 2009-08-26 | 阿特西斯公司 | Tricyclic indeno-pyrrole derivatives as serotonin receptor modulators |
| WO2007108011A2 (en) * | 2006-03-20 | 2007-09-27 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure donepezil |
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| CN108467332A (en) * | 2018-04-26 | 2018-08-31 | 山东海益化工科技有限公司 | Free agent causes the method that propylene high-temperature chlorination prepares chloropropene |
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Denomination of invention: A preparation method for the related substance E of donepezil hydrochloride Effective date of registration: 20230426 Granted publication date: 20190716 Pledgee: Weihai Branch of Shanghai Pudong Development Bank Co.,Ltd. Pledgor: Dijia Pharmaceutical Group Co.,Ltd. Registration number: Y2023980039205 |