CN106631989B - A kind of preparation method of the Doneppezil Hydrochloride in relation to substance E - Google Patents
A kind of preparation method of the Doneppezil Hydrochloride in relation to substance E Download PDFInfo
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- CN106631989B CN106631989B CN201611056290.7A CN201611056290A CN106631989B CN 106631989 B CN106631989 B CN 106631989B CN 201611056290 A CN201611056290 A CN 201611056290A CN 106631989 B CN106631989 B CN 106631989B
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- 239000000126 substance Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 235000019441 ethanol Nutrition 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
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- SGIBOXBBPQRZDM-UHFFFAOYSA-N 1-benzylpiperidine-4-carbaldehyde Chemical compound C1CC(C=O)CCN1CC1=CC=CC=C1 SGIBOXBBPQRZDM-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 6
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 6
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 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
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 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 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 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
- 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 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
- 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
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 2
- 150000003254 radicals Chemical class 0.000 claims 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 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
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 claims 1
- 229910003445 palladium oxide Inorganic materials 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 103
- 238000010792 warming Methods 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 20
- 238000000926 separation method Methods 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 13
- 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
- 238000005406 washing Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000005352 clarification Methods 0.000 description 5
- 239000003513 alkali Substances 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 230000006837 decompression Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- -1 iodo succinyl Chemical group 0.000 description 3
- WZJZMVSJWUHDOB-UHFFFAOYSA-N 3-chloropyrrolidine-2,5-dione Chemical compound ClC1CC(=O)NC1=O WZJZMVSJWUHDOB-UHFFFAOYSA-N 0.000 description 2
- 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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-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
- 239000003480 eluent Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 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
- JNETYVLEGPSOFY-UHFFFAOYSA-N 3-bromopyrrolidine-2,5-dione Chemical compound BrC1CC(=O)NC1=O JNETYVLEGPSOFY-UHFFFAOYSA-N 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 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
- 238000000034 method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 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
A kind of a kind of preparation method of preparation method of the Doneppezil Hydrochloride in relation to substance E the present invention relates to Doneppezil Hydrochloride in relation to substance E, with 5,6- dimethoxy -1- indone for starting material, by four-step reaction, in high yield, high-purity obtain related substance E.
Description
Technical field
A kind of preparation method the present invention relates to Doneppezil Hydrochloride in relation to substance E belongs to pharmaceutical technology field.
Background technique
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, structural formula are shown below:
Newest United States Pharmacopeia has described nine kinds of related substances of following A, B, C, D, E, F, G, H, I, and defines each
Limit standard in relation to substance, structural formula are as follows:
Compare newest United States Pharmacopeia (USP38) and a upper pharmacopeia, it can be seen that newly increased in relation to substance B and related
Substance E, wherein related substance B finds related substance E not yet since its structure is simply easy preparation, and by Literature Consult
Preparation method.
Summary of the invention
A kind of preparation method the object of the present invention is to provide Doneppezil Hydrochloride in relation to substance E.
The technical scheme is that a kind of preparation method of Doneppezil Hydrochloride in relation to substance E, is obtained through the following steps
:
Wherein, substituent X is selected from halogen, preferably chlorine, bromine or iodine in compound I.
The first step, substrate 5,6- dimethoxy -1- indone and halide reagent are prepared under radical initiator effect to be changed
Close object I；
Second step, compound I obtain compound II through Basic fluxing raction；
Third step, compound II react prepare compound III with N- benzyl-4-piperidinealdehyde；
4th step, the hydrogenated reduction of compound III obtain related substance E；
According to the present invention, the solvent of first step reaction is selected from non-protonic solvent, preferably carbon tetrachloride, acetonitrile or chloroform,
More preferable carbon tetrachloride；The halide reagent is selected from bromine, bromo-succinimide, chlorosuccinimide, iodo succinyl
One of imines, bromine chloride or lodine chloride, preferably bromo-succinimide；The radical initiator is selected from benzoyl peroxide first
Acyl, azodiisobutyronitrile or illumination, preferably benzoyl peroxide.
According to the present invention, in more detail, 5,6- dimethoxy -1- indone and halide reagent are added to non-matter the first step
In sub- property solvent, radical initiator or illumination, back flow reaction to end of reaction, isolated compound I, substituent group was added
X is defined as above.
According to the present invention, the preferred water of solvent used in second step hydrolysis-tetrahydrofuran mixed solvent, water: tetrahydro furan
Volume ratio of muttering is (0.1-1): 1；
According to the present invention, second step hydrolysis is needed using alkali, and alkali used is selected from lithium carbonate, cesium carbonate, calcium carbonate, carbon
One of sour magnesium, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, preferably potassium carbonate.
According to the present invention, the solvent of third step reaction is selected from organic solvent miscible with water, preferably methanol, ethyl alcohol, isopropyl
Alcohol, acetone, acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide, n,N-dimethylacetamide, more preferable first
Alcohol；Preferred 50-90 DEG C of reaction temperature, more preferable 60-70 DEG C.
According to the present invention, third step reaction is needed using alkali, and alkali used is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, hydrogen-oxygen
Change sodium or potassium hydroxide, preferably potassium carbonate.
According to the present invention, the solvent of four-step reaction hydrogenation process is selected from alcohol or chlorohydrocarbon, the preferred methanol of the alcohol, second
Alcohol, isopropanol, more preferable methanol；The preferred methylene chloride of the chlorohydrocarbon, chloroform, more preferable methylene chloride.
According to the present invention, the catalyst of four-step reaction hydrogenation process reaction is palladium carbon, palladium dydroxide, palladium acetate, dioxy
Change platinum, preferably palladium carbon；The hydrogen source of catalytic hydrogenation is selected from ammonium acetate, ammonium formate, formic acid, hydrogen, preferably hydrogen.
According to the present invention, it carries out isolating and purifying the related object that can be obtained high-purity, meet pharmacopoeial requirements by column chromatography
Matter E.
The beneficial effects of the invention are as follows, for starting material, by four-step reaction, received with 5,6- dimethoxy -1- indone with height
Rate, high-purity obtain related substance E.
Specific embodiment:
Content for a better understanding of the present invention is described further combined with specific embodiments below, but the present invention not only office
It is limited to this.
Embodiment 1
Under room temperature, 5,6- dimethoxy -1- indone (15.0g, 78mmol) is added into 150ml carbon tetrachloride,
After being warming up to 50 DEG C of dissolved clarifications, it is addedN-Bromo-succinimide (15.3g, 86mmol), benzoyl peroxide (0.1g,
0.4mmol), it is warming up to 4 h of back flow reaction, heating is closed, is filtered after being cooled to room temperature, 300ml eluent methylene chloride, decompression rotation
Steam organic phase, column chromatography for separation (methylene chloride: acetone=100:8) compound I(17.0g, 80.4%).
Under room temperature, compound I(10.0g, 37mmol) is added into 300ml water, tetrahydrofuran 100ml is added,
It is added potassium carbonate (25.5g, 184mmol), is warming up to back flow reaction 2h, close heating, be cooled to room temperature, methylene chloride
(150ml*3) extraction, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry, vacuum rotary steam organic phase, column chromatography
Separate (methylene chloride: acetone=100:15) compound II(6.1g, 79.2%).
Under room temperature, compound II(4.0g, 19mmol) is added into 40ml methanol, is warming up to 40-50 DEG C, be added dropwise
After being added dropwise, the methanol of 1- benzyl-4-piperidinealdehyde is added dropwise in wet chemical (18.0g potassium carbonate is dissolved in 180ml water)
Solution (4.3g is dissolved in 40ml methanol), is added dropwise, and is warming up to 60-70 DEG C of reaction 4h, TLC detection, and end of reaction is closed and added
Heat is cooled to room temperature, and methylene chloride (200ml*2) extraction, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry,
Vacuum rotary steam organic phase, column chromatography for separation (methylene chloride: acetone: methanol=100:100:1) obtain compound III(4.5g,
60.2%).
Under room temperature, compound III(3.4g, 8.6mmol) is added mixed to 68ml methanol and 68ml methylene chloride
It in bonding solvent, is added palladium carbon (0.68g), pours hydrogen, react at room temperature 2.5 h, TLC detection, end of reaction, filtering, decompression rotation
Organic phase is steamed, column chromatography for separation (methylene chloride: acetone: methanol=100:100:1) obtains impurity E (2.8g, 82.4%).
Embodiment 2
Under room temperature, 5,6- dimethoxy -1- indone (15.0g, 78mmol) is added into 150ml carbon tetrachloride,
After being warming up to 50 DEG C of dissolved clarifications, it is addedNBromo-succinimide (15.3g, 86mmol), and benzoyl peroxide (0.1g, 0.
4mmol), it is warming up to back flow reaction 4h, heating is closed, is filtered after being cooled to room temperature, 300ml eluent methylene chloride, vacuum rotary steam
Organic phase, column chromatography for separation (methylene chloride: acetone=100:8) compound I(17.0g, 80.4%).
Under room temperature, compound I(10.0g, 37mmol) is added into 300ml water, tetrahydrofuran 30ml is added, adds
Enter sodium carbonate (19.5g, 184mmol), be warming up to back flow reaction 2h, closes heating, be cooled to room temperature, methylene chloride (150ml*
3) it extracts, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry, vacuum rotary steam organic phase, column chromatography for separation (two
Chloromethanes: acetone=100:15) obtain compound II(6.0g, 77.9 %).
Under room temperature, compound II(4.0g, 19mmol) is added into 40ml methanol, is warming up to 40-50 DEG C, be added dropwise
After being added dropwise, the methanol of 1- benzyl-4-piperidinealdehyde is added dropwise in wet chemical (18.0g potassium carbonate is dissolved in 180ml water)
Solution (4.3g is dissolved in 40ml methanol), is added dropwise, and is warming up to 60-70 DEG C of reaction 4h, TLC detection, and end of reaction is closed and added
Heat is cooled to room temperature, and methylene chloride (200ml*2) extraction, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry,
Vacuum rotary steam organic phase, column chromatography for separation (methylene chloride: acetone: methanol=100:100:1) obtain compound III(4.5g,
60.2%).
Under room temperature, compound III(3.4g, 8.6mmol) is added mixed to 68ml methanol and 68ml methylene chloride
It in bonding solvent, is added palladium carbon (0.68g), is filled with hydrogen, react at room temperature 2.5 h, TLC detection, end of reaction, filtering, decompression rotation
Organic phase is steamed, column chromatography for separation (methylene chloride: acetone: methanol=100:100:1) obtains impurity E (2.8g, 82.4%).
Embodiment 3
Under room temperature, 5,6- dimethoxy -1- indone (15.0g, 78mmol) is added into 150ml chloroform, heating
It to 50 DEG C of dissolved clarifications, is added bromine (13.8g, 86mmol), azodiisobutyronitrile (0.1g, 0. 6mmol), it is anti-to be warming up to reflux
6h is answered, heating is closed, is filtered after being cooled to room temperature, vacuum rotary steam organic phase, column chromatography for separation (methylene chloride: acetone=100:8)
Compound I(14.9.0g, 70.5%).
Under room temperature, compound I(10.0g, 37mmol) is added into 300ml water, tetrahydrofuran 60ml is added, adds
Enter cesium carbonate (60.0 g, 184mmol), be warming up to back flow reaction 2h, closes heating, be cooled to room temperature, methylene chloride (150ml*
3) it extracts, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry, column chromatography for separation (dichloromethane after vacuum rotary steam
Alkane: acetone=100:15) obtain compound II(5.7g, 73.4 %).
Under room temperature, compound II(4.0g, 19mmol) is added into 40ml ethyl alcohol, is warming up to 40-50 DEG C, hydrogen-oxygen
Change sodium water solution (5.2g sodium hydroxide is dissolved in 52ml water), after being added dropwise, the ethyl alcohol that 1- benzyl-4-piperidinealdehyde is added dropwise is molten
Liquid (4.3g is dissolved in 40ml ethyl alcohol), is added dropwise, and is warming up to 70-80 DEG C of reaction 6h, TLC detection, and end of reaction is closed and added
Heat is cooled to room temperature, and methylene chloride (200ml*2) extraction, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry,
After vacuum rotary steam, column chromatography for separation (methylene chloride: acetone: methanol=100:100:1) compound III(3.7g, 50.0%).
Under room temperature, the mixing of compound III(3.4g, 8.6mmol) addition to 68ml ethyl alcohol and 68ml chloroform is molten
It in agent, is added palladium carbon (0.68g), pours hydrogen, react at room temperature 2.5 h, TLC detection, end of reaction filters, and vacuum rotary steam has
After machine phase, column chromatography for separation (methylene chloride: acetone: methanol=100:100:1) obtains impurity E (2.2g, 64.9%).
Example IV
Under room temperature, 5,6- dimethoxy -1- indone (15.0g, 78mmol) is added into 150ml acetonitrile, heating
To 50 DEG C of dissolved clarifications, it is addedNChlorosuccinimide (11.5g, 86mmol), azodiisobutyronitrile (0.1g, 0. 6mmol),
It is warming up to back flow reaction 8h, heating is closed, is filtered after being cooled to room temperature, vacuum rotary steam organic phase, column chromatography for separation (dichloromethane
Alkane: acetone=100:8) compound I(9.0g, 50.8%).
Under room temperature, compound I(8.4g, 37mmol) is added into 300ml water, tetrahydrofuran 60ml is added, adds
Enter sodium bicarbonate (15.5g, 185mmol), be warming up to back flow reaction 3h, closes heating, be cooled to room temperature, methylene chloride
(150ml*3) extraction, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry, column chromatography for separation after vacuum rotary steam
(methylene chloride: acetone=100:15) obtains compound II(4.8g, 62.3 %).
Under room temperature, compound II(4.0g, 19mmol) is added into 40ml acetone, is warming up to 40-50 DEG C, be added dropwise
After being added dropwise, the acetone of 1- benzyl-4-piperidinealdehyde is added dropwise in aqueous sodium carbonate (13.0g sodium carbonate is dissolved in 130ml water)
Solution (4.3g is dissolved in 40ml acetone), is added dropwise, and is warming up to 50-60 DEG C of reaction 6h, TLC detection, and end of reaction is closed and added
Heat is cooled to room temperature, and methylene chloride (200ml*2) extraction, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry,
After vacuum rotary steam, column chromatography for separation (methylene chloride: acetone: methanol=100:100:1) compound III(3.2g, 43.2%).
Under room temperature, compound III(3.2g, 8.1mmol) is added mixed to 68ml ethyl alcohol and 68ml methylene chloride
It in bonding solvent, being added palladium carbon (0.64g), is added ammonium formate (5.0g), be warming up to back flow reaction 2h, TLC is detected, end of reaction,
Filtering, after vacuum rotary steam organic phase, column chromatography for separation (methylene chloride: acetone: methanol=100:100:1) impurity E (2.0g,
62.5%).
Embodiment five
Under room temperature, 5,6- dimethoxy -1- indone (15.0g, 78mmol) is added into 150ml chloroform, heating
To 50 DEG C of dissolved clarifications, it is addedNChlorosuccinimide (11.5g, 86mmol), benzoyl peroxide (0.1g, 0. 4mmol),
It is warming up to back flow reaction 8h, heating is closed, is filtered after being cooled to room temperature, vacuum rotary steam organic phase, column chromatography for separation (dichloromethane
Alkane: acetone=100:8) compound I(10.3g, 58.1%).
Under room temperature, compound I(8.4g, 37mmol) is added into 300ml water, tetrahydrofuran 80ml is added, adds
Enter sodium hydroxide (7.4g, 185mmol), be warming up to back flow reaction 0.5h, closes heating, be cooled to room temperature, methylene chloride
(150ml*3) extraction, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry, column chromatography for separation after vacuum rotary steam
(methylene chloride: acetone=100:15) compound II(4.1g, 53.2%).
Under room temperature, compound II(4.0g, 19mmol) is added into 40ml acetonitrile, is warming up to 40-50 DEG C, be added dropwise
After being added dropwise, the acetonitrile of 1- benzyl-4-piperidinealdehyde is added dropwise in wet chemical (18.0g potassium carbonate is dissolved in 180ml water)
Solution (4.3g is dissolved in 40ml acetonitrile), is added dropwise, and is warming up to 80-90 DEG C of reaction 6h, TLC detection, and end of reaction is closed and added
Heat is cooled to room temperature, and methylene chloride (200ml*2) extraction, saturated sodium chloride solution (200ml) washing, anhydrous sodium sulfate is dry,
After vacuum rotary steam, column chromatography for separation (methylene chloride: acetone: methanol=100:100:1) compound III(3.4g, 45.3%).
Claims (9)
1. a kind of preparation method of Doneppezil Hydrochloride in relation to substance E, which is characterized in that
,
The first step, substrate 5,6- dimethoxy -1- indone and halide reagent the prepare compound I under radical initiator effect,
Second step, compound I obtain compound II through alkaline hydrolysis,
Third step, compound II react prepare compound III with N- benzyl-4-piperidinealdehyde,
4th step, the hydrogenated reduction of compound III obtain related substance E,
Wherein, the substituent X in compound I is halogen.
2. preparation method according to claim 1, which is characterized in that the reaction dissolvent of the first step is selected from non-protonic solvent
Carbon tetrachloride, acetonitrile or chloroform.
3. preparation method according to claim 1, which is characterized in that the first step reaction halide reagent is selected from bromine
Element, bromo-succinimide, chlorosuccinimide, N-iodosuccinimide, bromine chloride or lodine chloride, the free radical draw
It sends out agent and is selected from benzoyl peroxide, azodiisobutyronitrile or illumination.
4. preparation method according to claim 1, which is characterized in that second step reaction alkaline hydrolysis reagent be selected from sodium carbonate,
Potassium carbonate, lithium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide.
5. preparation method according to claim 1, which is characterized in that second step reaction solvent used is selected from water-tetrahydro
Furans mixed solvent, water: tetrahydrofuran volume ratio is (0.1-1): 1.
6. preparation method according to claim 1, which is characterized in that the reaction dissolvent of third step has selected from miscible with water
Solvent methanol, ethyl alcohol, isopropanol, acetone, acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide or N, N-
Dimethyl acetamide, 50-90 DEG C of reaction temperature.
7. preparation method according to claim 1, which is characterized in that the catalyst of the four-step reaction is palladium carbon, hydrogen
The hydrogen source of palladium oxide, palladium acetate or platinum dioxide, catalytic hydrogenation is selected from ammonium acetate, ammonium formate, formic acid or hydrogen.
8. preparation method according to claim 1, which is characterized in that the substituent X in compound I is selected from chlorine, bromine or iodine.
9. preparation method according to claim 1, which is characterized in that third step reaction temperature is 60-70 DEG C.
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| 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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| 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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