CN102311406A - Method for preparing lasofoxifene intermediate - Google Patents
Method for preparing lasofoxifene intermediate Download PDFInfo
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- CN102311406A CN102311406A CN2010102143069A CN201010214306A CN102311406A CN 102311406 A CN102311406 A CN 102311406A CN 2010102143069 A CN2010102143069 A CN 2010102143069A CN 201010214306 A CN201010214306 A CN 201010214306A CN 102311406 A CN102311406 A CN 102311406A
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 229960002367 lasofoxifene Drugs 0.000 title claims abstract description 13
- GXESHMAMLJKROZ-IAPPQJPRSA-N lasofoxifene Chemical compound C1([C@@H]2[C@@H](C3=CC=C(C=C3CC2)O)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 GXESHMAMLJKROZ-IAPPQJPRSA-N 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- -1 inorganic acid salt Chemical class 0.000 claims abstract description 30
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 22
- 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 abstract description 19
- 238000005893 bromination reaction Methods 0.000 claims abstract description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 17
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 17
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 15
- 235000010755 mineral Nutrition 0.000 claims description 15
- 239000011707 mineral Substances 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- 235000017550 sodium carbonate Nutrition 0.000 claims description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 11
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 9
- 239000004327 boric acid Substances 0.000 claims description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- ZPATUOFYXSBHMN-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [H+].[H+].[H+].[Br-].[Br-].[Br-].C1=CC=NC=C1 ZPATUOFYXSBHMN-UHFFFAOYSA-N 0.000 claims description 7
- 238000003747 Grignard reaction Methods 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 239000000543 intermediate Substances 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 1
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 2
- 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 abstract 2
- 239000007818 Grignard reagent Substances 0.000 abstract 2
- 150000004795 grignard reagents Chemical class 0.000 abstract 2
- MNALUTYMBUBKNX-UHFFFAOYSA-N 6-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(OC)=CC=C21 MNALUTYMBUBKNX-UHFFFAOYSA-N 0.000 abstract 1
- 208000001132 Osteoporosis Diseases 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 235000002639 sodium chloride Nutrition 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FCLZCOCSZQNREK-UHFFFAOYSA-N Pyrrolidine, hydrochloride Chemical compound Cl.C1CCNC1 FCLZCOCSZQNREK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- INEHJXCWEVNEDZ-LUDNRVPPSA-N (2s,3s)-2,3-dihydroxybutanedioic acid;(5r,6s)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.C1([C@@H]2[C@@H](C3=CC=C(C=C3CC2)O)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 INEHJXCWEVNEDZ-LUDNRVPPSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004334 fluoridation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for preparing a lasofoxifene intermediate (namely, a compound IV) or an inorganic acid salt thereof. The method comprises the following steps: after a compound I is converted into a Grignard reagent, reacting the Grignard reagent with 6-methoxy tetralone so as to obtain a compound II or an inorganic acid salt thereof; carrying out bromination reaction on the obtained compound II or the inorganic acid salt thereof so as to obtain a compound III or an inorganic acid salt thereof; and then, carrying out coupling reaction on the obtained compound III or the inorganic acid salt thereof so as to obtain the lasofoxifene intermediate (namely, the compound IV) or the inorganic acid salt thereof. The compound IV or inorganic acid salt thereof is a key intermediate for preparing a medicament lasofoxifene for treating osteoporosis. The method provided by the invention is low in production cost, good for environmental protection, and suitable for industrial production.
Description
Technical field
The invention belongs to chemical field; Relate to a kind of novel method for preparing the Lasofoxifene midbody; Be specifically related to the novel method of a kind of preparation 1-[2-[4-(6-methoxyl group-2-phenyl-3,4-dihydronaphthalene-1-yl) phenoxy] ethyl] tetramethyleneimine (Nafoxidene) and inorganic acid salt thereof.
Background technology
Lasofoxifene (trade(brand)name: Fablyn) be a kind of medicine that is used to treat post-menopausal osteoporosis.Its chemical name is (-) cis-6 (S)-phenyl-5 (R)-[4-(2-tetramethyleneimine-1-base oxethyl) phenyl]-5,6,7,8-tetrahydro-Betanaphthol, like following structural formula:
Lasofoxifene has been reported multiple compound method, wherein relates to a key intermediate 1-[2-[4-(6-methoxyl group-2-phenyl-3,4-dihydronaphthalene-1-yl) phenoxy] ethyl] tetramethyleneimine (being Nafoxidene, compound IV), shown in following structural formula.Nafoxidene is prone to be combined into stable salt with acid, existing bibliographical information Nafoxidene hydrochloride (like compound IV ' shown in).
Bibliographical information has two kinds and prepares compound IV ' method.U.S. Pat 3274213B1 discloses a kind of preparation method, shown in the following reaction scheme of preparation route.This method begins from starting raw material, and the preparation route is long, and has used highly toxic product Potssium Cyanide and severe corrosive reagent hydrogen fluoride; Operate dangerously, and handle to the three wastes and to bring difficulty, personnel are required height with production unit; Be not suitable for suitability for industrialized production; The yield of final step grignard reaction is merely 24% in this method, and the whole yield of this method is low, and production cost is also high.
European patent EP 0802910A1 discloses another kind of preparation method, shown in the following reaction scheme.This method is a starting raw material with 6-methoxyl group-1-Tetralone an intermediate of Sertraline and 1-[2-(4-bromine phenoxy)-ethyl] tetramethyleneimine; Reaction under the effect of anhydrous cerous compounds and n-Butyl Lithium; Again after tribromide pyridine bromination; In the presence of four triphenyl phosphorus palladiums,, behind hcl acidifying, make compound IV again ' with the phenylo boric acid reaction.In this method, the cerous compounds large usage quantity, market value is expensive, and also needs-78 ℃ condition of ultralow temperature, production unit is required high.The whole yield of this method is not high, and production cost is high, also is unfavorable for suitability for industrialized production.
Summary of the invention
Lasofoxifene midbody of the present invention is meant 1-[2-[4-(6-methoxyl group-2-phenyl-3,4-dihydronaphthalene-1-yl) phenoxy] ethyl] tetramethyleneimine (being Nafoxidene, compound IV) or its inorganic acid salt.
Technical problem to be solved by this invention provides a kind of novel method for preparing compound IV or its inorganic acid salt, and this method yield is high, and cost is low, is fit to suitability for industrialized production more.
For this reason, the detailed technology scheme taked of the present invention is shown in following reaction scheme:
Explain: mineral acid is hydrochloric acid or Hydrogen bromide
The invention provides a kind of method for preparing the Lasofoxifene midbody, comprise following steps:
A: compound I is carried out grignard reaction in the presence of MAGNESIUM METAL 99, makes compound I I or its inorganic acid salt with 6-methoxyl group tetralin reactive ketone again;
The product that B, steps A make is dissolved in the organic solvent, in the presence of bromizating agent, makes compound III or its inorganic acid salt through bromination reaction;
The product that C, step B make is dissolved in the organic solvent, in the presence of mineral alkali, carries out linked reaction with phenylo boric acid and makes compound IV or its inorganic acid salt;
Said organic solvent is THF or 1, and 4-dioxane, said mineral acid are hydrochloric acid or Hydrogen bromide.
The preferred THF of above-mentioned organic solvent.
The preferred hydrochloric acid of above-mentioned mineral acid.
Among the above-mentioned steps A: said grignard reaction carries out under normal temperature or reflux, and the preferred THF of the solvent of grignard reaction preferably adds initiator, and initiator is iodine, methyl iodide or glycol dibromide, preferred glycol dibromide.The feed ratio of MAGNESIUM METAL 99 and compound I is 0.95～1.2: 1 (mol ratio), preferred 1.0～1.1: 1 (mol ratio).6-methoxyl group tetralin ketone with feed ratio compound I be 1.0～2.0: 1 (mol ratio), preferred 1～1.5: 1 (mol ratio).
Above-mentioned steps A makes reaction conditions gentle, is easy to suitability for industrialized production, has also simplified operation, and in addition, the contriver is surprised to find that also the reaction yield of steps A is higher, has exceeded expection.
In above-mentioned steps B, the preferred tribromide pyridine of the bromizating agent of use or simple substance bromine, more preferably tribromide pyridine; For making reaction obtain preferable transformation efficiency and higher this step product purity, bromizating agent is 0.9～1.5: 1 (mol ratio) at the feed ratio with compound I I or its mineral acid, preferred 1.0～1.2: 1 (mol ratio); The compound III that makes or its inorganic acid salt can not purifiedly can directly be used for step reaction down.
In above-mentioned steps C; The preferred tetra-triphenylphosphine palladium of described palladium catalyst, Palladous chloride or its various parts, palladium or its various parts; For example two (the triphenylphosphine)-palladium chlorides, 1 of described part; 1 '-two (diphenyl phosphine)-diamyls paste palladium chloride (II) methylene dichloride mixture, triphenylphosphine palladium acetate etc., and palladium catalyst is tetra-triphenylphosphine palladium more preferably.The carbonate of said mineral alkali preferred as alkali or acid carbonate, more preferably yellow soda ash or salt of wormwood.
In above-mentioned steps C, obtain preferable transformation efficiency and higher this step product purity for making reaction, the charging capacity of control phenylo boric acid, the feed ratio of preferred phenylo boric acid and compound III or its inorganic acid salt is 1.0～2.0: 1 (mol ratio).When preparing the inorganic acid salt of compound IV; Can the compound IV of elder generation be dissolved in the following solvent; Add mineral acid again and carry out acidifying; Make corresponding compounds IV salt, these solvents are selected from the mixing of one or more solvents in methyl alcohol, ethanol, Virahol, methylene dichloride, ETHYLE ACETATE, THF, dioxane, acetonitrile and the acetone, preferred ethylene dichloride or ETHYLE ACETATE; Mineral acid as stated.
Compare prior art, method provided by the invention can be accomplished under normal temperature or common heating condition, need not very low temperature, hypertoxic reaction reagent, fluoridation condition and equipment, and route is brief, and is easy and simple to handle, is fit to suitability for industrialized production more.In addition, the whole yield of method of the present invention has raising significantly, and uses cheap relatively raw material, makes that the production cost of compound IV or its hydrogen salt is significantly reduced.
Embodiment
To combine embodiment that summary of the invention is further described below, but the present invention is not limited.
Embodiment 1
The preparation of 1-(2-(4-(6-methoxyl group-3,4-dihydro-1-yl) phenoxy) ethyl) pyrrolidine hydrochloride (compound I I ')
Magnesium ribbon 2.7g (114mmol) is put in the 500mL there-necked flask, adds the 10mL THF, stir several 1 of addings down; The 2-ethylene dibromide; Drip the tetrahydrofuran solution 114mL of compound I 31g (114mmol), begin reacting by heating after dripping to refluxing, all dissolve disappearance to magnesium ribbon after; Drip the tetrahydrofuran solution 114mL of 6-methoxyl group tetralin ketone 20g (114mmol), add the continued back flow reaction and spend the night.Reaction finishes postcooling to room temperature, adds 50mL water and 200mL ETHYLE ACETATE, and stir and use diatomite filtration after 10 minutes, and with ETHYLE ACETATE drip washing several times; Filtrating concentrates, and in resistates, adds 2N hydrochloric acid 200mL, and the aqueous solution washs with MTBE, uses methylene dichloride 100mL * 3 extractions again; Organic phase with 1N hydrochloric acid 100mL washing, is used dried over mgso more then, filters, and concentrates; Vacuum-drying obtains 21.9g solid (being compound I I ', yield 55%).The evaluation parameter of compound I I ':
(MS：350.2[P
++1])；
1H?NMR(400MHz，CDCl
3)：δ12.62(br，1H)，7.22(d，J＝8.6Hz，2H)，6.91(m，3H)，6.77(d，J＝2.6Hz，1H)，6.63(dd，J＝8.6，2.6Hz，1H)，5.91(t，J＝4.6Hz，1H)，4.56(t，J＝6.0Hz，2H)，3.89(m，2H)，3.81(s，3H)，3.54(m，2H)，3.04(m，2H)，2.80(t，J＝7.6Hz，2H)，2.37(m，2H)，2.26(m，2H)，2.09(m，2H)。
Embodiment 2
The preparation of 1-(2-(4-(6-methoxyl group-3,4-dihydro-1-yl) phenoxy) ethyl) tetramethyleneimine (compound I I)
5g compound I I ' (preparation method is with reference to embodiment 1) is dissolved in the 50mL methylene dichloride,, washs with the 25ml saturated sodium-chloride water solution again with the washing of 25mL saturated aqueous sodium carbonate; Organic phase is used anhydrous sodium sulfate drying; Concentrated, vacuum-drying obtain compound I I (4.5g, yield 99%).Compound I I identifies parameter:
(MS：350.2[P
++1])；
1H?NMR(400MHz，CDCl
3)：δ7.28(d，J＝8.4Hz，2H)，6.95(m，3H)，6.79(d，J＝2.6Hz，1H)，6.65(dd，J＝8.4，2.6Hz，1H)，5.93(t，J＝4.6Hz，1H)，4.18(t，J＝6.0Hz，2H)，3.82(s，3H)，2.98(m，2H)，2.83(m，2H)，2.69(m，4H)，2.39(m，2H)，1.86(m，4H)。
Embodiment 3
The preparation of 1-(2-(4-(2-bromo-6-methoxyl group-3,4-dihydronaphthalene-1-yl) phenoxy) ethyl) pyrrolidine hydrochloride (compound III ')
Compound I I ' 9.0g (25mmol, or the compound I I of equivalent) is dissolved in the 250mL THF, adds tribromide pyridine 8.0g (25mmol), stirring at room 3 days.Reaction solution adds MTBE 100mL revolving concentrated doing in the steaming in resistates, filter; The gained solid is dissolved in the 200mL methylene dichloride, with 0.5N hydrochloric acid 100mL washed twice, anhydrous magnesium sulfate drying then; Filter, concentrate; Get 12.4g red-brown solid, i.e. compound III ', directly be used for step reaction down.Compound III ' the evaluation parameter:
(MS：428.2/430.2[P
++1])；
1H?NMR(400MHz，CDCl
3)：δ11.77(br，1H)，7.18(d，J＝8.4Hz，2H)，6.97(d，J＝8.4Hz，2H)，6.72(d，1H)，6.57(m，2H)，4.61(m，2H)，3.95(m，2H)，3.79(s，3H)，3.57(m，2H)，3.11(m，2H)，2.95(m，4H)，2.28(m，2H)，2.16(m，2H)。
Embodiment 4
The preparation of 1-(2-(4-(2-bromo-6-methoxyl group-3,4-dihydronaphthalene-1-yl) phenoxy) ethyl) tetramethyleneimine (compound III)
With the 5g compound III ' (preparation method is with reference to embodiment 3) be dissolved in the 50mL methylene dichloride; With the washing of 25mL saturated aqueous sodium carbonate, with the washing of 25ml saturated sodium-chloride water solution, organic phase is used anhydrous sodium sulfate drying again; Concentrated, vacuum-drying obtain compound III (4.6g).Compound III is identified parameter:
(MS：428.2/430.2[P
++1])；
1H?NMR(400MHz，CDCl
3)：δ7.15(d，J＝8.4Hz，2H)，6.98(d，J＝8.4Hz，2H)，6.70(d，1H)，6.57(m，2H)，4.18(t，2H)，3.79(s，3H)，2.95(m，6H)，2.63(m，4H)，1.83(m，4H)。
Embodiment 5
The preparation of 1-[2-[4-(6-methoxyl group-2-phenyl-3,4-dihydronaphthalene-1-yl) phenoxy] ethyl] pyrrolidine hydrochloride (compound IV ')
Get compound III respectively ' 12g (25mmol; Or the compound III of equivalent), phenylo boric acid 4.6g (38mmol) and four triphenyl phosphorus palladium 1.1g; Be dissolved in the 250mL THF, stir adding 80mL aqueous sodium carbonate (yellow soda ash solid 8.0g is dissolved in the 80mL water) down, heating reflux reaction spends the night.Stopped reaction was cooled to room temperature in second day, added entry 100mL and ETHYLE ACETATE 200mL, the vibration separatory; Water is used ethyl acetate extraction twice again, and organic phase gets a dark oil thing after concentrating and doing, and adds the dissolving of 200mL methylene dichloride; Organic solution is with 1N salt acid elution 2 times, and again with saturated aqueous sodium carbonate washing 1 time, organic phase concentrates to be done the back and add 100mL ETHYLE ACETATE; Fully stirring is dissolved it fully, and the gained dark solution under agitation slowly drips concentrated hydrochloric acid and is acid until solution, has solid precipitation to separate out gradually; Solid collected by filtration and vacuum-drying 5 hours obtain solid 9.5g (be the compound IV ', yield 82%).Compound IV ' the evaluation parameter:
(MS：426.3[P
++1])；
1H?NMR(400MHz，CDCl
3)：δ12.47(br，1H)，7.25～6.95(m，7H)，6.80～6.50(m，5H)，4.48(m，2H)，3.84(m，2H)，3.80(s，3H)，3.52(m，2H)，3.08(m，2H)，2.97(m，2H)，2.76(m，2H)，2.25(m，2H)，2.15(m，2H)。
Embodiment 6
The preparation of 1-[2-[4-(6-methoxyl group-2-phenyl-3,4-dihydronaphthalene-1-yl) phenoxy] ethyl] tetramethyleneimine (compound IV)
With the 5g compound IV ' (preparation method is with reference to embodiment 5) be dissolved in the 50mL methylene dichloride; With the washing of 25mL saturated aqueous sodium carbonate, with the washing of 25ml saturated sodium-chloride water solution, organic phase is used anhydrous sodium sulfate drying again; Concentrated, vacuum-drying obtain compound IV (4.6g).Compound IV is identified parameter:
(MS：426.3[P
++1])；
1H?NMR(400MHz，CDCl
3)：δ7.25～6.95(m，7H)，6.81～6.50(m，5H)，4.10(t，2H)，3.83(s，3H)，2.92(m，4H)，2.79(m，2H)，2.57(m，4H)，1.85(m，4H)。
Claims (10)
1. Lasofoxifene intermediates preparation comprises following steps:
A, compound I are carried out grignard reaction in the presence of MAGNESIUM METAL 99, make compound I I or its inorganic acid salt with 6-methoxyl group tetralin reactive ketone again;
The product that B, steps A make is dissolved in the organic solvent, in the presence of bromizating agent, makes compound III or its inorganic acid salt through bromination reaction;
The product that C, step B make is dissolved in the organic solvent, in the presence of mineral alkali, carries out linked reaction with phenylo boric acid and makes compound IV or its inorganic acid salt;
Said organic solvent is THF or 1, and 4-dioxane, said mineral acid are hydrochloric acid or Hydrogen bromide.
2. method according to claim 1 is characterized in that the molar ratio of MAGNESIUM METAL 99 and compound I is 0.95～1.2: 1 in the steps A, and the molar ratio of 6-methoxyl group tetralin ketone and compound I is 1～2.0: 1.
3. method according to claim 1 is characterized in that the molar ratio of bromizating agent and compound I I or its inorganic acid salt is 0.9～1.5: 1 among the step B, and mineral acid as stated.
4. according to claim 1 or 3 described methods, it is characterized in that the described bromizating agent of step B is the tribromide pyridine.
5. method according to claim 1 is characterized in that the molar ratio of phenylo boric acid and compound III or its inorganic acid salt is among the step C: 1.0～2.0: 1, and mineral acid is as stated.
6. method according to claim 1 is characterized in that the described catalyzer of step C is tetra-triphenylphosphine palladium, Palladous chloride or its various parts, palladium or its various parts.
7. method according to claim 6 is characterized in that the described catalyzer of step C is a tetra-triphenylphosphine palladium.
8. method according to claim 1 is characterized in that described mineral alkali is yellow soda ash, salt of wormwood, cesium carbonate, sodium hydrogencarbonate or saleratus.
9. method according to claim 8 is characterized in that the described mineral alkali of step C is yellow soda ash or salt of wormwood.
10. Lasofoxifene intermediates preparation may further comprise the steps:
A, compound I are in the presence of MAGNESIUM METAL 99 and THF; Like trace 1; The 2-ethylene dibromide carries out grignard reaction as initiator; Make compound I I or its inorganic acid salt with 6-methoxyl group tetralin reactive ketone again, the molar ratio of MAGNESIUM METAL 99 and compound I is 0.95～1.2: 1, and the molar ratio of 6-methoxyl group tetralin ketone and compound I is 1.0～2.0: 1;
B, compound I I or its inorganic acid salt add the tribromide pyridine in THF carries out bromination reaction and makes compound III or its inorganic acid salt, and the molar ratio of said tribromide pyridine and compound I I or its inorganic acid salt is 0.9～1.5: 1;
C, compound I I or its inorganic acid salt are dissolved in the THF; Adding yellow soda ash or salt of wormwood, four triphenyl phosphorus palladiums of catalytic amount, phenylo boric acid react and make compound IV or its inorganic acid salt; The molar ratio of phenylo boric acid and compound III or its inorganic acid salt is 1.0～2.0: 1, and the molar ratio of yellow soda ash or salt of wormwood and compound III or its inorganic acid salt is 1～5: 1; Said mineral acid is hydrochloric acid or Hydrogen bromide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113323A (en) * | 2013-02-05 | 2013-05-22 | 南京华威医药科技开发有限公司 | Preparation method of lasofoxifene tartrate intermediate compound |
| CN105418436A (en) * | 2015-11-16 | 2016-03-23 | 成都倍特药业有限公司 | Method for preparing high-purity melitracen |
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| US3274213A (en) * | 1961-09-05 | 1966-09-20 | Upjohn Co | Alkoxy-substituted 2-phenyl-1-(tertiary-aminoalkoxy)phenyl-3, 4-dihydronaphthalenes |
| EP1151998A1 (en) * | 1995-01-09 | 2001-11-07 | Pfizer Inc. | Estrogen agonists/antagonists |
| CN1283625C (en) * | 2002-03-28 | 2006-11-08 | 辉瑞产品公司 | Purified LASOFOXIFENE and a method for purification of racemic LASOFOXIFENE by recrystallization |
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2010
- 2010-06-29 CN CN2010102143069A patent/CN102311406A/en active Pending
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| US3274213A (en) * | 1961-09-05 | 1966-09-20 | Upjohn Co | Alkoxy-substituted 2-phenyl-1-(tertiary-aminoalkoxy)phenyl-3, 4-dihydronaphthalenes |
| EP1151998A1 (en) * | 1995-01-09 | 2001-11-07 | Pfizer Inc. | Estrogen agonists/antagonists |
| CN1283625C (en) * | 2002-03-28 | 2006-11-08 | 辉瑞产品公司 | Purified LASOFOXIFENE and a method for purification of racemic LASOFOXIFENE by recrystallization |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113323A (en) * | 2013-02-05 | 2013-05-22 | 南京华威医药科技开发有限公司 | Preparation method of lasofoxifene tartrate intermediate compound |
| CN103113323B (en) * | 2013-02-05 | 2015-11-11 | 南京华威医药科技开发有限公司 | The preparation method of Lasofoxifene tartrate intermediate |
| CN105418436A (en) * | 2015-11-16 | 2016-03-23 | 成都倍特药业有限公司 | Method for preparing high-purity melitracen |
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