CN106187791A - The new preparation process of Toremifene Citrate intermediate - Google Patents
The new preparation process of Toremifene Citrate intermediate Download PDFInfo
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- CN106187791A CN106187791A CN201610260397.7A CN201610260397A CN106187791A CN 106187791 A CN106187791 A CN 106187791A CN 201610260397 A CN201610260397 A CN 201610260397A CN 106187791 A CN106187791 A CN 106187791A
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- toremifene citrate
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- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 title claims abstract description 15
- 229960004167 toremifene citrate Drugs 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 18
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 10
- OOCCDEMITAIZTP-UHFFFAOYSA-N allylic benzylic alcohol Natural products OCC=CC1=CC=CC=C1 OOCCDEMITAIZTP-UHFFFAOYSA-N 0.000 claims abstract description 9
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 claims abstract description 8
- AXMVYSVVTMKQSL-UHFFFAOYSA-N UNPD142122 Natural products OC1=CC=C(C=CC=O)C=C1O AXMVYSVVTMKQSL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940117916 cinnamic aldehyde Drugs 0.000 claims abstract description 8
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000012805 post-processing Methods 0.000 claims abstract description 6
- 239000003799 water insoluble solvent Substances 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000012965 benzophenone Substances 0.000 claims abstract description 4
- 239000002274 desiccant Substances 0.000 claims abstract description 4
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 230000004044 response Effects 0.000 claims abstract description 3
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 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 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000003021 water soluble solvent Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 1
- 239000012736 aqueous medium Substances 0.000 claims 1
- 239000000292 calcium oxide Substances 0.000 claims 1
- 235000012255 calcium oxide Nutrition 0.000 claims 1
- 238000011085 pressure filtration Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 52
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 5
- WQMAANNAZKNUDL-UHFFFAOYSA-N 2-dimethylaminoethyl chloride Chemical compound CN(C)CCCl WQMAANNAZKNUDL-UHFFFAOYSA-N 0.000 abstract description 3
- 239000011230 binding agent Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 abstract 2
- 235000010290 biphenyl Nutrition 0.000 abstract 1
- 239000004305 biphenyl Substances 0.000 abstract 1
- 125000006267 biphenyl group Chemical group 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 22
- 239000003651 drinking water Substances 0.000 description 13
- 235000020188 drinking water Nutrition 0.000 description 13
- 239000007787 solid Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- 229910000831 Steel Inorganic materials 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000010959 steel Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229960005026 toremifene Drugs 0.000 description 5
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000003825 pressing Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- -1 N, N-dimethylamino chlorine Ethane hydrochloride Chemical compound 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 102000015694 estrogen receptors Human genes 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- OVBICQMTCPFEBS-SATRDZAXSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-[bi Chemical class CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 OVBICQMTCPFEBS-SATRDZAXSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 240000004307 Citrus medica Species 0.000 description 1
- FCCWFMJMJVRYBV-UHFFFAOYSA-N Cl.CCCCCCC.CN(C)C(=C)Cl Chemical compound Cl.CCCCCCC.CN(C)C(=C)Cl FCCWFMJMJVRYBV-UHFFFAOYSA-N 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses production and prepare Toremifene Citrate key intermediate 4 [2 (N, N dimethylamino) ethyoxyl] benzophenone (calling intermediate 1 in the following text) and 1,2 diphenyl 1 [4 [2 (N, N dimethylamino) ethyoxyl] phenyl] new method of Isosorbide-5-Nitrae butanediol (calling intermediate 2 in the following text).The preparation of intermediate 1 is with water-insoluble solvent as main solvent, water-soluble reagent is secondary solvent, acid binding agent made by inorganic base, by 4 dihydroxy benaophenonels and N, N dimethylamino ethyl chloride hydrochlorate prepares through alkylated reaction, and this response speed is fast, post processing handy and safe, the three wastes are few, and the yield of intermediate 1 and purity are high, are especially suitable for industrialized production.The preparation of intermediate 2 is completed in ether solvent by cinnamic aldehyde (or cinnamyl alcohol), Lithium Aluminium Hydride and intermediate 1, post processing uses alkali liquor to destroy, desiccant dryness, the mode separation of intermediates 2 directly filtered, have quickly, environmental protection, yield high.
Description
Technical field
The present invention relates to new preparation process and the technique of Toremifene Citrate intermediate, belong to field of medicine and chemical technology.
Background technology
Toremifene (Toremifene) is that Famos company of Finland resists in the estrogen receptor antagon class that nineteen eighty-three develops
Tumour medicine, for treating postmenopausal women's estrogen receptor positive or not quite clear metastatic breast cancer, 1996 by Orion
Company lists in European Union, trade name Fareston.Toremifene is with citric acid form oral administration.Toremifene and tamoxifen
Fragrant structure is alike, the mechanism of action is similar to, and belongs to the antiestrogen of triaryl butylene class.Research in recent years finds, citron
Acid toremifene is the active drug of suppression Ebola virus.
4-[2-(N, N-dimethylamino) ethyoxyl] benzophenone (intermediate 1) and 1,2-diphenyl-1-[4-[2-(N, N-
Dimethylamino) ethyoxyl] phenyl]-BDO (intermediate 2) is that two in Toremifene Citrate preparation process are important
Intermediate.The synthesis of Toremifene Citrate is with 4-dihydroxy benaophenonel as raw material, with N, N-dimethylamino ethyl chloride hydrochlorate
Occurring O-alkylated reaction to generate intermediate 1, under the effect of Lithium Aluminium Hydride, intermediate 1 reacts with cinnamic aldehyde and obtains intermediate
2, chemical equation is as follows:
According to document (Xu Xiaoguang, the synthesis of Toremifene Citrate, Chinese Journal of Pharmaceuticals, 2002,33 (9), 417-
418 and slow general et al., the optimization of synthesis of Toremifene Citrate, contemporary Chinese medicinal application, 2013,7 (12), 236-
237) report, the synthesis of intermediate 1 is all with acetone as solvent, and with water as secondary solvent, have has also used phase transfer catalysis
Agent tetrabutylammonium chloride.With the synthesis technique of acetone as solvent, even if reaction can quantitatively complete, but it is not fee from acetone in alkalescence
Under the conditions of self-condensation, condensation product separate with intermediate 1 difficulty may result in intermediate 1 purity decline.Intermediate 2 is made
During Bei, post processing typically uses water or aqueous ammonium chloride solution to destroy unreacted Lithium Aluminium Hydride, the then conventional behaviour such as layering
Make.Owing to ether solvent water solublity is relatively big, causes a large amount of solvent and portioned product to bring aqueous phase into and cause yield to reduce, also result in water
Body pollution, the drawback such as complex operation.
Summary of the invention
In order to overcome above-mentioned technological deficiency, it is ensured that the intermediate 1 and 2 economy in industrialized production, safe and environment-friendly etc.
Feature, we have invented the new preparation process of Toremifene Citrate intermediate 1 and 2, and details are as follows:
With 4-dihydroxy benaophenonel and N, N-dimethylamino ethyl chloride hydrochlorate is initiation material, with water-insoluble solvent is
Solvent, a small amount of water-soluble reagent is secondary solvent, and acid binding agent made by inorganic base, reacts at a certain temperature to raw material 4-hydroxyl hexichol
Ketone disappears substantially.Add drinking water stirring layering, organic layer alkali liquid washing after cooling, then wash for several times with drinking water.Subtract
Pressure is concentrated into solvent-free steaming, and obtains light yellow solid, i.e. Toremifene Citrate intermediate 1, yield 92～98% after cooling.With
Former technique is compared, and eliminates the trouble using and concentrating of a large amount of acetone, reduces the generation of impurity.
The preparation of intermediate 2 of above-mentioned document report be by cinnamic aldehyde, Lithium Aluminium Hydride and intermediate 1 in oxolane anti-
Should complete.We use literature method, destroy with alkali liquor the most upon reaction completion, add desiccant, then add quantitative water, mistake
Filter inorganic salt, concentrating under reduced pressure, intermediate 2, yield 89～95% can be obtained easily.
Separately have document (Zhang Ruiren etc., the intermediate improvement in synthesis of Toremifene Citrate, Heilungkiang medical science,
2012,35 (4), 29-30) report employing cinnamyl alcohol and directly react in oxolane, with medium yield system with intermediate 1
The standby method obtaining intermediate 2.Can prove that the method is not from theoretical (valent state non-conservation before and after reaction) and experiment
Set up.We are with cinnamyl alcohol as raw material, and with ethers reagent as solvent, Lithium Aluminium Hydride is reducing agent, first prepares cinnamyl alcohol
Organometallic complex, then adds intermediate 1 and obtains the reactant liquor containing intermediate 2.Use above-mentioned similar post processing side
Method, it is also possible to obtain Toremifene Citrate intermediate 2, yield 85～90% easily.Chemical equation is as follows:
Compared with prior art, the present invention has a following four advantage:
1, with non-water-soluble solvent replacement acetone such as toluene as reaction dissolvent, reaction temperature is improved so that the response time
Shorten, save manufacturing man-hours；
2, with non-water-soluble solvent replacement acetone such as toluene as reaction dissolvent, the consumption of acid binding agent potassium carbonate reduces, after
Process and directly carry out in a kettle., and reaction dissolvent can eliminate centrifugal with recovery and the operations such as acetone is evaporated off, operation
Simplifying, solid waste reduces, and man-hour is saved, and cost reduces, and also ensure that the health of producers simultaneously；
3, substitute acetone as reaction dissolvent with the non-water-soluble solvent such as toluene, it is to avoid acetone in the basic conditions from
Body condensation reaction, so that the purity of intermediate 1 and yield are all improved；
4, the post processing in intermediate 2 preparation process uses the method filtering replacement extraction to isolate intermediate 2, operation letter
Changing, quickly, waste reduces, it is ensured that the health of producers, solves the wastewater problem in production simultaneously.
Detailed description of the invention
The present invention is described by the following specific embodiments, the present invention be may be better understood by embodiment, but
The scope of the present invention is not restricted by the embodiments.
Embodiment 1
Equipped with in churned mechanically 10L there-necked flask, add 4-dihydroxy benaophenonel 400g, potassium carbonate 696g, toluene
5.4kg, 95% industrial alcohol 140g, 53～58 DEG C are stirred 1 hour.It is cooled to less than 40 DEG C, puts into N, N-dimethylamino chloroethene
Heptane hydrochloride salt 436g, is warming up to 80～85 DEG C and reacts 4 hours.TLC monitoring has converted substantially to raw material 4-dihydroxy benaophenonel, cold
But to less than 40 DEG C, drinking water 2.4kg is added, stirring, layering, abandon lower floor's aqueous phase.Toluene layer is with 4.6 liter of 4% sodium hydroxide solution
Wash in three times, then wash in two times with 2 liters of drinking waters.Reduce pressure at 55～60 DEG C and steam solvent, give light yellow oil 521g,
Light yellow solid, intermediate 1 yield 95.8% is obtained after cooling.
Embodiment 2
In 5L there-necked flask, throw 1.2kg oxolane, 54g Lithium Aluminium Hydride, temperature control 20～28 DEG C, be slowly added dropwise cinnamic aldehyde
Tetrahydrofuran solution (containing cinnamic aldehyde 318g, oxolane 960g), drips complete, stirs 45 minutes at 20～28 DEG C.At this
At a temperature of add intermediate 1 tetrahydrofuran solution (containing 465g intermediate 1,1.2kg oxolane).Finish, in 38～43 DEG C
Stir 1 hour.Reactant liquor is transferred in 20 liters of glass reaction stills, adds oxolane 7L, be slowly added dropwise 20% sodium hydroxide
Solution 132g, stirs 10 minutes, adds 960g anhydrous sodium sulfate, then drip drinking water 132g, drip complete, stirs half an hour, takes out
Filter.Filter cake 1L oxolane washs.Remove oxolane under reduced pressure, add 2.64kg toluene, be heated to 90～100 DEG C molten clearly, slow
Slow cool down refines again to room temperature, sucking filtration, filter cake 2.4kg toluene.Being cooled to sucking filtration after room temperature, 60 DEG C of normal pressure air blast are dried
Off-white color solid 650g, intermediate 2 yield 92.8%, HPLC content 98.7%.
Embodiment 3
Toluene 1080kg, 95% industrial alcohol 28kg, potassium carbonate 140kg, 4-hydroxyl is put in 2000L glassed steel reaction vessels
Base benzophenone 80kg, stirs 1 hour in 53～58 DEG C.It is cooled to less than 40 DEG C, under nitrogen protection, throws N, N-dimethylamino chlorine
Ethane hydrochloride 87.5kg, throws and finishes, and is to slowly warm up to 80～85 DEG C and stirs 4 hours.It is cooled to less than 40 DEG C, adds drinking water
500kg, stirs 15 minutes, stratification.Upper organic phase 900kg 4% sodium hydrate aqueous solution washs in three times, organic
Wash in two times with 800kg drinking water mutually.Being not less than 0.085MPa in vacuum, interior temperature reduces pressure dense under the conditions of being not higher than 80 DEG C
Contracting solvent, to steaming without fraction, obtains grease 105.5kg, obtains light yellow solid, intermediate 1 yield 97% after cooling.
Embodiment 4
100kg oxolane, 4.5kg Lithium Aluminium Hydride is put in 500L glassed steel reaction vessels.Temperature control 20～28 DEG C, slowly
The tetrahydrofuran solution (containing cinnamic aldehyde 26.5kg, oxolane 80kg) of dropping cinnamic aldehyde.Drip complete, stir at 20～28 DEG C
45 minutes.Add the tetrahydrofuran solution (containing 38.7kg intermediate 1,100kg oxolane) of intermediate 1 at such a temperature.Add
Finish, stir 1 hour in 38～43 DEG C.Reactant liquor is transferred in 2000L glassed steel reaction vessels, adds oxolane 600kg, dropping
20% sodium hydroxide solution 11kg, continues stirring 15 minutes.Stirring is lower puts into anhydrous sodium sulfate 80kg, drips drinking water 11kg.
Drip complete continuation to stir 40 minutes.Filter pressing, filter cake 120kg oxolane filter pressing drip washing, decompression steams oxolane.Add first
Benzene 220kg is heated to 90～100 DEG C and molten is cooled to room temperature crystallize clearly, centrifugal, obtains the crude product of intermediate 2.Crude product is warded off at 500L
Glass reaction still is heated to 90～100 DEG C with 150kg toluene and molten is down to room temperature crystallize clearly, centrifugal after solid subtract in 70 DEG C
Pressure is dried, and obtains off-white color solid 53kg, intermediate 2 yield 91%, HPLC content 98.6%.
Embodiment 5
In 5L there-necked flask, throw 1.2kg oxolane, 54g Lithium Aluminium Hydride, temperature control 20～28 DEG C, be slowly added dropwise cinnamyl alcohol
Tetrahydrofuran solution (containing cinnamyl alcohol 322g, oxolane 960g), drips complete, stirs 45 minutes at 20～28 DEG C.At this
At a temperature of add intermediate 1 tetrahydrofuran solution (containing 465g intermediate 1,1.2kg oxolane).Finish, in 38～43 DEG C
Stir 1 hour.Reactant liquor is transferred in 20 liters of glass reaction stills, adds oxolane 7L, be slowly added dropwise 20% sodium hydroxide
Solution 132g, stirs 10 minutes, adds 960g anhydrous sodium sulfate, then drip drinking water 132g, drip complete, stirs half an hour, takes out
Filter.Filter cake 1L oxolane washs.Remove oxolane under reduced pressure, add 2.64kg toluene, be heated to 90～100 DEG C molten clearly, slow
Slow cool down refines again to room temperature, sucking filtration, filter cake 2.4kg toluene.Being cooled to sucking filtration after room temperature, 60 DEG C of normal pressure air blast are dried
Off-white color solid 600g, intermediate 2 yield 85.6%.
Embodiment 6
100kg oxolane, 4.5kg Lithium Aluminium Hydride is put in 500L glassed steel reaction vessels.Temperature control 20～28 DEG C, slowly
The tetrahydrofuran solution (containing cinnamyl alcohol 26.9kg, oxolane 80kg) of dropping cinnamyl alcohol.Drip complete, stir at 20～28 DEG C
45 minutes.Add the tetrahydrofuran solution (containing 38.7kg intermediate 1,100kg oxolane) of intermediate 1 at such a temperature.Add
Finish, stir 1 hour in 38～43 DEG C.Reactant liquor is transferred in 2000L glassed steel reaction vessels, adds oxolane 600kg, dropping
20% sodium hydroxide solution 11kg, continues stirring 15 minutes.Stirring is lower puts into anhydrous sodium sulfate 80kg, drips drinking water 11kg.
Drip complete continuation to stir 40 minutes.Filter pressing, filter cake 120kg oxolane filter pressing drip washing, decompression steams oxolane.Add
Toluene 220kg is heated to 90～100 DEG C and molten is cooled to room temperature crystallize clearly, centrifugal, obtains the crude product of intermediate 2.By crude product at 500L
Glassed steel reaction vessels is heated to 90～100 DEG C with 150kg toluene and molten is down to room temperature crystallize clearly, centrifugal after solid in 70 DEG C
Decompression drying, obtains off-white color solid 51.3kg, intermediate 2 yield 88%.
Embodiment 7
Equipped with in churned mechanically 500mL there-necked flask, add 4-dihydroxy benaophenonel 20g, potassium carbonate 34.8g, toluene
190g, acetone 10g, drinking water 2g, be heated to 75～80 DEG C of back flow reaction 5 hours, and TLC shows raw material 4-dihydroxy benaophenonel not
Reduce again.It is cooled to less than 40 DEG C, adds drinking water 120g, stirring, layering, abandon lower floor's aqueous phase.Toluene layer is with 220 milliliter of 4% hydrogen
Sodium hydroxide solution is washed in three times, then washs in two times with 200 milliliters of drinking waters.At 55～60 DEG C, decompression steams solvent, obtains shallow
Yellow oil 19.4g, obtains light yellow solid, intermediate 1 yield 71.3% after cooling.
Claims (8)
1. prepare Toremifene Citrate intermediate 4-[2-(N, N-dimethylamino) ethyoxyl] benzophenone (intermediate 1)
Method, it is characterized in that two reactants are solvent at water-insoluble solvent, aqueous media is secondary solvent, and inorganic base is tied up
Carry out under acid agent.
The most according to claim 1 prepare intermediate 1, it is characterized in that water-insoluble solvent be benzene, toluene, dichloromethane,
1,2-dichloroethanes, dimethylbenzene, chlorobenzene；Water solublity auxiliary solvent is methanol, ethanol, 95% ethanol, acetone, butanone, N, N-bis-
Methylformamide, acetonitrile, dimethyl sulfoxide and their aqueous solution, also include pure water.
The most according to claim 1 prepare intermediate 1, it is characterized in that inorganic base be sodium carbonate, potassium carbonate, sodium hydroxide,
Potassium hydroxide etc., alkali liquor is the aqueous solution of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
The most according to claim 1 preparing intermediate 1, it is characterized in that reaction temperature is 30～140 DEG C, the response time is with former
Material reaction is as the criterion completely.
The consumption of water-insoluble solvent the most according to claim 2 is 5～20 times of (weight of raw material 4-dihydroxy benaophenonel
Than), water-soluble solvent consumption is 0.1%～50% (percentage by weight) of water-insoluble solvent.
6. Toremifene Citrate intermediate 1,2-diphenyl-1-[4-[2-(N, N-dimethylamino) ethyoxyl] phenyl]-Isosorbide-5-Nitrae-
The new preparation method of butanediol (intermediate 2) by cinnamic aldehyde (or cinnamyl alcohol), Lithium Aluminium Hydride and intermediate 1 in ether solvent
Reaction preparation, is characterized in that post processing uses alkali liquor to destroy, and desiccant dryness, the mode of direct malleation or negative pressure filtration separates to be removed
Remove inorganic salt.
The most according to claim 6 prepare intermediate 2, it is characterized in that alkali liquor includes that sodium hydroxide solution, potassium hydroxide are molten
Liquid, solution of potassium carbonate, sodium carbonate liquor etc..
The most according to claim 7 prepare intermediate 2, it is characterized in that desiccant include anhydrous sodium sulfate, anhydrous magnesium sulfate,
Anhydrous calcium chloride, quick lime etc..
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| WO2011013108A1 (en) * | 2009-07-31 | 2011-02-03 | Ranbaxy Laboratories Limited | Polymorphic form of toremifene citrate and process for its preparation |
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| CN106966911B (en) * | 2016-04-19 | 2019-06-14 | 福安药业集团宁波天衡制药有限公司 | The preparation method of Toremifene Citrate intermediate |
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