CN106966911B - The preparation method of Toremifene Citrate intermediate - Google Patents
The preparation method of Toremifene Citrate intermediate Download PDFInfo
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- CN106966911B CN106966911B CN201710248184.7A CN201710248184A CN106966911B CN 106966911 B CN106966911 B CN 106966911B CN 201710248184 A CN201710248184 A CN 201710248184A CN 106966911 B CN106966911 B CN 106966911B
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- China
- Prior art keywords
- ethyoxyl
- tetrahydrofuran
- dimethylamino
- added dropwise
- benzophenone
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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 26
- 229960004167 toremifene citrate Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 N, N- dimethylamino Chemical group 0.000 claims abstract description 75
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 47
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000012965 benzophenone Substances 0.000 claims abstract description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 33
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 31
- 239000004305 biphenyl Substances 0.000 claims abstract description 31
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000003756 stirring Methods 0.000 claims abstract description 30
- WERYXYBDKMZEQL-UHFFFAOYSA-N 1,4-butanediol Substances OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003651 drinking water Substances 0.000 claims abstract description 19
- 235000020188 drinking water Nutrition 0.000 claims abstract description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 125
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 40
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 claims description 23
- 229910000831 Steel Inorganic materials 0.000 claims description 13
- 238000005352 clarification Methods 0.000 claims description 13
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 13
- 239000010959 steel Substances 0.000 claims description 13
- OOCCDEMITAIZTP-UHFFFAOYSA-N allylic benzylic alcohol Natural products OCC=CC1=CC=CC=C1 OOCCDEMITAIZTP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- 230000006837 decompression Effects 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 8
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims description 8
- 229930016911 cinnamic acid Natural products 0.000 claims description 8
- 235000013985 cinnamic acid Nutrition 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims description 8
- 238000003825 pressing Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000005119 centrifugation Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 206010013786 Dry skin Diseases 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 239000001257 hydrogen Substances 0.000 claims 4
- SBYBCJUEWBGSSB-UHFFFAOYSA-N diphenylmethanone;oxolane Chemical compound C1CCOC1.C=1C=CC=CC=1C(=O)C1=CC=CC=C1 SBYBCJUEWBGSSB-UHFFFAOYSA-N 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 239000004411 aluminium Substances 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 12
- 238000001816 cooling Methods 0.000 abstract description 6
- 238000001514 detection method Methods 0.000 abstract description 5
- 150000007529 inorganic bases Chemical class 0.000 abstract description 5
- 238000005406 washing Methods 0.000 abstract description 4
- 238000010792 warming Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 25
- 239000000543 intermediate Substances 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 12
- 235000011121 sodium hydroxide Nutrition 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 229960005026 toremifene Drugs 0.000 description 6
- 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 6
- 150000002576 ketones Chemical class 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 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
- ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 2
- 240000004307 Citrus medica Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 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
- 239000007864 aqueous solution Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-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
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- 238000005303 weighing Methods 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
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- PACSAUUPYNDFSY-UHFFFAOYSA-N CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC[SiH3] Chemical group CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC[SiH3] PACSAUUPYNDFSY-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 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 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
- 230000009471 action Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 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
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- 235000012255 calcium oxide Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 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
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 150000002170 ethers Chemical class 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
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000012360 testing method Methods 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
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
- 238000003911 water pollution Methods 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
-
- 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
- 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 present invention relates to Toremifene Citrate intermediate 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone and 1, the preparation method of 2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol；Wherein 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone the preparation method comprises the following steps: by 4- dihydroxy benaophenonel, inorganic base, the first solvent and the second solvent mix, it is stirred 0.8~2 hour at 53~58 DEG C, it is subsequently cooled to 40 DEG C or less, N is added, N- dimethylamino chloroethanes hydrochloride is warming up to 80~85 DEG C and is stirred to react 2~5 hours；Be cooled to 40 DEG C hereinafter, plus drinking water, stirring be allowed to be layered, take upper oil phase；Oily mutually first washed with 4% sodium hydroxide solution to TLC detection 4- dihydroxy benaophenonel disappears, then with drink water washing to pH be 8~9；Obtained product depressurizes at 55~60 DEG C and steams solvent, obtains Toremifene Citrate intermediate 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone after cooling.
Description
Technical field
The present invention relates to field of medicine and chemical technology, a kind of especially Toremifene Citrate intermediate 4- [2- (N, N- diformazan ammonia
Base) ethyoxyl] benzophenone and 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol
Preparation method.
Background technique
Toremifene (Toremifene) is that the estrogen receptor antagon class that Famos company, Finland develops in nineteen eighty-three is anti-
Tumour medicine, for treating postmenopausal women's estrogen receptor positive or unknown metastatic breast cancer, 1996 by Orion
Company lists in European Union, trade name Fareston.Toremifene is administered orally in the form of citric acid.Toremifene and tamoxifen
Fragrant structure is alike, the mechanism of action is similar, belongs to the antiestrogen of triaryl butylene class.In recent years the study found that citron
Sour Toremifene is the active drug for inhibiting Ebola virus.
4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone (4- (2- (dimethylamino) ethoxy) phenyl)
(phenyl) methanone) and 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4- butanediol
(1- (4- (2- (dimethylamino) ethoxy) phenyl) -1,2-diphenylbutane-1,4-diol) is citric acid support
Two important intermediates in Rui meter Fen preparation process.The synthesis of Toremifene Citrate is original with 4- dihydroxy benaophenonel
Material, with N, N- dimethylamino chloroethanes hydrochloride occurs O- alkylated reaction and generates 4- [2- (N, N- dimethylamino) ethyoxyl] two
Benzophenone, under the action of Lithium Aluminium Hydride, 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone is obtained with cortex cinnamomi aldehyde reaction
1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol, chemical equation are 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, 4- [2- (N, N- dimethylamino) ethyoxyl] synthesis of benzophenone are auxiliary with water using acetone as solvent
Solvent, some have also used phase transfer catalyst tetrabutylammonium chloride.It, can be fixed even if reacting with the synthesis technology of acetone as solvent
Amount is completed, but the self-condensation of unavoidable acetone under alkaline condition, condensation product and 4- [2- (N, N- dimethylamino) ethoxy
Base] benzophenone separation difficulty will lead to 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone purity decline.1,2-
General use is post-processed in diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol preparation process
Water or aqueous ammonium chloride solution destroy unreacted Lithium Aluminium Hydride, then the routine operations such as layering.Due to ether solvent water solubility compared with
Greatly, causing a large amount of solvents and portioned product to bring water phase into causes yield to reduce, and also causes water pollution, the drawbacks such as cumbersome.
" Heilungkiang medical science " ((Zhang Ruiren etc., 2012,35 (4), 29-30)) report " Toremifene Citrate
Intermediate improvement in synthesis " method, propose using cinnamyl alcohol directly with 4- [2- (N, N- dimethylamino) ethyoxyl] hexichol first
Ketone reacts in tetrahydrofuran, prepares 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethoxy with medium yield
Base] phenyl] -1,4-butanediol method.It theoretically derives, since this method reacts front and back valent state non-conservation, the party
Method cannot prepare Toremifene Citrate intermediate；And it is verified through actual tests, this method cannot equally prepare citron
Sour Toremifene intermediate 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol.
Summary of the invention
There is provided the technical problem to be solved by the present invention is to the status for the prior art a kind of can effectively inhibit to prepare
Toremifene Citrate intermediate 4- [2- (N, N- dimethylamino) ethyoxyl] hexichol first of side reaction generation and high income in journey
The preparation method of ketone.
Another technical problem to be solved by this invention is to provide a kind of easy to operate and ring for the status of the prior art
The Toremifene Citrate intermediate 1 of guarantor, 2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl]-Isosorbide-5-Nitrae-fourth
The preparation method of glycol.
The technical scheme of the invention to solve the technical problem is: Toremifene Citrate intermediate 4- [2-
(N, N- dimethylamino) ethyoxyl] benzophenone preparation method, it is characterised in that include the following steps:
4- dihydroxy benaophenonel, inorganic base, the first solvent and the second solvent are mixed, 0.8~2 is stirred at 53~58 DEG C
Hour, 40 DEG C are subsequently cooled to hereinafter, N is added, and N- dimethylamino chloroethanes hydrochloride is warming up to 80~85 DEG C and is stirred to react 2
~5 hours；
40 DEG C are cooled to hereinafter, plus drinking water, the dosage of the drinking water are 5~8 times of 4- dihydroxy benaophenonel weight；
Stirring is allowed to be layered, and takes upper oil phase；
It is oily mutually first to be washed with 4% sodium hydroxide solution to TLC detection 4- dihydroxy benaophenonel disappearance, then with drinking water washing
It is 8~9 to pH；Obtained product depressurizes at 55~60 DEG C and steams solvent, obtains among Toremifene Citrate after cooling
Body 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone；
The 4- dihydroxy benaophenonel and the N, the molar ratio of N- dimethylamino chloroethanes hydrochloride are 1:1.1~2.0；
The solvent is the mixture of the first solvent, the second solvent and inorganic base；The dosage of first solvent is 4- hydroxyl
5~20 times of weight of base benzophenone, the dosage of second solvent are 0.1~50wt% of first solvent usage；Institute
The dosage for stating inorganic base is 1~5 times of mole of 4- dihydroxy benaophenonel；
First solvent is selected from any one in benzene, toluene, methylene chloride, 1,2- dichloroethanes, dimethylbenzene and chlorobenzene
Kind；Second solvent is selected from methanol, ethyl alcohol, 95% ethyl alcohol, acetone, butanone, n,N-Dimethylformamide, acetonitrile, dimethyl
At least one of sulfoxide and their aqueous solution and water.
It is preferred that the inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
Toremifene Citrate intermediate 4- [2- (N, the N- dimethylamino) ethyoxyl] hexichol prepared using the above method
Ketone prepares Toremifene Citrate intermediate 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,
The preparation method of 4- butanediol, it is characterised in that including lower book step:
Tetrahydrofuran and Lithium Aluminium Hydride are mixed by the weight ratio of 10~30:1,20~28 DEG C of dropwises addition concentration for 10~
The cinnamyl alcohol of 30wt% or the tetrahydrofuran solution of cinnamic acid, after being added dropwise, continuing stirring to reaction solution at 20~28 DEG C is in
White opacity liquid；
Then the Toremifene Citrate that concentration is 10~35wt% is added dropwise into reaction system at 20~28 DEG C
The tetrahydrofuran solution of intermediate 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone, after being added dropwise, in 38~43 DEG C
Continue stirring to reaction solution dissolved clarification；
Then the Toremifene Citrate intermediate 4- [2- (N, N- dimethylamino) ethoxy is added into reaction system
Base] 10~20 times of benzophenone quality of tetrahydrofuran, 2.3~2.6 times of Lithium Aluminium Hydride quality dense is added dropwise after charging again
The lye that degree is 20% continues stirring 15 minutes；Desiccant is put into again, and the dosage of the desiccant is the citric acid Tuo Rui meter
2.0~2.5 times of fragrant intermediate 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone quality；Add Lithium Aluminium Hydride quality
2.3~2.6 times of drinking water；
Then the Toremifene Citrate intermediate 4- [2- (N, N- dimethylamino) ethoxy is added into reaction system
Base] 3~4 times of benzophenone quality of toluene, it is heated to 90~100 DEG C of solution clarifications；Then reaction system is cooled to room temperature；
Positive press filtration or negative pressure filtration are carried out to reaction system, take solid, decompression drying obtains Toremifene Citrate
Intermediate 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol.
It is preferred that the lye is sodium hydroxide solution, potassium hydroxide solution, solution of potassium carbonate or sodium carbonate liquor.
The desiccant is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride or quick lime.
A kind of compared with prior art, provided by the present invention completely new Toremifene Citrate intermediate 4- [2- (N,
N- dimethylamino) ethyoxyl] benzophenone preparation method, using the first water-insoluble solvent as reaction dissolvent, reaction temperature
Spend moderate, the reaction time is short, saves manufacturing man-hours；And it post-processes and directly carries out in a kettle, reaction dissolvent can return
Receipts are applied, and eliminate centrifugation and the processes such as acetone are evaporated off, and operation simplifies, and solid waste is reduced, and cost reduces, and also ensure operator
Working environment；The trouble for using and being concentrated that a large amount of acetone are omitted in the prior art is avoided simultaneously, reduces the life of impurity
At, avoid acetone under alkaline condition self-condensation reaction, improve 4- [2- (N, N- dimethylamino) ethyoxyl] hexichol
The purity and yield of ketone, yield can reach 92~98%.
Intermediate 1, the preparation of 2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol
Method, using cinnamyl alcohol as raw material, using ethers reagent as solvent, Lithium Aluminium Hydride is reducing agent, first prepares organic gold of cinnamyl alcohol
Metal complex is then added 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone and obtains containing 1,2- diphenyl -1- [4-
[2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol reaction solution；Chemical equation is as follows:
Post-processing is destroyed using lye, and desiccant, then the water for the amount of reordering is added, is filtered to remove inorganic salts, is concentrated under reduced pressure, behaviour
Make simplified, quick, waste reduction, 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol
Yield can reach 89~95%, while it is environmental-friendly, avoid the generation of waste water.
Specific embodiment
Present invention is further described in detail with reference to embodiments.
Embodiment 1
Equipped in churned mechanically 10L there-necked flask, 4- dihydroxy benaophenonel 400g, potassium carbonate 696g, toluene is added
5.4kg, 95% industrial alcohol 140g, 53~58 DEG C are stirred 1 hour.
40 DEG C are cooled to hereinafter, investment N, N- dimethylamino chloroethanes hydrochloride 436g, it is small to be warming up to 80~85 DEG C of reactions 4
When.
Be cooled to 40 DEG C hereinafter, plus drinking water 2.4kg, stir, layering, abandon lower layer's water phase.
Oily mutually to be washed in three times with 4.6 liter of 4% sodium hydroxide solution, TLC detects 4- dihydroxy benaophenonel and disappears；Again with 2
It rises drinking water to wash in two times, washing to pH is 8.
Obtained product depressurizes at 55~60 DEG C and steams solvent, give light yellow oil 521g, obtains after cooling light yellow
Solid, i.e. 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone；Weighing calculates 4- [2- (N, N- dimethylamino) ethyoxyl]
Benzophenone yield 95.8%.
The calculation method of 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone yield is as follows:
Wherein, m1 is the output quality of 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone, and m0 is 4- hydroxyl hexichol
The quality that feeds intake of ketone, 198.22 be the relative molecular mass of 4- dihydroxy benaophenonel, and 269.34 be 4- [2- (N, N- diformazan ammonia
Base) ethyoxyl] benzophenone relative molecular mass.
Embodiment 2
1.2kg tetrahydrofuran is thrown into 5L there-necked flask, 20~28 DEG C of temperature control, cinnamic acid is slowly added dropwise in 54g Lithium Aluminium Hydride
Tetrahydrofuran solution (318g containing cinnamic acid, tetrahydrofuran 960g), is added dropwise, and stirs 45 minutes at 20~28 DEG C.Then
The tetrahydrofuran solution of 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone prepared by embodiment 1 is added at such a temperature
(containing 465g4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone, 1.2kg tetrahydrofuran).It finishes, stirs 1 in 38~43 DEG C
Hour.
Reaction solution is transferred in 20 liters of glass reaction kettles, tetrahydrofuran 7L is added, it is molten that 20% sodium hydroxide is slowly added dropwise
Liquid 132g is stirred 10 minutes, is added 960g anhydrous sodium sulfate, then drinking water 132g is added dropwise, be added dropwise, and stirs half an hour, is filtered.
Filter cake is washed with 1L tetrahydrofuran.It removes tetrahydrofuran under reduced pressure, adds 2.64kg toluene, be heated to 90~100 DEG C of dissolved clarifications, it is then cold
But it to room temperature, filters, filter cake is eluted again with 2.4kg toluene, is heated to 90~100 DEG C of dissolved clarifications, takes out after then cooling to room temperature
Off-white powder 650g, i.e. 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethoxy are dried to obtain in filter, 60 DEG C of normal pressure air blast
Base] phenyl] -1,4-butanediol；Weighing calculates 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,
4- butanediol yield is 92.8%, HPLC content 98.7%.
The yield calculating side of 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol
Method are as follows:
Wherein, m1 is the quality that feeds intake of 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone, m2 1,2- diphenyl-
The output quality of 1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol, 269.34 be 4- [2- (N, N- bis-
Methylamino) ethyoxyl] benzophenone relative molecular mass, 405.53 be 1,2- diphenyl -1- [4- [2- (N, N- diformazan ammonia
Base) ethyoxyl] phenyl] and -1,4-butanediol relative molecular mass
HPLC content assaying method is as follows:
Chromatographic condition and system suitability: being filler (250 × 4.6mm) with melissyl silane group silica gel,
40 DEG C of column temperature, Detection wavelength 240nm, using methanol: water: trifluoroacetic acid carries out gradient elution as mobile phase.Initial liquid phase is A:B
=(50:50) is then increased the ratio of B with per minute 1.33% speed, after 30 minutes, B ratio is made to rise to 90%, A ratio
It is down to 10%.Keep this ratio 15 minutes.It takes this product appropriate, adds methanol dissolution that the solution in every 1ml containing about 1mg is made, as
Test solution takes 20ul to inject liquid chromatograph, and record chromatogram is to 1.5 times of main peak retention time, by area normalization
Method calculates.(A: methanol: water: trifluoroacetic acid=100:900:1；B: methanol: water: trifluoroacetic acid=900:100:1)
In formula: X: the percentage composition of total impurities, % in test solution；
A1: the peak area of total impurities in test solution；
A2: total peak area in test solution.
Embodiment 3
Toluene 1080kg, 95% industrial alcohol 28kg, potassium carbonate 140kg and 4- are put into 2000L glassed steel reaction vessels
Dihydroxy benaophenonel 80kg is stirred 1 hour in 53~58 DEG C.
40 DEG C are cooled to hereinafter, putting into N under nitrogen protection, N- dimethylamino chloroethanes hydrochloride 87.5kg throws and finishes, heating
It is stirred 4 hours to 80~85 DEG C.
Be cooled to 40 DEG C hereinafter, plus drinking water 500kg, stir 15 minutes, stratification.Upper organic phase 900kg4%
Sodium hydrate aqueous solution washs in three times, until TLC detection 4- dihydroxy benaophenonel disappears；Obtained organic phase is drunk with 800kg again
It is 9 with moisture secondary washing to pH value.It is not less than 0.085MPa in vacuum degree, interior temperature is concentrated under reduced pressure molten under the conditions of being not higher than 80 DEG C
Agent to no fraction steams, and obtains grease 105.5kg, obtains light yellow solid, i.e. 4- [2- (N, N- dimethylamino) ethoxy after cooling
Base] benzophenone, 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone yield 97%.
Embodiment 4
100kg tetrahydrofuran, 4.5kg Lithium Aluminium Hydride are put into 500L glassed steel reaction vessels.It 20~28 DEG C of temperature control, is added dropwise
The tetrahydrofuran solution (26.5kg containing cinnamic acid, tetrahydrofuran 80kg) of cinnamic acid.It is added dropwise, 45 points is stirred at 20~28 DEG C
Clock.The tetrahydrofuran that 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone prepared by embodiment 3 is added at such a temperature is molten
Liquid (contains 38.7kg4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone, 100kg tetrahydrofuran).It finishes, in 38~43 DEG C
Stirring 1 hour.
Reaction solution is transferred in 2000L glassed steel reaction vessels, tetrahydrofuran 600kg is added, it is molten that 20% sodium hydroxide is added dropwise
Liquid 11kg continues stirring 15 minutes.Stirring is lower to put into anhydrous sodium sulfate 80kg, and drinking water 11kg is added dropwise.It is added dropwise and continues to stir
It mixes 40 minutes.Filters pressing, filter cake are eluted with 120kg tetrahydrofuran filters pressing, and decompression steams tetrahydrofuran.Toluene 220kg is added to be heated to
90~100 DEG C of dissolved clarifications, are cooled to room temperature crystallization, and centrifugation obtains 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl]
Phenyl] -1,4-butanediol crude product.By crude product in 500L glassed steel reaction vessels with 150kg toluene be heated to 90~100 DEG C it is molten
Clearly, it is down to room temperature crystallization, the solid after centrifugation obtains off-white powder 53kg, i.e. 1,2- diphenyl -1- in 70 DEG C of decompression dryings
[4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol, calculated yield 91%, HPLC content 98.6%.
Embodiment 5
1.2kg tetrahydrofuran is thrown into 5L there-necked flask, 20~28 DEG C of temperature control, cinnamyl alcohol is slowly added dropwise in 54g Lithium Aluminium Hydride
Tetrahydrofuran solution (322g containing cinnamyl alcohol, tetrahydrofuran 960g), is added dropwise, and stirs 45 minutes at 20~28 DEG C.At this
At a temperature of the tetrahydrofuran solution of 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone prepared by embodiment 3 be added (contain
465g4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone, 1.2kg tetrahydrofuran).It finishes, it is small in 38~43 DEG C of stirrings 1
When.Reaction solution is transferred in 20 liters of glass reaction kettles, tetrahydrofuran 7L is added, 20% sodium hydroxide solution is slowly added dropwise
132g is stirred 10 minutes, is added 960g anhydrous sodium sulfate, then drinking water 132g is added dropwise, be added dropwise, and stirs half an hour, is filtered.Filter
Cake is washed with 1L tetrahydrofuran.It removes tetrahydrofuran under reduced pressure, adds 2.64kg toluene, be heated to 90~100 DEG C of dissolved clarifications, Slow cooling
It to room temperature, filters, filter cake is refined again with 2.4kg toluene.It is filtered after being cooled to room temperature, off-white color is dried to obtain in 60 DEG C of normal pressure air blast
Solid 600g, 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol yield 85.6%.
Embodiment 6
Equipped in churned mechanically 500mL there-necked flask, 4- dihydroxy benaophenonel 20g, potassium carbonate 34.8g, toluene is added
190g, acetone 10g and drinking water 2g, are heated to 75~80 DEG C of back flow reactions 5 hours, and TLC shows raw material 4- dihydroxy benaophenonel
No longer reduce.
Be cooled to 40 DEG C hereinafter, plus drinking water 120g, stir, layering, abandon lower layer's water phase.Oily mutually 220 milliliter of 4% hydrogen-oxygen
Change sodium solution to wash in three times, until TLC detection 4- dihydroxy benaophenonel disappears；Again with 200 milliliters of drinking water wash in two times to
PH value is 8.Decompression steams solvent at 55~60 DEG C, and give light yellow oil 19.4g obtains light yellow solid, 4- [2- after cooling
(N, N- dimethylamino) ethyoxyl] benzophenone yield 71.3%.
Embodiment 7
100kg tetrahydrofuran, 4.5kg Lithium Aluminium Hydride are put into 500L glassed steel reaction vessels.20~28 DEG C of temperature control, slowly
The tetrahydrofuran solution (26.9kg containing cinnamyl alcohol, tetrahydrofuran 80kg) of cinnamyl alcohol is added dropwise.It is added dropwise, is stirred at 20~28 DEG C
45 minutes.The tetrahydro furan of 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone prepared by embodiment 6 is added at such a temperature
It mutters solution (containing 38.7kg4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone, 100kg tetrahydrofuran).It finishes, in 38~
43 DEG C are stirred 1 hour.
Reaction solution is transferred in 2000L glassed steel reaction vessels, tetrahydrofuran 600kg is added, it is molten that 20% sodium hydroxide is added dropwise
Liquid 11kg continues stirring 15 minutes.Stirring is lower to put into anhydrous sodium sulfate 80kg, and drinking water 11kg is added dropwise.It is added dropwise and continues to stir
It mixes 40 minutes.Filters pressing, filter cake are eluted with 120kg tetrahydrofuran filters pressing, and decompression steams tetrahydrofuran.Toluene 220kg is added to be heated to
90~100 DEG C of dissolved clarifications, are cooled to room temperature crystallization, and centrifugation obtains 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl]
Phenyl] -1,4-butanediol crude product.By crude product in 500L glassed steel reaction vessels with 150kg toluene be heated to 90~100 DEG C it is molten
Clearly, it is down to room temperature crystallization, the solid after centrifugation obtains off-white powder 51.3kg, 1,2- diphenyl -1- in 70 DEG C of decompression dryings
[4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol yield 88%.
Claims (4)
1. Toremifene Citrate intermediate 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl]-Isosorbide-5-Nitrae -
The preparation method of butanediol, it is characterised in that include the following steps:
1.2kg tetrahydrofuran is thrown into 5L there-necked flask, 54g Lithium Aluminium Hydride, is slowly added dropwise containing cinnamic acid by 20~28 DEG C of temperature control
The cinnamic acid tetrahydrofuran solution of 318g, tetrahydrofuran 960g, it is added dropwise, is stirred 45 minutes at 20~28 DEG C；In the temperature
Degree is lower to be added 4- [2- (N, the N- bis- for containing 465g4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone and 1.2kg tetrahydrofuran
Methylamino) ethyoxyl] benzophenone tetrahydrofuran solution；It finishes, is stirred 1 hour in 38~43 DEG C；Reaction solution is transferred to
In 20 liters of glass reaction kettles, tetrahydrofuran 7L is added, 20% sodium hydroxide solution 132g is slowly added dropwise, stirs 10 minutes, adds
960g anhydrous sodium sulfate, then drinking water 132g is added dropwise, it is added dropwise, stirs half an hour, filter；Filter cake is washed with 1L tetrahydrofuran
It washs；It removes tetrahydrofuran under reduced pressure, adds 2.64kg toluene, be heated to 90~100 DEG C of dissolved clarifications, be slowly cooled to room temperature, filter, filter cake
It is refined again with 2.4kg toluene；It is filtered after being cooled to room temperature, off-white powder 1,2- diphenyl-are dried to obtain in 60 DEG C of normal pressure air blast
1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol.
2. Toremifene Citrate intermediate 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl]-Isosorbide-5-Nitrae -
The preparation method of butanediol, it is characterised in that include the following steps: to put into 100kg tetrahydro furan into 500L glassed steel reaction vessels
It mutters, 4.5kg Lithium Aluminium Hydride；20~28 DEG C of temperature control, the four of the cinnamic acid of 26.5kg containing cinnamic acid, tetrahydrofuran 80kg are slowly added dropwise
Hydrogen tetrahydrofuran solution；It is added dropwise, is stirred 45 minutes at 20~28 DEG C；[2- (N, the N- diformazan containing 38.7kg4- is added at such a temperature
Amino) ethyoxyl] benzophenone, 100kg tetrahydrofuran 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone tetrahydro
Tetrahydrofuran solution；It finishes, is stirred 1 hour in 38~43 DEG C；Reaction solution is transferred in 2000L glassed steel reaction vessels, tetrahydro furan is added
Mutter 600kg, and 20% sodium hydroxide solution 11kg is added dropwise, and continues stirring 15 minutes；Stirring is lower to put into anhydrous sodium sulfate 80kg, is added dropwise
Drinking water 11kg；It is added dropwise and continues stirring 40 minutes；Filters pressing, filter cake are eluted with 120kg tetrahydrofuran filters pressing, and decompression steams four
Hydrogen furans；Add toluene 220kg to be heated to 90~100 DEG C of dissolved clarifications, be cooled to room temperature crystallization, is centrifuged, obtains 1,2- diphenyl -1- [4-
[2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol crude product；Crude product is used in 500L glassed steel reaction vessels
150kg toluene is heated to 90~100 DEG C of dissolved clarifications, is down to room temperature crystallization, and the solid after centrifugation obtains off-white color in 70 DEG C of decompression dryings
Solid 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol.
3. Toremifene Citrate intermediate 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl]-Isosorbide-5-Nitrae -
The preparation method of butanediol, it is characterised in that include the following steps: to throw 1.2kg tetrahydrofuran, 54g tetrahydro aluminium into 5L there-necked flask
20~28 DEG C of temperature control, the tetrahydrofuran solution of the cinnamyl alcohol of 322g containing cinnamyl alcohol, tetrahydrofuran 960g is slowly added dropwise in lithium, is added dropwise
It finishes, is stirred 45 minutes at 20~28 DEG C；It is added at such a temperature and contains 465g4- [2- (N, N- dimethylamino) ethyoxyl] two
Benzophenone, 1.2kg tetrahydrofuran 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone tetrahydrofuran solution；It finishes,
It is stirred 1 hour in 38~43 DEG C；Reaction solution is transferred in 20 liters of glass reaction kettles, tetrahydrofuran 7L is added, is slowly added dropwise
20% sodium hydroxide solution 132g is stirred 10 minutes, is added 960g anhydrous sodium sulfate, then drinking water 132g is added dropwise, be added dropwise, stir
It mixes half an hour, filters；Filter cake is washed with 1L tetrahydrofuran；It removes tetrahydrofuran under reduced pressure, adds 2.64kg toluene, it is heated to 90~
100 DEG C of dissolved clarifications, are slowly cooled to room temperature, and filter, and filter cake is refined again with 2.4kg toluene；It is filtered after being cooled to room temperature, 60 DEG C often
Drum pressure wind dries to obtain off-white powder 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl]-Isosorbide-5-Nitrae-fourth two
Alcohol.
4. Toremifene Citrate intermediate 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl]-Isosorbide-5-Nitrae -
The preparation method of butanediol, it is characterised in that include the following steps: to put into 100kg tetrahydro furan into 500L glassed steel reaction vessels
It mutters, 4.5kg Lithium Aluminium Hydride；20~28 DEG C of temperature control, the four of the cinnamyl alcohol of 26.9kg containing cinnamyl alcohol, tetrahydrofuran 80kg are slowly added dropwise
Hydrogen tetrahydrofuran solution；It is added dropwise, is stirred 45 minutes at 20~28 DEG C；[2- (N, the N- diformazan containing 38.7kg4- is added at such a temperature
Amino) ethyoxyl] benzophenone, 100kg tetrahydrofuran 4- [2- (N, N- dimethylamino) ethyoxyl] benzophenone tetrahydro
Tetrahydrofuran solution；It finishes, is stirred 1 hour in 38~43 DEG C；Reaction solution is transferred in 2000L glassed steel reaction vessels, tetrahydro furan is added
Mutter 600kg, and 20% sodium hydroxide solution 11kg is added dropwise, and continues stirring 15 minutes；Stirring is lower to put into anhydrous sodium sulfate 80kg, is added dropwise
Drinking water 11kg；It is added dropwise and continues stirring 40 minutes；Filters pressing, filter cake are eluted with 120kg tetrahydrofuran filters pressing, and decompression steams four
Hydrogen furans；Add toluene 220kg to be heated to 90~100 DEG C of dissolved clarifications, be cooled to room temperature crystallization, is centrifuged, obtains 1,2- diphenyl -1- [4-
[2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol crude product；Crude product is used in 500L glassed steel reaction vessels
150kg toluene is heated to 90~100 DEG C of dissolved clarifications, is down to room temperature crystallization, and the solid after centrifugation obtains off-white color in 70 DEG C of decompression dryings
Solid 1,2- diphenyl -1- [4- [2- (N, N- dimethylamino) ethyoxyl] phenyl] -1,4-butanediol.
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| CN106187791A (en) * | 2016-04-19 | 2016-12-07 | 福安药业集团宁波天衡制药有限公司 | The new preparation process of Toremifene Citrate intermediate |
| CN110305024B (en) * | 2018-03-27 | 2021-09-28 | 鲁南制药集团股份有限公司 | Synthetic method of Beloraib intermediate |
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| EP2459517A1 (en) * | 2009-07-31 | 2012-06-06 | Ranbaxy Laboratories Limited | Polymorphic form of toremifene citrate and process for its preparation |
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| CN106187791A (en) | 2016-12-07 |
| CN106966911A (en) | 2017-07-21 |
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