CN114276384A - Synthesis method of demethyl olopatadine and intermediate thereof - Google Patents
Synthesis method of demethyl olopatadine and intermediate thereof Download PDFInfo
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- CN114276384A CN114276384A CN202210016513.6A CN202210016513A CN114276384A CN 114276384 A CN114276384 A CN 114276384A CN 202210016513 A CN202210016513 A CN 202210016513A CN 114276384 A CN114276384 A CN 114276384A
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- demethylolopatadine
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- triphenylphosphine
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- -1 demethyl olopatadine Chemical compound 0.000 title claims abstract description 66
- 229960004114 olopatadine Drugs 0.000 title claims abstract description 41
- 238000001308 synthesis method Methods 0.000 title claims description 17
- 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 abstract description 87
- 239000002904 solvent Substances 0.000 claims abstract description 83
- 239000012074 organic phase Substances 0.000 claims abstract description 48
- 239000002994 raw material Substances 0.000 claims abstract description 44
- 238000003756 stirring Methods 0.000 claims abstract description 29
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 28
- 229910052751 metal Inorganic materials 0.000 claims abstract description 28
- 239000002184 metal Substances 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 21
- 239000003513 alkali Substances 0.000 claims abstract description 20
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 20
- 238000001035 drying Methods 0.000 claims abstract description 20
- 238000010438 heat treatment Methods 0.000 claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 20
- PQIYSSSTRHVOBW-UHFFFAOYSA-N 3-bromopropan-1-amine;hydron;bromide Chemical compound Br.NCCCBr PQIYSSSTRHVOBW-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000605 extraction Methods 0.000 claims abstract description 19
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000007787 solid Substances 0.000 claims abstract description 18
- 239000002274 desiccant Substances 0.000 claims abstract description 14
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 238000010189 synthetic method Methods 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 9
- 239000007789 gas Substances 0.000 claims abstract description 7
- 230000001681 protective effect Effects 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 76
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 238000010791 quenching Methods 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 230000000171 quenching effect Effects 0.000 claims description 24
- COPZBGVEAWELFU-UHFFFAOYSA-M 3-(methylamino)propyl-triphenylphosphanium;bromide Chemical group [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCNC)C1=CC=CC=C1 COPZBGVEAWELFU-UHFFFAOYSA-M 0.000 claims description 23
- UPYKKMDXNPTXPZ-UHFFFAOYSA-M 3-aminopropyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCN)C1=CC=CC=C1 UPYKKMDXNPTXPZ-UHFFFAOYSA-M 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 16
- 238000001953 recrystallisation Methods 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 238000004440 column chromatography Methods 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 230000002194 synthesizing effect Effects 0.000 claims description 14
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229950011455 isoxepac Drugs 0.000 claims description 12
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 12
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 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
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 229960001701 chloroform Drugs 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 abstract description 6
- 238000001914 filtration Methods 0.000 abstract description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 13
- 230000001276 controlling effect Effects 0.000 description 12
- 238000001514 detection method Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000011162 core material Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- WCRQUKCFPDWETG-UHFFFAOYSA-N NCCCC(C=CC=C1)=C1P(C1=CC=CC=C1)C1=CC=CC=C1.Br Chemical compound NCCCC(C=CC=C1)=C1P(C1=CC=CC=C1)C1=CC=CC=C1.Br WCRQUKCFPDWETG-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VQMJUHOJPCPUAM-IDUWFGFVSA-N N-Monodemethylolopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCNC)\C2=CC=CC=C21 VQMJUHOJPCPUAM-IDUWFGFVSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- POCGFRCQICXVJO-SOFYXZRVSA-N 2-[(11z)-11-(3-aminopropylidene)-6h-benzo[c][1]benzoxepin-2-yl]acetic acid Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN)\C2=CC=CC=C21 POCGFRCQICXVJO-SOFYXZRVSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- HVRLZEKDTUEKQH-NOILCQHBSA-N Olopatadine hydrochloride Chemical compound Cl.C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 HVRLZEKDTUEKQH-NOILCQHBSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229960003139 olopatadine hydrochloride Drugs 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- PBXUTOSYJJQBIP-UHFFFAOYSA-N BrCCCC(C=CC=C1)=C1P(C1=CC=CC=C1)C1=CC=CC=C1.Br Chemical compound BrCCCC(C=CC=C1)=C1P(C1=CC=CC=C1)C1=CC=CC=C1.Br PBXUTOSYJJQBIP-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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Abstract
The application relates to the field of drug synthesis, and discloses a synthetic method of demethyl olopatadine and an intermediate thereof, wherein the synthetic method of the demethyl olopatadine intermediate comprises the following steps: adding a solvent, triphenylphosphine and a first raw material, and heating and stirring under a protective gas atmosphere; distilling under reduced pressure until the organic phase is dry, adding water, adding an extraction solvent, separating the liquid and keeping an organic phase, washing the organic phase by using a neutralizing alkali solution, separating the liquid and keeping the organic phase, drying the organic phase by using a drying agent, and distilling until the organic phase is dry; recrystallizing, filtering to obtain white solid, and drying the white solid to constant weight; the first raw material is (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide. In the application, the first raw material is introduced to react with triphenylphosphine respectively, and hydrogen bromide molecules of an intermediate are directly neutralized and removed, so that the consumption of a metal reducing agent is reduced in the subsequent synthesis of demethylolopatadine, and the purposes of high efficiency and safety risk reduction are achieved.
Description
Technical Field
The application relates to the field of drug synthesis, and mainly relates to a synthetic method of demethylolopatadine and an intermediate thereof.
Background
N-demethylolopatadine and N, N-dedimethylolopatadine are commonly used to calibrate novel H1Impurities in olopatadine hydrochloride as receptor antagonist to determine the purity of olopatadine hydrochloride. Chemical name of N-demethylolopatadine (N-Desmethyl Olopatadine): (Z) -11- [3- (methylamino) propylene]-6, 11-dihydrodibenzo [ 2 ]b,e]Oxazepine-2-acetic acid, 2- [ (11Z) -11- [3- (methylamino)
propylidene]-6H-benzo[c][1]benzoxepin-2-yl]acetic acid, CAS: 113835-92-0. Chemical name of N, N-dedimethyl Olopatadine (N, N-Didesmethyl Olopatadine): (Z) -11- [3- (amino) propylidene group]-6, 11-dihydrodibenzo [ 2 ]b,e]Oxazepine-2-acetic acid, 2- [ (11Z) -11- [3- (amino) propylidene]-6H-benzo[c][1]benzoxepin-2-yl]acetic acid, CAS: 113835-94-2. The structural formulas of N-demethylolopatadine, N-demethylolopatadine and olopatadine are respectively shown as the following formulas:
the methods for obtaining N-demethylolopatadine and N, N-demethylolopatadine are few, and a target product can be synthesized by referring to an olopatadine synthesis method, wherein a compound containing a tertiary amine structure is replaced by a compound containing a primary amine or secondary amine structure in the synthesis process, and then the olopatadine synthesis method is adopted.
For example, EP0235796 reports the synthesis of (3-methylaminopropyl) triphenylphosphine bromide hydrobromide and (3-aminopropyl) triphenylphosphine bromide hydrobromide using (3-bromopropyl) triphenylphosphine bromide, methylamine, ammonia as initial solvents, which are combined with isoxofenac to synthesize trans-N-desmethyl olopatadine methyl ester, trans-N, N-desmethyl olopatadine methyl ester and N, N-desmethyl olopatadine methyl ester, which are obtained by column chromatography. And hydrolyzing the N-demethylolopatadine methyl ester and the N, N-dedimethyl olopatadine methyl ester to obtain the N-demethylolopatadine and the N, N-dedimethyl olopatadine. In the synthesis method, high-temperature reaction is needed in the synthesis process, the reaction risk is increased by dangerous chemicals such as n-butyllithium and the like, and the overall yield is seriously reduced due to the long reaction steps. The synthetic route is shown as the following formula:
accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the above-mentioned shortcomings of the prior art, the present application aims to provide a method for synthesizing demethylolopatadine and its intermediate, which aims to solve the problems of complex synthetic route and low yield of the existing N-demethylolopatadine and N, N-dedimethylamolopatadine.
The technical scheme of the application is as follows:
a synthetic method of an intermediate of demethyl olopatadine, wherein the intermediate of demethyl olopatadine is (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide, and comprises the following steps:
adding a first solvent, triphenylphosphine and a first raw material, and heating and stirring under a protective gas atmosphere;
distilling under reduced pressure until the organic phase is dry, adding water, adding an extraction solvent, separating the liquid and keeping an organic phase, washing the organic phase by using a neutralizing alkali solution, separating the liquid and keeping the organic phase, drying the organic phase by using a drying agent, and distilling until the organic phase is dry;
adding a recrystallization solvent, recrystallizing, performing suction filtration to obtain a white solid, and drying the white solid to constant weight;
the first raw material is (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide;
when the first raw material is the (3-bromopropyl) (N-methyl) amine hydrobromide, the prepared product is (3-methylaminopropyl) triphenyl phosphonium bromide; when the first raw material is the 3-bromopropylamine hydrobromide, the product prepared is (3-aminopropyl) triphenyl phosphonium bromide.
In the application, the (3-bromopropyl) (N-methyl) amine hydrobromide and the 3-bromopropylamine hydrobromide are respectively introduced to react with triphenylphosphine, and then hydrogen bromide molecules of an intermediate are directly neutralized and removed, so that the metal reducing agent dosage is reduced in the subsequent synthesis of N-demethylolopatadine and N, N-dedimethylamolopatadine, and the purposes of high efficiency and safety risk reduction are achieved.
The synthesis method of the intermediate of demethyl olopatadine is characterized in that the molar ratio of the triphenylphosphine to the (3-bromopropyl) (N-methyl) amine hydrobromide is 1: (1.1-2.3);
the molar ratio of the triphenylphosphine to the 3-bromopropylamine hydrobromide is 1: (1.1-2.4).
Triphenylphosphine is too much worked up to remove unreacted triphenylphosphine, so triphenylphosphine is less abundant than (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide, which are another core material.
The synthesis method of the intermediate of demethyl olopatadine comprises the following steps of (1) taking argon or nitrogen as protective gas;
the first solvent is one of isopropanol, propanol, mixed propanol, acetonitrile, n-butanol, tert-butanol or isobutanol, and the mass ratio of the first solvent to the triphenylphosphine is (4-7): 1;
the extraction solvent is one of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, 1-dichloroethane, ethyl acetate, toluene or benzene; the mass ratio of the water to the triphenylphosphine is (5-7): 1, the mass ratio of the extraction solvent to the triphenylphosphine is (10-15): 1;
the neutralizing alkali is one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia water, diethylamine or triethylamine; the mass concentration range of the neutralizing alkali solution is 10-30%, and the mass ratio of the content of the neutralizing alkali in the neutralizing alkali solution to the triphenylphosphine is (0.2-0.6): 1;
the drying agent is one of anhydrous sodium sulfate, anhydrous magnesium sulfate or a molecular sieve, and the mass ratio of the drying agent to triphenylphosphine is (0.5-1): 1;
the recrystallization solvent is one of tetrahydrofuran, dioxane, acetonitrile, ethyl acetate or diethyl ether; the mass ratio of the recrystallization solvent to the triphenylphosphine is (1-2): 1.
the synthesis method of the intermediate of demethyl olopatadine is characterized in that the first solvent is isopropanol;
the extraction solvent is dichloromethane;
the neutralizing alkali is sodium hydroxide;
the drying agent is anhydrous sodium sulfate;
the recrystallization solvent is tetrahydrofuran.
The synthesis method of the demethyl olopatadine intermediate comprises the following steps of heating to 75-82 ℃ and stirring for 10-16 hours;
the recrystallization process comprises the steps of heating to a material dissolution temperature range of 60-66 ℃, and then cooling to a material crystallization temperature range of-5 ℃;
and the temperature is controlled to be 55-65 ℃ in the drying process.
A synthetic method of demethyl olopatadine, wherein the demethyl olopatadine is N-demethyl olopatadine or N, N-demethyl olopatadine, comprises the following steps:
preparing a second raw material by adopting the synthesis method of the intermediate of the demethyl olopatadine, wherein the second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide;
adding the second raw material and a second solvent, starting stirring, controlling the temperature, adding a metal reducing agent, controlling the temperature after the addition, and reacting for a plurality of hours;
adding isoxofenac, stirring for a plurality of hours at a controlled temperature, cooling, adding a first quenching solvent, adding a second quenching solvent, and finally adding water to quench and react;
adding acid to adjust pH value, distilling under reduced pressure to dryness, and separating by column chromatography;
when the second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide, the prepared product is N-demethylolopatadine; when the second raw material is (3-aminopropyl) triphenyl phosphonium bromide, the prepared product is N, N-dedimethyl olopatadine.
The synthesis method of demethyl olopatadine comprises the following steps of (1.5-2.5): 1;
when the second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide, adjusting the pH value to 7.2-7.8; and when the second raw material is (3-aminopropyl) triphenyl phosphonium bromide, adjusting the pH value to 8.0-8.4.
The synthesis method of demethyl olopatadine comprises the following steps of (1) preparing a second solvent, wherein the second solvent is one of tetrahydrofuran, chloroform or toluene, and the mass ratio of the solvent to isoxeloxolone is (5-15): 1;
the metal reducing agent is one of potassium hydride, sodium hydride, calcium hydride, n-butyl lithium, tert-butyl lithium or lithium aluminum hydride, the mass concentration range of the metal reducing agent is 30-35%, and the mass ratio of the content of the metal reducing agent in the metal reducing agent to the isoxofenac is (0.4-0.8): 1;
the first quenching solvent is absolute methanol or absolute ethanol, and the mass ratio of the first quenching solvent to the isoxepac is (0.2-0.4): 1, the second quenching solvent is a tetrahydrofuran aqueous solution, the mass concentration of the tetrahydrofuran aqueous solution is 40-60%, and the mass ratio of the tetrahydrofuran content in the tetrahydrofuran aqueous solution to the isoxepac is (1.5-2.5): 1; the mass ratio range of the water to the isoxepac is (10-20): 1;
the acid is one of hydrochloric acid, sulfuric acid or acetic acid;
in the column chromatography separation process, the eluent is an ethyl acetate and methanol system, an ethyl acetate and ethanol system or an ethyl acetate and acetone system, and the filler in the chromatographic column is silica gel and alkaline alumina.
The synthesis method of demethyl olopatadine is characterized in that the second solvent is tetrahydrofuran;
the metal reducing agent is potassium hydride;
the first quenching solvent is absolute methanol;
the acid is concentrated hydrochloric acid, and the mass concentration of the concentrated hydrochloric acid is 20-38%;
the eluent is an ethyl acetate and methanol system, and the proportion of ethyl acetate to methanol is (6-10): 1.
the synthesis method of demethyl olopatadine comprises the following steps of controlling the temperature, wherein the step of adding the metal reducing agent is to control the temperature to be 18-25 ℃, and adding the metal reducing agent;
controlling the temperature after the addition, wherein the reaction is carried out for a plurality of hours, specifically controlling the temperature to be 58-66 ℃ after the addition, and reacting for 1-2 hours;
the process of adding the isoxaglic acid, stirring for a plurality of hours at a controlled temperature and then cooling specifically comprises the steps of adding the isoxaglic acid, stirring for 1.5-3.5 hours at a controlled temperature of 58-66 ℃, and then cooling to 5-10 ℃.
Has the advantages that: the synthetic method of demethyl olopatadine provided by the application upgrades and reforms key steps on the basis of the prior art, and has the following advantages: 1. unnecessary molecules are removed from the intermediate, so that the risk of the next reaction is reduced; 2. reaction steps are reduced, loss is reduced, and production efficiency is improved; 3. the metal reducing agent is replaced, and the reaction and post-treatment risks are reduced; 4. the post-treatment is simple and the direct separation is realized; 5. the reaction condition is mild, and the requirement on equipment is not high; 6. high yield and high quality.
Drawings
Fig. 1 is a diagram showing the HPLC detection result of N-desmethyl olopatadine obtained in example 1 of the present application.
Fig. 2 is a graph showing the HPLC detection result of the product N, N-dedimethylamolopatadine obtained in example 2 of the present application.
Fig. 3 is a diagram showing the HPLC detection result of the product N-desmethyl olopatadine obtained in example 3 of the present application.
Fig. 4 is a graph showing the HPLC detection result of the product N, N-dedimethylamolopatadine obtained in example 4 of the present application.
Detailed Description
The present application provides a method for synthesizing demethylolopatadine and a method for synthesizing an intermediate thereof, which are further described in detail below in order to make the objects, technical schemes and effects of the present application clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
In the present application, the intermediate of demethylolopatadine is (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide, and demethylolopatadine is N-demethylolopatadine or N, N-dedimethylamolopatadine.
In the present application, reference is made to compounds comprising: triphenylphosphine (CAS: 603-35-0), (3-bromopropyl) (N-methyl) amine hydrobromide (CAS: 60035-88-3), 3-bromopropylamine hydrobromide (CAS: 5003-71-4), (3-methylaminopropyl) triphenylphosphine bromide (CAS: 145126-87-0), (3-aminopropyl) triphenylphosphine bromide (CAS: 89996-01-0), and isoxeloxolic acid (CAS: 55453-87-7), each having the following molecular structure:
the application provides a method for synthesizing an intermediate of demethyl olopatadine, which comprises the steps of introducing (3-bromopropyl) (N-methyl) amine hydrobromide and 3-bromopropylamine hydrobromide to react with triphenylphosphine respectively, and then directly neutralizing and removing hydrogen bromide molecules of the intermediate, so that the metal reducing agent consumption is reduced in the subsequent synthesis of N-demethyl olopatadine and N, N-demethyl olopatadine, and the purposes of high efficiency and safety risk reduction are achieved.
Specifically, the synthesis method of the intermediate of demethyl olopatadine is (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide, and comprises the following steps:
adding a first solvent, triphenylphosphine and a first raw material, and heating and stirring under a protective gas atmosphere;
distilling under reduced pressure until the organic phase is dry, adding water, adding an extraction solvent, separating the liquid and keeping an organic phase, washing the organic phase by using a neutralizing alkali solution, separating the liquid and keeping the organic phase, drying the organic phase by using a drying agent, and distilling until the organic phase is dry;
adding a recrystallization solvent, recrystallizing, filtering to obtain a white solid, and drying the white solid until the weight is constant to obtain the (3-methylaminopropyl) triphenyl phosphonium bromide or the (3-aminopropyl) triphenyl phosphonium bromide.
The first raw material is (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide. When the first raw material is (3-bromopropyl) (N-methyl) amine hydrobromide, the prepared product is (3-methylaminopropyl) triphenyl phosphine bromide; when the first starting material was 3-bromopropylamine hydrobromide, the product prepared was (3-aminopropyl) triphenylphosphine bromide.
Triphenylphosphine is used as a core raw material of a chemical reaction, participates in the building of a chemical structure, and excessive triphenylphosphine is not beneficial to removing unreacted triphenylphosphine during aftertreatment, so that the triphenylphosphine is less than (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide serving as another core raw material. Thus, in the present application, the triphenylphosphine to (3-bromopropyl) (N-methyl) amine hydrobromide molar ratio was 1: (1.1-2.3); the molar ratio of triphenylphosphine to 3-bromopropylamine hydrobromide is 1: (1.1-2.4).
The first solvent can be one of isopropanol, propanol, mixed propanol, acetonitrile, n-butanol, tert-butanol or isobutanol, and the mass ratio of the first solvent to triphenylphosphine can be (4-7): 1. in the scheme of the embodiment of the application, isopropanol is taken as a first solvent, the temperature required by the reaction can be reached, two products can be dissolved, the same effect can be achieved if other alternative solvents are replaced, only the problem of the reaction time is solved, and the other alternative solvents are n-propanol, mixed propanol, acetonitrile, n-butanol, tert-butanol and isobutanol.
The protective gas may be argon or nitrogen. The heating and stirring process is specifically heating to 75-82 ℃ and stirring for 10-16 hours.
In the embodiment of the present application, the first solvent and the subsequent extraction solvent have a certain mutual solubility, so the first solvent is removed by distillation and then extracted. After distillation, water is selected for dissolving and then extraction by the extraction solvent, but the extraction solvent is not directly taken for filtration, because two phases are both liquid phase, the product can be extracted more completely, the yield is improved, the liquid separation of the organic phase and the aqueous phase is simpler in actual production compared with filtration, the solid which is not dissolved by the extraction solvent is likely to form large solid, the discharge and filtration from a bottom valve of a production kettle are not facilitated in actual production, and the unreacted raw material (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide can be dissolved in dichloromethane and always exists as impurities if the unreacted raw material is anhydrous.
The extraction solvent can be one of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, 1-dichloroethane, ethyl acetate, toluene or benzene. After the vacuum distillation is carried out till the water is dried, the mass ratio of the added amount of the water to the triphenylphosphine can be (5-7): 1, the mass ratio of the addition amount of the extraction solvent to the triphenylphosphine can be (10-15): 1. in the scheme of the embodiment of the application, dichloromethane is selected as an extraction solvent, because the dichloromethane is strong in intersolubility with products, low in toxicity, low in price, low in boiling point, easy to distill and immiscible with water, and can be used for separating liquid. Other alternative extraction solvents may be chloroform, carbon tetrachloride, 1, 2-dichloroethane, 1-dichloroethane, ethyl acetate, toluene or benzene.
The neutralizing base can be one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia, diethylamine or triethylamine. In the step, the mass concentration range of the neutralizing alkali solution can be 10-30%, and the mass ratio range of the content of the neutralizing alkali in the neutralizing alkali solution to the triphenylphosphine can be (0.2-0.6): 1. in the scheme of the embodiment of the application, the organic phase selects a sodium hydroxide solution as a neutralizing alkali solution for agitation washing, and the main purpose is to remove hydrobromic acid molecules in (3-methylaminopropyl) triphenylphosphine bromide hydrobromide or (3-aminopropyl) triphenylphosphine bromide hydrobromide so as to obtain a free product of (3-methylaminopropyl) triphenylphosphine bromide or (3-aminopropyl) triphenylphosphine bromide, and meanwhile, the sodium hydroxide is convenient and easy to obtain, has low price and is beneficial to industrial production. Besides sodium hydroxide solution, the neutralizing alkali solution can also be a solution prepared from potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia water, diethylamine or triethylamine, and the solutions also have the same effect.
In the process of drying the organic phase by using the drying agent, the drying agent can be one of anhydrous sodium sulfate, anhydrous magnesium sulfate or a molecular sieve, and the mass ratio of the addition amount of the drying agent to the triphenylphosphine can be (0.5-1): 1.
the organic phase is dried by a drying agent and then distilled to be dry, and then recrystallized by a recrystallization solvent, so that the product can be effectively dissolved, cooled and separated out, and impurities can be well removed to achieve the purpose of purification. The recrystallization solvent may be one of tetrahydrofuran, dioxane, acetonitrile, ethyl acetate or diethyl ether. The recrystallization process comprises the steps of heating and cooling, wherein the temperature is raised to a temperature range of 60-66 ℃ for dissolving the material, and the temperature is cooled to a temperature range of-5 ℃ for crystallizing the material. The mass ratio of the addition amount of the recrystallization solvent to the triphenylphosphine can be (1-2): 1. in the embodiment of the present application, the recrystallization solvent is tetrahydrofuran, and the replaceable solvent is dioxane, acetonitrile, ethyl acetate or diethyl ether.
The temperature is controlled to be 55-65 ℃ in the drying process, and a hot air circulation oven, a vacuum oven, a double-cone dryer or a fluidized bed can be used.
The application also provides a synthetic method of demethyl olopatadine, wherein the demethyl olopatadine is N-demethyl olopatadine or N, N-demethyl olopatadine, an intermediate of the demethyl olopatadine obtained by the synthetic method is used as a second raw material, the using amount of a metal reducing agent can be reduced, meanwhile, an isomer is directly separated in subsequent post-treatment to obtain a target product, the step of separating into ester and then hydrolyzing is omitted, the reaction step is reduced, the synthetic route of the demethyl olopatadine is simplified, and the yield is improved.
Specifically, the synthesis method of demethyl olopatadine comprises the following steps:
adding a second raw material and a second solvent, starting stirring, controlling the temperature to be 18-25 ℃, adding a metal reducing agent, controlling the temperature to be 58-66 ℃ after the addition, and reacting for 1-2 hours;
adding isoxofenac, controlling the temperature to be 58-66 ℃, stirring for 1.5-3.5 hours, cooling to 5-10 ℃, slowly adding a first quenching solvent, then adding a second quenching solvent, and finally adding water to quench and react;
regulating the pH of the reaction solution by acid, then distilling the reaction solution under reduced pressure to dryness, and separating the dried product by column chromatography to obtain the finished product of N-demethylolopatadine or N, N-demethylolopatadine.
The second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide, and the mass ratio of the second raw material to the isoxepac is (1.5-2.5): 1. when the second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide, the prepared product is N-demethylolopatadine; when the second raw material is (3-aminopropyl) triphenyl phosphonium bromide, the prepared product is N, N-dedimethyl olopatadine. The (3-methylaminopropyl) triphenyl phosphonium bromide or the (3-aminopropyl) triphenyl phosphonium bromide is uniform free alkali, so that the use amount of the metal reducing agent can be effectively reduced, and the production risk can be reduced. The second raw material is a core raw material for synthesizing a finished product, participates in the construction of a product structure, and has no other replaceable raw materials.
The isoxelode is a core raw material for synthesizing a finished product and participates in the structure construction of the product. Although isoxaglac acid methyl ester can be used instead of isoxaglac acid, hydrolysis into products is also carried out after the reaction is finished, and the yield is reduced by increasing the reaction steps. Therefore, in the present application, isoxepac is selected as one of the core raw materials.
The second solvent can be one of tetrahydrofuran, chloroform or toluene, and the mass ratio of the second solvent to the isoxepac is (5-15): 1. in the scheme of the embodiment of the application, tetrahydrofuran is selected as the second solvent, the temperature required by the reaction can be reached, two products can be dissolved, the same effect can be achieved if other alternative solvents are used, and the problem is only the reaction time. Other alternative solvents are chloroform or toluene.
The metal reducing agent can be one of potassium hydride, sodium hydride, calcium hydride, n-butyl lithium, tert-butyl lithium or lithium aluminum hydride, the mass concentration range of the metal reducing agent can be 30-35%, and the mass ratio of the content of the metal reducing agent in the metal reducing agent to the isoxofenac is (0.4-0.8): 1. in the scheme of the embodiment of the application, potassium hydride is used as a metal reducing agent, so that oxygen atoms of ketone carbonyl in isoxofenac can be effectively extracted to be activated, and bromine atoms in (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide can be extracted to achieve the purpose of activation and promote the reaction. Compared with other metal reducing agents, the potassium hydride is mild, can reduce the production risk and is beneficial to industrialization. If the synthesis efficiency and safety are not considered, sodium hydride, calcium hydride, n-butyllithium, t-butyllithium or lithium aluminum hydride may be substituted.
In the application, the first quenching solvent is absolute methanol or absolute ethanol, and the mass ratio of the first quenching solvent to the isoxepac is (0.2-0.4): 1, the second quenching solvent is a tetrahydrofuran aqueous solution, the mass concentration of the tetrahydrofuran aqueous solution is 40-60%, and the mass ratio of the tetrahydrofuran content in the tetrahydrofuran aqueous solution to the isoxepac is (1.5-2.5): 1. in the embodiment of the present application, the combination of anhydrous methanol and tetrahydrofuran aqueous solution is selected as the quenching solvent, because the quenching is usually methanol or water, and the direct reaction of water and unreacted potassium hydride in the system is more severe, the anhydrous methanol and tetrahydrofuran aqueous solution is selected for gradual quenching in this application, so as to reduce the safety risk and also effectively control the temperature to improve the quenching efficiency.
In the application, in the process of finally adding water for quenching reaction, the mass ratio of water to isoxepac is (10-20): 1.
in the present application, the acid may be one of hydrochloric acid, sulfuric acid, or acetic acid. In the scheme of the embodiment of the application, concentrated hydrochloric acid is selected to adjust the pH value, the mass concentration of the concentrated hydrochloric acid is 20% -38%, the concentrated hydrochloric acid is cheaper and commonly used than other acids, and hydrochloric acid, sulfuric acid or acetic acid can also be used as substitutes. When the second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide, adjusting the pH value to 7.2-7.8; and when the second raw material is (3-aminopropyl) triphenyl phosphonium bromide, adjusting the pH value to 8.0-8.4.
In the application, the eluent used in the column chromatography separation process can be an ethyl acetate and methanol system, an ethyl acetate and ethanol system or an ethyl acetate and acetone system; the filler in the chromatographic column can be silica gel and basic alumina. In the scheme of the embodiment of the application, a system of ethyl acetate and methanol is selected, and the proportion of ethyl acetate to methanol is (6-10): 1, because the ethyl acetate and the methanol are cheap and easy to obtain, the system can be replaced by an ethyl acetate and ethanol system or an ethyl acetate and acetone system.
The synthetic method of demethyl olopatadine provided by the application upgrades and reforms key steps on the basis of the prior art, and has the following advantages:
1. by replacing the initial raw materials, the whole reaction steps are reduced from 4 steps to 2 steps, and the intermediate and the demethylolopatadine are synthesized, wherein the synthetic route is shown as the following formula, so that the materials are saved, and the total yield is effectively improved:
2. reaction conditions are improved, the generation of impurities and isomers is effectively reduced, and the yield of a target product is improved;
3. the post-treatment difficulty is reduced, and the quality and the yield are ensured;
4. the post-treatment conditions are optimized, the ultra-high temperature harsh reaction is eliminated, and the dependence on equipment is reduced;
5. the whole reaction is simple and easy to operate, and the synthesis is stable without special requirements, thus being suitable for industrial production.
The present invention is further illustrated by the following specific examples.
Example 1
Synthesis of (3-methylaminopropyl) triphenyl phosphine bromide
Into a four-necked flask were charged 150g of isopropyl alcohol, 26.2g of triphenylphosphine and 28.0g of (3-bromopropyl) (N-methyl) amine hydrobromide. Stirring at 80 ℃ for 15 hours under the protection of nitrogen. Distilling under reduced pressure until the mixture is dry, adding 150g of water, adding 300g of dichloromethane, separating the mixture to keep an organic phase, washing the organic phase by 50g of 20% sodium hydroxide solution, separating the mixture to keep the organic phase, drying the organic phase by 20g of anhydrous sodium sulfate, distilling until the organic phase is dry, adding 50g of tetrahydrofuran, heating to 65 ℃, cooling to 0 ℃, carrying out suction filtration to obtain a white solid, and drying the solid in an oven at 60 ℃ until the weight is constant. 27.1g of (3-methylaminopropyl) triphenyl phosphonium bromide is obtained, and the yield of the step is 65.5 percent.
Synthesis of di, N-demethylolopatadine
Adding 20.7g of (3-methylaminopropyl) triphenyl phosphonium bromide into a three-necked bottle, adding 100g of anhydrous tetrahydrofuran, starting stirring, controlling the temperature to be 20 ℃, adding 17g of 30% potassium hydride, heating to 65 ℃ after the addition, and reacting for 1 h. Then adding 10.7g of isoxolone, stirring for 2 hours at 65 ℃, cooling to 8 ℃, slowly adding 3g of anhydrous methanol, then adding 40g of tetrahydrofuran aqueous solution with the mass concentration of 50%, and finally adding 160g of water to quench and react. The reaction solution is adjusted to pH =7.5 by concentrated hydrochloric acid (mass concentration is 30%), then the reaction solution is distilled under reduced pressure until the reaction solution is dried, the dried product is subjected to column chromatography (ethyl acetate: methanol =9: 1) (200-300 mesh column chromatography silica gel) to obtain a finished product of N-demethylolopatadine, and HPLC detection results are shown in figure 1 and table 1, wherein the purity is 99.78% (Z/E = 99.78: 0.22), the yield is 7.9g, and the yield in the step is 61.3%.
TABLE 1
Example 2
Synthesis of (3-aminopropyl) triphenyl phosphine bromide
Into a four-necked flask were charged 150g of isopropyl alcohol, 26.2g of triphenylphosphine and 26.3g of 3-bromopropylamine hydrobromide. Stirring at 80 ℃ for 15 hours under the protection of nitrogen. Distilling under reduced pressure until the mixture is dry, adding 150g of water, adding 300g of dichloromethane, separating the mixture to keep an organic phase, washing the organic phase by 50g of 20% sodium hydroxide solution, separating the mixture to keep the organic phase, drying the organic phase by 20g of anhydrous sodium sulfate, distilling until the organic phase is dry, adding 50g of tetrahydrofuran, heating to 65 ℃, cooling to 0 ℃, carrying out suction filtration to obtain a white solid, and drying the solid in an oven at 60 ℃ until the weight is constant. To obtain 20.1g of (3-aminopropyl) triphenyl phosphonium bromide, and the yield of the step is 64.9%.
Synthesis of di, N-demethylolopatadine
Adding 20.0g of (3-aminopropyl) triphenyl phosphonium bromide into a three-necked bottle, then adding 100g of anhydrous tetrahydrofuran, starting stirring, controlling the temperature to be 20 ℃, adding 17g of 30% potassium hydride, heating to 65 ℃ after the addition, and reacting for 1 h. Then adding 10.7g of isoxolone, stirring for 2 hours at 65 ℃, cooling to 8 ℃, slowly adding 3g of anhydrous methanol, then adding 40g of tetrahydrofuran aqueous solution with the mass concentration of 50%, and finally adding 160g of water to quench and react. The reaction solution is adjusted to pH =8.0 by concentrated hydrochloric acid (mass concentration of 30%), then the reaction solution is distilled under reduced pressure to be dry, the dry product is subjected to column chromatography (ethyl acetate: methanol =9: 1) (200-300 mesh column chromatography silica gel) to obtain a finished product of N, N-demethylolopatadine, and HPLC detection results are shown in figure 2 and table 2, wherein the purity is 99.71% (Z/E = 99.76: 0.18), the yield is 7.8g, and the yield of the step is 60.5%.
TABLE 2
Example 3
Synthesis of (3-methylaminopropyl) triphenyl phosphine bromide
Into a four-necked flask were charged 200g of isopropyl alcohol, 34.1g of triphenylphosphine and 36.4g of (3-bromopropyl) (N-methyl) amine hydrobromide. Stirring was carried out at 76 ℃ for 13 hours under nitrogen. Distilling under reduced pressure until the mixture is dry, adding 200g of water, adding 400g of dichloromethane, separating the mixture to keep an organic phase, washing the organic phase by using 70g of 20% sodium hydroxide solution, separating the mixture to keep the organic phase, drying the organic phase by using 30g of anhydrous sodium sulfate, distilling until the organic phase is dry, adding 65g of tetrahydrofuran, heating to 60 ℃, cooling to 2 ℃, performing suction filtration to obtain a white solid, and drying the solid in an oven at 65 ℃ to constant weight. 35.1g of (3-methylaminopropyl) triphenyl phosphonium bromide is obtained, and the yield of the step is 65.2 percent.
Synthesis of di, N-demethylolopatadine
Adding 26.9g of (3-methylaminopropyl) triphenyl phosphonium bromide into a three-necked bottle, adding 150g of anhydrous tetrahydrofuran, starting stirring, controlling the temperature to be 22 ℃, adding 19g of 35% potassium hydride, heating to 62 ℃ after the addition, and reacting for 2 hours. Then 13.9g of isoxolone is added, stirred for 3 hours at 62 ℃, cooled to 6 ℃, 4g of anhydrous methanol is slowly added, 65g of tetrahydrofuran aqueous solution with the mass concentration of 40 percent is added, and finally 200g of water is added for quenching reaction. The reaction solution is adjusted to pH =7.2 by concentrated hydrochloric acid (mass concentration of 30%), then the reaction solution is distilled under reduced pressure to be dry, the dry product is subjected to column chromatography (ethyl acetate: methanol =7: 1) (200-300 mesh column chromatography silica gel) to obtain a finished product of N-demethylolopatadine, and HPLC detection results are shown in fig. 3 and table 3, wherein the purity is 99.76% (Z/E = 99.71: 0.22), the yield is 10.1g, and the yield of the step is 60.1%.
TABLE 3
Example 4
Synthesis of (3-aminopropyl) triphenyl phosphine bromide
Into a four-necked flask were charged 200g of isopropyl alcohol, 34.1g of triphenylphosphine and 34.2g of 3-bromopropylamine hydrobromide. Stirring was carried out at 77 ℃ for 14 hours under nitrogen. Distilling under reduced pressure until the mixture is dry, adding 200g of water, adding 400g of dichloromethane, separating the mixture to keep an organic phase, washing the organic phase by 72g of 20% sodium hydroxide solution, separating the mixture to keep the organic phase, drying the organic phase by 30g of anhydrous sodium sulfate, distilling until the organic phase is dry, adding 65g of tetrahydrofuran, heating to 61 ℃, cooling to 1 ℃, carrying out suction filtration to obtain a white solid, and drying the solid in an oven at 63 ℃ until the weight is constant. 26.2g of (3-aminopropyl) triphenyl phosphonium bromide is obtained, and the yield of the step is 64.8 percent.
Synthesis of di, N-demethylolopatadine
Adding 26.0g of (3-aminopropyl) triphenyl phosphonium bromide into a three-necked bottle, adding 160g of anhydrous tetrahydrofuran, starting stirring, controlling the temperature to be 23 ℃, adding 20g of 35% potassium hydride, heating to 62 ℃ after the addition, and reacting for 1.5 h. Then 13.9g of isoxolone is added, the mixture is stirred for 2.5 hours at the temperature of 64 ℃, then the temperature is reduced to 7 ℃, 4g of anhydrous methanol is slowly added, 44g of tetrahydrofuran aqueous solution with the mass concentration of 60 percent is added, and finally 200g of water is added for quenching reaction. The reaction solution is adjusted to pH =8.2 by concentrated hydrochloric acid (mass concentration of 30%), then the solution is distilled under reduced pressure until the solution is dry, the dry product is subjected to column chromatography (ethyl acetate: methanol =8: 1) (200-300 mesh column chromatography silica gel) to obtain a finished product of N, N-demethylolopatadine with the purity of 99.83% (Z/E = 99.83: 0.17), and HPLC detection results are shown in FIG. 4 and Table 4, the yield is 9.8g, and the yield in the step is 61.3%.
TABLE 4
It can be seen from the above examples that the method successfully synthesizes N-demethylolopatadine and N, N-dedimethylamylopatadine by reducing the reaction steps, the total yield reaches 39.2%, and the method has a good industrial application value. 99.7% of the N-demethylolopatadine and the N, N-demethylolopatadine prepared by the method can be applied to chemical analysis, and can also be applied to biological property research or further synthesis as a medical intermediate.
It should be understood that the application of the present application is not limited to the above examples, and that modifications or changes may be made by those skilled in the art based on the above description, and all such modifications and changes are intended to fall within the scope of the appended claims.
Claims (10)
1. A synthetic method of an intermediate of demethyl olopatadine is characterized in that the intermediate of demethyl olopatadine is (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide, and comprises the following steps:
adding a first solvent, triphenylphosphine and a first raw material, and heating and stirring under a protective gas atmosphere;
distilling under reduced pressure until the organic phase is dry, adding water, adding an extraction solvent, separating the liquid and keeping an organic phase, washing the organic phase by using a neutralizing alkali solution, separating the liquid and keeping the organic phase, drying the organic phase by using a drying agent, and distilling until the organic phase is dry;
adding a recrystallization solvent, recrystallizing, performing suction filtration to obtain a white solid, and drying the white solid to constant weight;
the first raw material is (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide;
when the first raw material is the (3-bromopropyl) (N-methyl) amine hydrobromide, the prepared product is (3-methylaminopropyl) triphenyl phosphonium bromide; when the first raw material is the 3-bromopropylamine hydrobromide, the product prepared is (3-aminopropyl) triphenyl phosphonium bromide.
2. The process for the synthesis of an intermediate of demethylolopatadine according to claim 1, wherein the molar ratio of triphenylphosphine to the (3-bromopropyl) (N-methyl) amine hydrobromide is 1: (1.1-2.3);
the molar ratio of the triphenylphosphine to the 3-bromopropylamine hydrobromide is 1: (1.1-2.4).
3. The method for synthesizing an intermediate of demethylolopatadine according to claim 1, wherein the protective gas is argon or nitrogen;
the first solvent is one of isopropanol, propanol, mixed propanol, acetonitrile, n-butanol, tert-butanol or isobutanol, and the mass ratio of the first solvent to the triphenylphosphine is (4-7): 1;
the extraction solvent is one of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, 1-dichloroethane, ethyl acetate, toluene or benzene; the mass ratio of the water to the triphenylphosphine is (5-7): 1, the mass ratio of the extraction solvent to the triphenylphosphine is (10-15): 1;
the neutralizing alkali is one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia water, diethylamine or triethylamine; the mass concentration range of the neutralizing alkali solution is 10-30%, and the mass ratio of the content of the neutralizing alkali in the neutralizing alkali solution to the triphenylphosphine is (0.2-0.6): 1;
the drying agent is one of anhydrous sodium sulfate, anhydrous magnesium sulfate or a molecular sieve, and the mass ratio of the drying agent to triphenylphosphine is (0.5-1): 1;
the recrystallization solvent is one of tetrahydrofuran, dioxane, acetonitrile, ethyl acetate or diethyl ether; the mass ratio of the recrystallization solvent to the triphenylphosphine is (1-2): 1.
4. the method for synthesizing an intermediate of demethylolopatadine according to claim 3, wherein the first solvent is isopropanol;
the extraction solvent is dichloromethane;
the neutralizing alkali is sodium hydroxide;
the drying agent is anhydrous sodium sulfate;
the recrystallization solvent is tetrahydrofuran.
5. The method for synthesizing an intermediate of demethylolopatadine according to claim 1, wherein the heating and stirring process is specifically heating to 75-82 ℃ and stirring for 10-16 hours;
the recrystallization process comprises the steps of heating to a material dissolution temperature range of 60-66 ℃, and then cooling to a material crystallization temperature range of-5 ℃;
and the temperature is controlled to be 55-65 ℃ in the drying process.
6. A method for synthesizing demethylolopatadine, wherein the demethylolopatadine is N-demethylolopatadine or N, N-dedimethylamolopatadine, which is characterized by comprising the following steps:
preparing a second starting material by the synthesis method of the intermediate of demethylolopatadine according to any one of claims 1 to 5, wherein the second starting material is (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide;
adding the second raw material and a second solvent, starting stirring, controlling the temperature, adding a metal reducing agent, controlling the temperature after the addition, and reacting for a plurality of hours;
adding isoxofenac, stirring for a plurality of hours at a controlled temperature, cooling, adding a first quenching solvent, adding a second quenching solvent, and finally adding water to quench and react;
adding acid to adjust pH value, distilling under reduced pressure to dryness, and separating by column chromatography;
when the second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide, the prepared product is N-demethylolopatadine; when the second raw material is (3-aminopropyl) triphenyl phosphonium bromide, the prepared product is N, N-dedimethyl olopatadine.
7. The method for synthesizing demethylolopatadine according to claim 6, wherein the mass ratio of the second starting material to isoxeloxolone ranges from (1.5-2.5): 1;
when the second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide, adjusting the pH value to 7.2-7.8; and when the second raw material is (3-aminopropyl) triphenyl phosphonium bromide, adjusting the pH value to 8.0-8.4.
8. The method for synthesizing demethylolopatadine according to claim 6, wherein the second solvent is one of tetrahydrofuran, chloroform or toluene, and the mass ratio of the second solvent to isoxeloxolone ranges from (5-15): 1;
the metal reducing agent is one of potassium hydride, sodium hydride, calcium hydride, n-butyl lithium, tert-butyl lithium or lithium aluminum hydride, the mass concentration range of the metal reducing agent is 30-35%, and the mass ratio of the content of the metal reducing agent in the metal reducing agent to the isoxofenac is (0.4-0.8): 1;
the first quenching solvent is absolute methanol or absolute ethanol, and the mass ratio of the first quenching solvent to the isoxepac is (0.2-0.4): 1, the second quenching solvent is a tetrahydrofuran aqueous solution, the mass concentration of the tetrahydrofuran aqueous solution is 40-60%, and the mass ratio of the tetrahydrofuran content in the tetrahydrofuran aqueous solution to the isoxepac is (1.5-2.5): 1; the mass ratio range of the water to the isoxepac is (10-20): 1;
the acid is one of hydrochloric acid, sulfuric acid or acetic acid;
in the column chromatography separation process, the eluent is an ethyl acetate and methanol system, an ethyl acetate and ethanol system or an ethyl acetate and acetone system, and the filler in the chromatographic column is silica gel and alkaline alumina.
9. The method of synthesizing demethylolopatadine according to claim 8, wherein the second solvent is tetrahydrofuran;
the metal reducing agent is potassium hydride;
the first quenching solvent is absolute methanol;
the acid is concentrated hydrochloric acid, and the mass concentration of the concentrated hydrochloric acid is 20-38%;
the eluent is an ethyl acetate and methanol system, and the proportion of ethyl acetate to methanol is (6-10): 1.
10. the method for synthesizing demethylolopatadine according to claim 6, wherein the temperature is controlled, and the metal reducing agent is added at a temperature of 18-25 ℃;
controlling the temperature after the addition, wherein the reaction is carried out for a plurality of hours, specifically controlling the temperature to be 58-66 ℃ after the addition, and reacting for 1-2 hours;
the process of adding the isoxaglic acid, stirring for a plurality of hours at a controlled temperature and then cooling specifically comprises the steps of adding the isoxaglic acid, stirring for 1.5-3.5 hours at a controlled temperature of 58-66 ℃, and then cooling to 5-10 ℃.
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