CN107216271B - 酒石酸匹莫范色林杂质及其制备方法 - Google Patents
酒石酸匹莫范色林杂质及其制备方法 Download PDFInfo
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- CN107216271B CN107216271B CN201710406997.4A CN201710406997A CN107216271B CN 107216271 B CN107216271 B CN 107216271B CN 201710406997 A CN201710406997 A CN 201710406997A CN 107216271 B CN107216271 B CN 107216271B
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- Prior art keywords
- impurity
- fanselin
- reaction
- organic solvent
- tartaric acid
- Prior art date
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- 239000012535 impurity Substances 0.000 title claims abstract description 50
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 235000002906 tartaric acid Nutrition 0.000 title claims abstract description 23
- 239000011975 tartaric acid Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 claims abstract description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 239000012044 organic layer Substances 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 239000003208 petroleum Substances 0.000 claims description 11
- 238000005915 ammonolysis reaction Methods 0.000 claims description 10
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- -1 chloromethanes Alkane Chemical class 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 5
- PWASYRSZCSTUIW-UHFFFAOYSA-N 4-(2-methylpropoxy)benzaldehyde Chemical class CC(C)COC1=CC=C(C=O)C=C1 PWASYRSZCSTUIW-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- QBNJPSHRAWSBDW-UHFFFAOYSA-N 2-methylpropane;hydrobromide Chemical compound Br.CC(C)C QBNJPSHRAWSBDW-UHFFFAOYSA-N 0.000 claims description 3
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical class OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- DWPIWDIFYXPDHX-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]methanol Chemical class CC(C)COC1=CC=C(CO)C=C1 DWPIWDIFYXPDHX-UHFFFAOYSA-N 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- 229960004217 benzyl alcohol Drugs 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 9
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 abstract description 8
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 abstract description 7
- 239000004202 carbamide Substances 0.000 abstract description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- FOXXAQRNEIMDEC-UHFFFAOYSA-N phenyl n-phenoxycarbonylcarbamate Chemical compound C=1C=CC=CC=1OC(=O)NC(=O)OC1=CC=CC=C1 FOXXAQRNEIMDEC-UHFFFAOYSA-N 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract 2
- 239000013558 reference substance Substances 0.000 abstract 1
- 239000012043 crude product Substances 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 208000020016 psychiatric disease Diseases 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 235000013877 carbamide Nutrition 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 5
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- JBVKKHDTYSDPHA-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]methanamine Chemical class CC(C)COC1=CC=C(CN)C=C1 JBVKKHDTYSDPHA-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000006502 nitrobenzyl group Chemical group 0.000 description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 206010006100 Bradykinesia Diseases 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 229940123603 Dopamine D2 receptor antagonist Drugs 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 206010061533 Myotonia Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 208000028752 abnormal posture Diseases 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013305 food Nutrition 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
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- RGSULKHNAKTFIZ-CEAXSRTFSA-N pimavanserin tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RGSULKHNAKTFIZ-CEAXSRTFSA-N 0.000 description 1
- 229940081770 pimavanserin tartrate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
- C07C271/66—Y being a hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
- C07C273/1836—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from derivatives of carbamic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/96—Esters of carbonic or haloformic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了酒石酸匹莫范色林杂质，即N‑(4‑异丁氧基苄基)亚氨基二甲酸二苯酯(杂质A)、4‑异丁氧基苄基碳酸苯酯(杂质B)、4‑氟苄基(1‑甲基哌啶‑4‑基)碳酸‑4‑异丁氧基苄基酯(杂质C)，N‑(4‑异丁氧基苄基)‑N’‑(4‑氟苄基)脲(杂质E)，此外，还公开了酒石酸匹莫范色林杂质A、杂质B、杂质C、杂质E、N,N’‑二(4‑异丁氧基苄基)脲(杂质D)的制备方法。本发明提供的酒石酸匹莫范色林相关杂质作为酒石酸匹莫范色林中间体、原料药及其复方制剂质量研究的对照品的用途，为酒石酸匹莫范色林质量研究夯实了基础。
Description
技术领域
本发明属于药物合成技术领域，涉及酒石酸匹莫范色林杂质及其制备方法。
背景技术
帕金森病(Parkinson’s disease,PD)，又称震颤麻痹，是一种中老年人常见的慢性进展性中枢神经系统变性疾病，主要由基底神经节多巴胺受体功能退化引起，临床表现为静止性震颤、肌强直、运动迟缓和姿势异常等症状。目前世界上约有700万-1000万帕金森病患者，其中一半的帕金森病患者会发展为精神病。帕金森精神病(Parkinson’s diseasepsychosis,PDP)往往在帕金森病后期出现，最常见的症状是视觉幻觉。全球每年因帕金森病患者治疗和护理而产生的花费为410亿英镑，给帕金森病患者带来严重的经济负担。
迄今为止，帕金森精神病的产生原因，医学界尚未研究确切。由于精神疾病发病机理一般认为与其患者脑内多巴胺过多相关，普遍抗精神病药物的作用机制是多巴胺D2受体的拮抗作用。然而，多巴胺D2受体拮抗剂除引起椎体外周的副作用，还会让有精神疾病的帕金森病患者病情加重。
阿卡迪亚(ACADIA Pharmaceuticals)是一家主要致力于精神神经类药物开发的公司，旗下药物NUPLAZIDTM(API:Pimavanserin Tartrate,中文名：酒石酸匹莫范色林)于2016年4月29日刚刚获得美国FDA的上市批准，主要适应症为帕金森症并发的精神疾病(幻觉和妄想症)，据悉NUPLAZIDTM是FDA批准的首个、也是目前唯一用于该适应症的药物。目前研究数据表明，酒石酸匹莫范色林疗效确切、安全性高、耐受性好，酒石酸匹莫范色林有望成为抗帕金森精神病药物中最成功的新药。
根据酒石酸匹莫范色林的合成工艺：
酒石酸匹莫范色林杂质产生情况如下：
目前专利US20070260064A1、WO2008144326A2、CN105153016A、CN101778821A仅报道了酒石酸匹莫范色林的两个杂质：杂质D、杂质F，其中杂质F为中间体，杂质D的合成方法未见相关报道；杂质A、杂质B、杂质C、杂质E及其定向合成方法未见相关报道。
通过定向合成目标杂质，建立目标杂质的检测方法，对酒石酸匹莫范色林中间体、原料药的质量进行有效控制具有重要的意义。
发明内容
本发明首次公开酒石酸匹莫范色林杂质A、杂质B、杂质C、杂质E。
具体地说，本发明公开的酒石酸匹莫范色林杂质A、杂质B、杂质C、杂质E，其化学结构式如下所示：
本发明涉及酒石酸匹莫范色林杂质A、杂质B、杂质C、杂质D、杂质E的制备方法。
本发明涉及酒石酸匹莫范色林杂质A、杂质B、杂质C的合成路线如下所示：
本发明涉及酒石酸匹莫范色林杂质D、杂质E的合成路线如下所示：
R为苯基、苄基、对硝基苯基、对硝基苄基。
本发明杂质的合成步骤如下：
(1)N-(4-异丁氧基苄基)亚氨基二甲酸二苯酯(杂质A)的制备
将4-异丁氧基苄胺、三乙胺、4-二甲氨基吡啶加入有机溶剂Ⅰ，将该溶液冷却至-10-5℃，此温度下滴加氯甲酸苯酯，滴毕转移至室温，回流反应，反应毕，5％-10％稀盐酸水溶液洗，饱和食盐水洗，有机层无水硫酸钠干燥，减压旋干溶剂，所得固体用石油醚和乙酸乙酯混合溶剂重结晶得杂质A。
上述制备方法中4-异丁氧基苄胺、氯甲酸苯酯、三乙胺、DMAP的摩尔比为1∶2.2-2.7∶3.5-5∶0.8-1.2
有机溶剂Ⅰ为二氯甲烷、三氯甲烷、乙腈、甲苯、乙酸乙酯,优选二氯甲烷
重结晶溶剂石油醚和乙酸乙酯的体积比为：5-7.5∶1。
(2)4-异丁氧基苄基碳酸苯酯(杂质B)的制备
4-羟基苯甲醛与溴代异丁烷经烃化反应制得4-异丁氧基苯甲醛，4-异丁氧基苯甲醛与硼氢化钠经还原反应制得4-异丁氧基苄醇，将4-异丁氧基苄醇与有机溶剂Ⅰ和碱Ⅱ混合，将该溶液冷却至-10-5℃，此温度下滴加氯甲酸苯酯，滴毕转移至室温反应，抽滤，滤液用质量分数1％-5％氢氧化钠水溶液洗0.5-1.5mol/L稀盐酸洗，饱和食盐水洗，无水硫酸钠干燥，减压旋干溶剂，所得粗品经硅胶柱层析纯化，洗脱剂采用石油醚/乙酸乙酯体系，乙酸乙酯：石油醚＝1:100-200。
上述合成步骤中碱Ⅱ为三乙胺、吡啶、碳酸钾，优选碳酸钾。
(3)4-氟苄基(1-甲基哌啶-4-基)碳酸-4-异丁氧基苄基酯(杂质C)的制备
方法1：将杂质B、杂质F、碱Ⅰ加入有机溶剂Ⅱ中，在一定温度下发生氨解反应，反应毕，抽滤，加入水，加入乙酸乙酯萃取，有机层饱和食盐水洗，无水硫酸钠干燥，减压旋干溶剂，所得粗品经硅胶柱层析纯化，洗脱剂采用石油醚/乙酸乙酯体系，乙酸乙酯：石油醚＝1:10-15。
上述合成步骤中碱Ⅰ为三乙胺、碳酸钾，优选碳酸钾。
上述合成步骤中有机溶剂Ⅱ为N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮,优选N,N-二甲基甲酰胺。
氨解反应温度50-70℃。
方法2：将4-异丁氧基苄醇、碱Ⅲ加入有机溶剂Ⅰ中，在冰浴条件下滴入固体光气的有机溶剂Ⅰ，冰浴下反应半小时，转移至室温反应2-4h。将上述反应液慢慢滴入到含碱Ⅲ、杂质F的有机溶剂Ⅰ中，冰浴下反应半小时，室温下反应4-8小时,反应毕加入饱和碳酸氢钠水溶液洗，有机溶剂Ⅰ萃取，有机层无水硫酸钠干燥，减压旋干溶剂，所得粗品经硅胶柱层析纯化，洗脱剂采用石油醚/乙酸乙酯体系，乙酸乙酯：石油醚＝1:10-15。
碱Ⅲ为三乙胺、碳酸钾、二异丙基乙基胺,优选二异丙基乙基胺。
(4)N,N’-二(4-异丁氧基苄基)脲(杂质D)的制备
将4-异丁氧基苄胺醋酸盐、碳酸钾加入有机溶剂Ⅰ中，将该溶液冷却至-10-5℃，此温度下滴加氯甲酸酯，滴毕转移至室温反应，反应毕抽滤，4％-8％稀盐酸水溶液洗，饱和食盐水洗，无水硫酸钠干燥，有机层减压旋干，得化合物Ⅰ。将化合物Ⅰ、碱Ⅰ、4-异丁氧基苄胺加入有机溶剂Ⅱ，一定温度下发生氨解反应，反应毕，抽滤，滤液加入水中剧烈搅拌，抽滤，滤饼烘干，用乙酸乙酯和无水乙醇混合溶剂重结晶。
化合物Ⅰ的化学结构
上述合成方法中R为苯基、苄基、对硝基苯基、对硝基苄基。
氨解反应温度为50-70℃。
重结晶溶剂乙酸乙酯与乙醇的体积比为4.5-6∶1。
(5)N-(4-异丁氧基苄基)-N’-(4-氟苄基)脲(杂质E)的制备
方法1：将化合物Ⅰ、碱Ⅰ、对氟苄胺加入有机溶剂Ⅱ，一定温度下发生氨解反应，反应毕，抽滤，滤液加入水中剧烈搅拌，抽滤，滤饼烘干，用乙酸乙酯重结晶。
氨解反应温度为50-70℃。
方法2：将对氟苄胺、碳酸钾加入有机溶剂Ⅰ中，将该溶液冷却至-10-5℃，此温度下滴加氯甲酸酯，滴毕转移至室温反应，反应毕抽滤，5％-10％稀盐酸水溶液洗，饱和食盐水洗，无水硫酸钠干燥，有机层旋干，得化合物Ⅱ。将化合物Ⅱ、碱Ⅰ、4-异丁氧基苄胺加入有机溶剂Ⅱ，一定温度下发生氨解反应，反应毕，抽滤，滤液加入水中剧烈搅拌，抽滤，滤饼烘干，用乙酸乙酯重结晶。
化合物Ⅱ的化学结构
化合物Ⅱ中R为：苯基、苄基、对硝基苯基、对硝基苄基。
氨解反应温度为50-70℃。
具体实施方式
下列实例进一步说明本发明，但本发明并不受其限制。
实施例1：N-(4-异丁氧基苄基)亚氨基二甲酸二苯酯(杂质A)制备
于室温下将5.2g(0.029mol)4-异丁氧基苄胺、11.7g(0.116mol)三乙胺、3.5g(0.029mol)4-二甲氨基吡啶(DMAP)加入300ml二氯甲烷中，将该溶液冷却至-5℃-0℃。在-5℃-0℃下滴加11.3g(0.072mol)氯甲酸苯酯，40min滴毕，转移至室温，升温至40℃下反应12h。反应毕，反应液用400ml×2(8％)稀盐酸水溶液洗涤，分层，有机层300ml水洗，300ml×2饱和食盐水洗，有机层用无水硫酸钠干燥，减压旋蒸除去溶剂得11.5g淡黄色固体粗品，加入60ml石油醚和8ml乙酸乙酯，60℃重结晶，得7.8g白色固体，收率：63.9％，纯度：99.1％，mp:93.8-95.4℃。ESI-MS m/z:442.3[M+Na]+，1H NMR(400MHz,DMSO-d6):δ7.44(t,J＝7.8Hz,4H,ArH)，7.39(d,J＝8.4Hz,2H,ArH(Isobutoxy))，7.29(t,J＝7.8Hz,2H,ArH)，7.20(d,J＝8.4Hz,4H,ArH)，6.97(d,J＝8.4Hz,2H,ArH(Isobutoxy))，5.04(s,2H,NCH2)，3.73(d,J＝6.6Hz,2H,OCH2)，2.04-1.97(m,1H,CH)，0.97(d,J＝6.6Hz,6H,2CH3).
实施例2：4-异丁氧基苄基碳酸苯酯(杂质B)制备
于室温下将50.0g(0.41mol)对羟基苯甲醛、84.8g(0.62mol)碳酸钾、2.0g(0.012mol)碘化钾加入200ml N,N-二甲基甲酰胺中，室温下搅拌10min，加入111.4g(0.82mol)溴代异丁烷，升温至83℃反应24h。反应毕，抽滤，滤液倒入300ml质量分数4％氢氧化钠水溶液搅拌5min，350×2的乙酸乙酯萃取2次，合并有机层，有机层500ml×2饱和食盐水洗，无水硫酸钠干燥，减压蒸除溶剂得64.6g淡黄色油状物粗品4-异丁氧基苯甲醛，收率：88.5％，
于室温下将27.6g(0.73mol)硼氢化钠加入300ml四氢呋喃中，将该混合物冷却至0℃，64.6g(0.36mol)4-异丁氧基苯甲醛粗品加入100ml四氢呋喃中，将此混合液滴加至冷却至0℃硼氢化钠的四氢呋喃混合液中，1h滴毕转移至室温反应18h。反应毕，加入20ml水淬灭，抽滤，滤液减压蒸除溶剂，残留物加入300ml二氯甲烷，200ml×3饱和食盐水洗，有机层无水硫酸钠干燥，减压蒸除溶剂得52.0g淡黄色油状物粗品4-异丁氧基苄醇，收率：80.3％，
于室温将52.0g(0.29mol)4-异丁氧基苄醇、60.0g(0.44mol)碳酸钾、加入400ml二氯甲烷中，将该悬浮液冷却至-5℃-0℃。在-5℃-0℃下滴加45.0g(0.29mol)氯甲酸苯酯，1h滴毕，转移至室温反应15h。反应毕，抽滤，滤液用400ml质量分数1％氢氧化钠水溶液洗，400ml×2的1mol/L稀盐酸洗，400ml×3饱和食盐水洗，无水硫酸钠干燥，减压蒸除溶剂得60.5g淡黄色油状物粗品，收率69.8％。粗品经硅胶柱层析纯化(乙酸乙酯：石油醚＝1:100)得无色透明液体。ESI-MSm/z:301.1[M+H]+，323.1[M+Na]+，1H NMR(400MHz，DMSO-d6):δ7.37(t,J＝8.0Hz,2H,ArH)，7.21(t,J＝8.4Hz,3H,ArH)，7.11(d,J＝8.0Hz,2H,ArH)，6.90(d,J＝8.4Hz,2H,ArH)，4.21(s,2H,OCH2)，3.72(d,6.4Hz,2H,OCH2)，2.05-1.95(m,1H,OCH2CH)，0.97(d,J＝6.8Hz,6H,2CH3)。
实施例3：以方法1制备4-氟苄基(1-甲基哌啶-4-基)碳酸-4-异丁氧基苄基酯(杂质C)
方法1：于室温下将15.0g(0.035mol)4-异丁氧基苄基碳酸苯酯(杂质B)粗品、7.8g(0.035mol)N-(4-氟苄基)-1-甲基-4-哌啶、8.0g(0.058mol)碳酸钾加入80ml N,N-二甲基甲酰胺中，升温至50℃反应5h。反应毕，抽滤，加入100ml水，150ml×2乙酸乙酯萃取，有机层300ml×3饱和食盐水洗，无水硫酸钠干燥，减压蒸除溶剂得10.5g黄褐色油状物粗品，收率70.0％。粗品经硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1)得无色透明液体。ESI-MS:429.4[M+H]+，451.3[M+Na]+，1H NMR(600MHz,DMSO-d6):δ7.25(dd,J＝8.4Hz,5.4Hz,2H,ArH)，7.11(d,J＝8.4Hz,4H,ArH)，6.84(d,J＝8.4Hz,2H,ArH)，4.42(s,2H,OCH2)，4.19(s,2H,NCH2)，4.09(m,1H,NCH)，3.70(d,J＝6.6Hz,2H,OCH2)，3.03(d,J＝11.4Hz,2H,CH2)，2.45-2.41(m,2H,CH2)，2.38(s,3H,NCH3)，2.02-1.96(m,1H,OCH2CH)，1.81-1.74(m,2H,CH2)，1.51(d,J＝12.6Hz,2H,CH2)，0.97(d,J＝6.6Hz,6H,2CH3)
实施例4：以方法2制备4-氟苄基(1-甲基哌啶-4-基)碳酸-4-异丁氧基苄基酯(杂质C)
方法2：将10.0g(0.056mol)4-异丁氧基苄醇、10.8g(0.084mol)二异丙基乙基胺加入50ml二氯甲烷中，在冰浴条件下滴入含16.5(0.056mol)三光气的20ml二氯甲烷混合液，冰浴下反应半小时，转移至室温反应2h。将上述反应液慢慢滴入到含3.6g(0.028mol)二异丙基乙基胺、12.3g(0.055mol)N-(4-氟苄基)-1-甲基-4-哌啶的30ml二氯甲烷混合液中，冰浴下反应半小时，室温下反应4小时,反应毕加入100ml饱和碳酸氢钠水溶液洗，30ml二氯甲烷萃取，无水硫酸钠干燥，减压旋干溶剂15.2g黄褐色油状物粗品，收率63.9％。粗品经硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1)得无色透明液体。ESI-MS:429.4[M+H]+451.3[M+Na]+，1H NMR(600MHz,DMSO-d6):δ7.28(dd,J＝8.4Hz,5.4Hz,2H,ArH)，7.15(d,J＝8.4Hz,4H,ArH)，6.82(d,J＝8.4Hz,2H,ArH)，4.39(s,2H,OCH2)，4.22(s,2H,NCH2)，4.07(m,1H,NCH)，3.73(d,J＝6.6Hz,2H,OCH2)，3.01(d,J＝11.4Hz,2H,CH2)，2.45-2.41(m,2H,CH2)，2.35(s,3H,NCH3)，2.02-1.96(m,1H,OCH2CH)，1.81-1.74(m,2H,CH2)，1.50(d,J＝12.6Hz,2H,CH2)，0.97(d,J＝6.6Hz,6H,2CH3)
实施例5：N,N’-二(4-异丁氧基苄基)脲(杂质D)制备
于室温将100g(0.418mol)4-异丁氧基苄胺醋酸盐、115.3g(0.836mol)碳酸钾加入800ml二氯甲烷中，将该悬浮液冷却至-5℃-0℃。在-5℃-0℃下滴加混有200ml二氯甲烷的68.5g(0.439mol)氯甲酸苯酯。1.5h滴毕，室温反应3h后TLC监测基本无4-异丁氧基苄胺醋酸盐剩余。反应完毕后，抽滤，以40ml×2二氯甲烷洗涤滤饼，滤液用800ml(10％)稀盐酸水溶液洗涤，分层，有机层水500ml×2洗涤，干燥后，35℃减压回收溶剂，得110.1g白色固体粗品。粗品加入120ml无水乙醇，78℃回流条件下固体全溶，反应液冷却至50℃-55℃，产物约在50℃析晶，在此温度下搅拌30min，冷却至室温继续析晶45min，抽滤，滤饼冷乙醇洗涤。于50℃下真空干燥8h，得101.3g N-(4-异丁氧基苄基)氨基甲酸苯酯白色颗粒状固体，收率81.0％，mp:97.9-99.3℃。ESI-MS m/z:322.2[M+Na]+，1H NMR(400MHz，DMSO-d6):δ8.24(t,J＝6.0Hz,1H,NH)，7.37(t,J＝8.0Hz,2H,ArH)，7.21(t,J＝8.4Hz,3H,ArH)，7.11(d,J＝8.0Hz,2H,ArH)，6.90(d,J＝8.4Hz,2H,ArH)，4.20(d,J＝6.0Hz,2H,NHCH2)，3.72(d,6.4Hz,2H,OCH2)，2.05-1.95(m,1H,OCH2CH)，0.97(d,J＝6.8Hz,6H,2CH3)。
于室温下将6.0g(0.02mol)N-(4-异丁氧基苄基)氨基甲酸苯酯、3.6g(0.02mol)4-异丁氧基苄胺、6.1g(0.044mol)碳酸钾加入40ml N,N-二甲基甲酰胺中，60℃下反应4h，反应毕抽滤，以5ml×2N,N-二甲基甲酰胺洗涤滤饼，合并滤液，将滤液缓慢倒入150ml水中，室温搅拌2h，抽滤，滤饼20ml×2水洗涤。得7.2g类白色粗品，80ml乙酸乙酯与15ml无水乙醇混合溶剂，回流条件下重结晶，得5.2g白色固体，收率：67.5％，纯度：98.7％，mp:156.8-157.8℃。ESI-MSm/z:385.3[M+H]+，407.3[M+Na]+，1H NMR(400MHz,DMSO-d6):δ7.14(d,J＝8.4Hz,4H,ArH)，6.86(d,J＝8.4Hz,4H,ArH)，6.29(t,J＝6.0Hz,2H,2NH)，4.14(d,J＝6.0Hz,4H,2NHCH2)，3.70(d,J＝6.4Hz,4H,2OCH2)，1.99(m,2H,2CH)，0.96(d,J＝6.8Hz,12H,4CH3)。
实施例6：以方法1制备N-(4-异丁氧基苄基)-N’-(4-氟苄基)脲(杂质E)
方法1：于室温下将5.0g(0.017mol)N-(4-异丁氧基苄基)氨基甲酸苯酯、2.1g(0.017mol)对氟苄胺、5.1g(0.037mol)碳酸钾加入40ml N,N-二甲基甲酰胺中，60℃下反应4h，反应毕抽滤，以5ml×2N,N-二甲基甲酰胺洗涤滤饼，合并滤液，将滤液缓慢倒入150ml水中，室温搅拌2h，抽滤，滤饼20ml×2水洗涤。得5.0g类白色粗品，50ml乙酸乙酯回流条件下重结晶，得4.1g白色固体，收率74.5％，纯度：98.3％，mp:138.3-139.2℃。ESI-MS m/z:331.3[M+H]+，353.2[M+Na]+，1H NMR(400MHz，DMSO-d6):δ7.27(m,J＝8.4Hz,2H,ArH)，7.14(m,J＝8.4Hz,4H,ArH)，6.86(d,J＝8.4Hz,2H,ArH)，6.42(t,J＝6.0Hz,1H,NH)，6.36(t,J＝6.0Hz,1H,NH)，4.20(d,J＝6.0Hz,2H,NHCH2)，4.14(d,J＝6.0Hz,2H,NHCH2)，3.70(d,J＝6.4Hz,2H,OCH2)，1.99(m,1H,CH)，0.97(d,J＝6.8Hz,6H,2CH3)。
实施例7：以方法2制备N-(4-异丁氧基苄基)-N’-(4-氟苄基)脲(杂质E)
方法2：于室温下将20g(0.16mol)对氟苄胺、44.1g(0.32mol)碳酸钾加入200ml二氯甲烷中，将该溶液冷却至-5℃-0℃。在-5℃-0℃下滴加24.9g氯甲酸苯酯，1.5h滴毕，转移至室温反应5h。反应毕，抽滤，以20ml×2二氯甲烷洗涤滤饼，合并滤液，滤液用300ml(5％)稀盐酸水溶液洗涤，分层，有机层300ml水洗，300ml饱和食盐水洗，有机层用无水硫酸钠干燥，减压除去溶剂得35g类白色固体粗品，加入30ml乙醇，回流条件下重结晶，得28g N-(4-氟苄基)氨基甲酸苯酯白色固体，收率：71.4％，mp:91.5-92.4℃。ESI-MS m/z:246.2[M+H]+，268.2[M+Na]+，1HNMR(600MHz,DMSO-d6):δ8.36(t,J＝6.0Hz,1H,NH)，7.40(d,J＝8.4Hz,2H,ArH)，7.38(dd,J＝8.4Hz,5.4Hz,2H,ArH)，7.22-7.15(m,5H,ArH)，4.31(d,J＝6.0Hz,2H,NHCH2)。
于室温下将7.0g(0.029mol)N-(4-氟苄基)氨基甲酸苯酯、5.2g(0.029mol)4-异丁氧基苄胺、8.7g(0.063mol)碳酸钾加入40ml N,N-二甲基甲酰胺中，60℃下反应4h，反应毕抽滤，以5ml×2N,N-二甲基甲酰胺洗涤滤饼，合并滤液，将滤液缓慢倒入150ml水中，室温搅拌2h，抽滤，滤饼20ml×2水洗涤。得8.5g类白色粗品，90ml乙酸乙酯回流条件下重结晶，得7.2g白色固体，收率76.6％，纯度：98.1％，mp:138.1-139.1℃。ESI-MS m/z:331.3[M+H]+，353.2[M+Na]+，1H NMR(400MHz，DMSO-d6):δ7.24(m,J＝8.4Hz,2H,ArH)，7.13(m,J＝8.4Hz,4H,ArH)，6.84(d,J＝8.4Hz,2H,ArH)，6.40(t,J＝6.0Hz,1H,NH)，6.34(t,J＝6.0Hz,1H,NH)，4.22(d,J＝6.0Hz,2H,NHCH2)，4.13(d,J＝6.0Hz,2H,NHCH2)，3.68(d,J＝6.4Hz,2H,OCH2)，1.98(m,1H,CH)，0.97(d,J＝6.8Hz,6H,2CH3)。
Claims (5)
1.酒石酸匹莫范色林杂质，其结构如下：
2.一种如权利要求1所述的酒石酸匹莫范色林杂质的制备方法，其特征在于，杂质A的制备步骤如下：
将4-异丁氧基苄胺、三乙胺、4-二甲氨基吡啶加入有机溶剂Ⅰ，将该溶液冷却至-10-5℃，滴加氯甲酸苯酯，滴毕转移至室温，回流反应，反应毕，5％-10％稀盐酸水溶液洗，饱和食盐水洗，有机层无水硫酸钠干燥，减压旋干溶剂，所得固体用石油醚和乙酸乙酯混合溶剂重结晶得杂质A。
3.根据权利要求2所述的制备方法，其特征在于，4-异丁氧基苄胺、氯甲酸苯酯、三乙胺、DMAP的摩尔比为1∶2.2-2.7∶3.5-5∶0.8-1.2；有机溶剂Ⅰ为二氯甲烷、三氯甲烷、乙腈、甲苯、乙酸乙酯；重结晶溶剂石油醚和乙酸乙酯的体积比为：5-7.5∶1。
4.一种如权利要求1所述的酒石酸匹莫范色林杂质的制备方法，其特征在于，杂质B的制备步骤如下：
4-羟基苯甲醛与溴代异丁烷经烃化反应制得4-异丁氧基苯甲醛，4-异丁氧基苯甲醛与硼氢化钠经还原反应制得4-异丁氧基苄醇，将4-异丁氧基苄醇与有机溶剂Ⅰ和碱Ⅱ混合，将该溶液冷却至-10-5℃，滴加氯甲酸苯酯，滴毕转移至室温反应，得杂质B，有机溶剂Ⅰ为二氯甲烷、三氯甲烷、乙腈、甲苯、乙酸乙酯；碱Ⅱ为三乙胺、吡啶、碳酸钾。
5.一种如权利要求1所述的酒石酸匹莫范色林杂质的制备方法，其特征在于，杂质C的制备步骤如下：
将杂质B、杂质F、碱Ⅰ加入有机溶剂Ⅱ中，在一定温度下发生氨解反应，得杂质C；碱Ⅰ为三乙胺、碳酸钾；有机溶剂Ⅱ为N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮；氨解反应温度50-70℃；
或将4-异丁氧基苄醇、碱Ⅲ加入有机溶剂Ⅰ中，在冰浴条件下滴入固体光气的有机溶剂Ⅰ，冰浴下反应半小时，转移至室温反应2-4h，将上述反应液慢慢滴入到含碱Ⅲ、杂质F的有机溶剂Ⅰ中，冰浴下反应半小时，室温下反应4-8h，得杂质C，有机溶剂Ⅰ为二氯甲烷、三氯甲烷、乙腈、甲苯、乙酸乙酯；碱Ⅲ为三乙胺、碳酸钾、二异丙基乙基胺，杂质F的结构为：
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