CN117088818A - Synthesis method of 4, 6-dichloro-2-propylthio-5-aminopyrimidine - Google Patents
Synthesis method of 4, 6-dichloro-2-propylthio-5-aminopyrimidine Download PDFInfo
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- CN117088818A CN117088818A CN202311086206.6A CN202311086206A CN117088818A CN 117088818 A CN117088818 A CN 117088818A CN 202311086206 A CN202311086206 A CN 202311086206A CN 117088818 A CN117088818 A CN 117088818A
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- Prior art keywords
- dichloro
- reaction
- aminopyrimidine
- propylthio
- synthesis
- Prior art date
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- CJJLJBFJNXMANZ-UHFFFAOYSA-N 4,6-dichloro-2-propylsulfanylpyrimidin-5-amine Chemical compound CCCSC1=NC(Cl)=C(N)C(Cl)=N1 CJJLJBFJNXMANZ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000001308 synthesis method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 238000000034 method Methods 0.000 claims abstract description 19
- -1 organosilane compounds Chemical class 0.000 claims abstract description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 14
- DDEDQHVHVPJFAC-UHFFFAOYSA-N 4,6-dichloro-5-nitro-2-propylsulfanylpyrimidine Chemical compound CCCSC1=NC(Cl)=C([N+]([O-])=O)C(Cl)=N1 DDEDQHVHVPJFAC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 239000012535 impurity Substances 0.000 claims abstract description 7
- 230000009467 reduction Effects 0.000 claims abstract description 6
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 4
- 239000003960 organic solvent Substances 0.000 claims abstract 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 8
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 7
- 239000005052 trichlorosilane Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000077 silane Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- QQQSFSZALRVCSZ-UHFFFAOYSA-N triethoxysilane Chemical compound CCO[SiH](OCC)OCC QQQSFSZALRVCSZ-UHFFFAOYSA-N 0.000 claims description 2
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 2
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 claims description 2
- AKQNYQDSIDKVJZ-UHFFFAOYSA-N triphenylsilane Chemical compound C1=CC=CC=C1[SiH](C=1C=CC=CC=1)C1=CC=CC=C1 AKQNYQDSIDKVJZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 239000000010 aprotic solvent Substances 0.000 claims 1
- 238000007670 refining Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 238000003756 stirring Methods 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 10
- 229960002528 ticagrelor Drugs 0.000 description 10
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229910017604 nitric acid Inorganic materials 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- GLKRAUOJZYHDSB-UHFFFAOYSA-N dimethyl 2-nitropropanedioate Chemical compound COC(=O)C([N+]([O-])=O)C(=O)OC GLKRAUOJZYHDSB-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- PHMVMACIFWKESN-UHFFFAOYSA-N 4-hydroxy-5-nitro-2-propylsulfanyl-1h-pyrimidin-6-one Chemical compound CCCSC1=NC(O)=C([N+]([O-])=O)C(O)=N1 PHMVMACIFWKESN-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000006396 nitration reaction Methods 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229910000510 noble metal Inorganic materials 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KJBJCAJCBCPBGV-UHFFFAOYSA-N 2-nitropropanedioic acid Chemical compound OC(=O)C(C(O)=O)[N+]([O-])=O KJBJCAJCBCPBGV-UHFFFAOYSA-N 0.000 description 2
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- JINBYESILADKFW-UHFFFAOYSA-N aminomalonic acid Chemical compound OC(=O)C(N)C(O)=O JINBYESILADKFW-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical group OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- SLLGVCUQYRMELA-UHFFFAOYSA-N chlorosilicon Chemical compound Cl[Si] SLLGVCUQYRMELA-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000001282 organosilanes Chemical class 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000012797 qualification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- PYEJQVYISBUGDU-UHFFFAOYSA-N 2-(3,4-difluorophenyl)cyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1C1=CC=C(F)C(F)=C1 PYEJQVYISBUGDU-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- JJKMIZGENPMJRC-UHFFFAOYSA-N 3-oxo-3-propan-2-yloxypropanoic acid Chemical class CC(C)OC(=O)CC(O)=O JJKMIZGENPMJRC-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000005005 aminopyrimidines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical group N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229960002662 propylthiouracil Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012954 risk control Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Abstract
The invention relates to a method for synthesizing 4, 6-dichloro-2-propylthio-5-aminopyrimidine, which uses organosilane compounds as reducing agents for the nitro reduction on 4, 6-dichloro-2-propylthio-5-nitropyrimidine, and reduces the nitro in organic solvents in the presence of organic alkali to prepare 4, 6-dichloro-2-propylthio-5-aminopyrimidine. The product prepared by the method has less impurities, the reaction process is easy to control and the cost is low.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for synthesizing 4, 6-dichloro-2-propylthio-5-aminopyrimidine.
Background
Ticagrelol (Ticagrelor), trade name of Beilinda, is a new drug developed by the company Aspirin, UK for treating Acute Coronary Syndrome (ACS). Acute coronary syndrome is a serious common cardiovascular disease, and clinically adopts the schemes of drug treatment, interventional treatment, bypass treatment and the like, wherein the drug treatment is the treatment basis. The ticagrelor has rapid onset of action when being orally taken, can effectively improve the symptoms of patients with polar coronary heart disease, exceeds clopidogrel in clinical use, and has gradually rising market share.
Ticagrelor was marketed in europe in 12 2010 and approved by the us FDA in 2011, 7. Ticagrelor is marketed for treatment of ACS patients by a number of international guidelines for treatment, including european cardiology department ESC guidelines, american cardiology department ACC guidelines, and the like. Ticagrelor 11 in 2012, obtained an import pharmaceutical license issued by the national food and pharmaceutical administration (CFDA) and approved for market in china.
Ticagrelor is chemically known as (1 s,2s,3r,5 s) -3- [7- { [ (1 r,2 s) -2- (3, 4-difluorobenzene) cyclopropyl ] amino } -5- (propylthiouracil) -3H- [1,2,3] -triazolo [4,5-D ] pyrimidin-3-yl ] -5- (2-hydroxyethyl) cyclopentane-1, 2-diol. The structural formula is as follows:
。
the ticagrelor bulk drug has various synthetic routes and production processes, but the production uses three intermediates, namely, 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine (intermediate I, aminopyrimidine) which is one of the key intermediates for producing the ticagrelor bulk drug.
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The synthesis of 4, 6-dichloro-2-propylthio-5-aminopyrimidine forms multiple synthetic routes depending on the starting materials chosen and the method of formation of the chemical functional groups. However, all reasonable synthetic routes involve a unit operation of converting a nitro group into an amino group.
The synthesis of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine is reported in patent WO2011036479 and patent WO 201213891. The thiobarbituric acid is used as a starting material, and 4, 6-dichloro-2-propylthio-5-aminopyrimidine is prepared through nucleophilic substitution, nitration, chlorination, catalytic hydrogenation and other reaction processes. According to the technical route, the nitro is reduced to the amino by adopting a catalytic hydrogenation method, expensive noble metal is used as a catalyst, meanwhile, the reaction of reducing the nitro to the amino by catalytic hydrogenation is carried out step by step, the unique product is difficult to ensure in the reaction process, the synthesized 4, 6-dichloro-2-propylthio-5-aminopyrimidine product contains various impurities, and the quality standard meeting the requirements of the production of ticagrelor bulk drug is difficult to obtain.
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The synthetic routes reported in patent WO 2005095358 and WO2007093368 take the strategy of preparing 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine by forming the diazene structure and then introducing 5-amino group by catalytic hydrogenation. The preparation process successfully avoids the process of introducing amino by nitro reduction, but the catalytic hydrogenation still needs to use expensive noble metal as a catalyst, and the safety risk control of the catalytic hydrogenation process is higher. The production cost of the 4, 6-dichloro-2-propylthio-5-aminopyrimidine is high.
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In order to prevent the problem of high impurity content caused by the later introduction of amino groups, patent WO2014023681 reports that the quality of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine obtained by synthesis is met by introducing the desired amino group early in the synthesis work. The strategy synthesizes 4, 6-dichloro-2-propylthio-5-aminopyrimidine through the reaction processes of cyclization, nucleophilic substitution, deprotection, chlorination and the like by using 2-amino-malonate as an initial raw material. The disadvantage of this route is the high price of the starting material 2-amino-malonate and the limited market supply.
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Chinese patent CN105884694 reports a synthetic route, which is to prepare 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine by using dimethyl malonate as a starting material and through the processes of nitration, cyclization, nucleophilic substitution, catalytic hydrogenation, chlorination, etc., under the condition of comprehensively considering the quality and raw materials of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine product. The reaction operation of converting nitro catalytic hydrogenation into amino reaches the front of chlorination reaction, so that the probability of bringing impurities of catalytic hydrogenation into 4, 6-dichloro-2-propylthio-5-aminopyrimidine products is reduced to a certain extent, and the product quality meets the requirements. However, the process route also adopts noble metal palladium as a catalyst for catalytic hydrogenation, so that the cost is high and the safety risk is high.
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For the synthesis of ticagrelor intermediate 4, 6-dichloro-2-propylthio-5-aminopyrimidine, fe/HOAc and Zn/HOAc systems are adopted in patents US5654285 and CN107033148 to reduce nitro groups, and sodium thiosulfate is adopted in patents CN103896857 and CN103130726 to reduce nitro groups. The methods have the defects of complicated post-reaction treatment, large wastewater amount and large pollution.
Disclosure of Invention
The invention aims to provide a synthesis method of 4, 6-dichloro-2-propylthio-5-aminopyrimidine, which has few impurities, easily controlled reaction process and low cost.
The invention adopts the following technical scheme:
a preparation method of 4, 6-dichloro-2-propylthio-5-aminopyrimidine comprises the following synthetic routes:
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wherein R is 1 Is a straight or branched alkyl group containing 1 to 3 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, and the like.
R 2 Is a halogen atom including, but not limited to F, cl, br, I and the like, or a methylsulfonate group, a benzenesulfonate group and the like.
R 3 Straight or branched alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen atoms, and the like, including but not limited to methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, F, cl, br, I, and the like.
Specifically, the synthesis of 4, 6-dichloro-2-propylthio-5-aminopyrimidine uses malonate as a starting material, and the whole preparation process comprises the following reactions:
(1) Nitration reaction: the malonate is nitrified with nitric acid in an aqueous solution.
The nitric acid can be concentrated nitric acid or fuming nitric acid, or a mixed acid system of nitric acid/sulfuric acid, and the reaction temperature is between-10 ℃ and 40 ℃. The malonates include, but are not limited to, methyl, ethyl, propyl, isopropyl malonates.
After the reaction, 2-nitromalonate is obtained by reduced pressure distillation.
(2) And (3) cyclization reaction: in the presence of alkali, the 2-nitromalonate is condensed and cyclized with thiourea in a solvent to generate thiobarbituric acid, and the reaction temperature is 0-100 ℃.
The alkali is inorganic alkali and mainly comprises sodium hydroxide, potassium hydroxide, sodium carbonate, calcium hydroxide and the like; the solvent is one or two of water, methanol and ethanol. The product 5-nitro-2 thiobarbituric acid is isolated by crystallization.
(3) Nucleophilic substitution reaction: in the presence of alkali, 5-nitro-2-thiobarbituric acid and a derivative of 1-n-propane undergo nucleophilic substitution reaction in a solvent to generate 4, 6-dihydroxyl-2-propylthio-5-nitropyrimidine, wherein the reaction temperature is 0-100 ℃.
The alkali is inorganic alkali or organic alkali and mainly comprises, but is not limited to, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride and the like; the solvent is one or two of water, methanol, ethanol, acetonitrile, N-dimethylformamide and tetrahydrofuran. The derivative of 1-n-propane refers to a derivative of F, cl, br, I including but not limited to 1-n-propane, or a derivative of methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, and the like.
The product 4, 6-dihydroxy-2-propylthio-5-nitropyrimidine is obtained by extraction and crystallization.
(4) Chlorination reaction: in the presence of a chlorinating reagent, 4, 6-dihydroxy-2-propylthio-5-nitropyrimidine undergoes a chlorinating reaction in a solvent to generate 4, 6-dichloro-2-propylthio-5-nitropyrimidine, and the reaction temperature is between-10 ℃ and 100 ℃.
The chlorinating reagent is phosphorus oxychloride, phosphorus pentachloride and the like. The solvent is one or two of phosphorus oxychloride, phosphorus pentachloride water, methylene dichloride, dichloroethane, benzene, toluene and xylene.
The product 4, 6-dichloro-2-propylthio-5-nitropyrimidine is obtained through extraction, acidification, crystallization and other separation and purification operations.
(5) Nitroreduction reaction: 4, 6-dichloro-2-propylthio-5-nitropyrimidine is subjected to reduction reaction with organosilane in a solvent in the presence of organic base to generate 4, 6-dichloro-2-propylthio-5-aminopyrimidine, wherein the reaction temperature is between-10 ℃ and 80 ℃.
The organic base includes, but is not limited to, pyridine, 4-N, N-lutidine, N-dimethylaniline, triethylamine, trimethylamine, triisopropylamine, diisopropylethylamine, and the like. Preferably triethylamine or diisopropylethylamine.
The organosilane reducing agent includes, but is not limited to, triethoxysilane, 1, 3-tetramethyldisiloxane, trichlorosilane, triethylsilane, trimethoxysilane, trimethylsilane, triphenylsilane, and the like. Trimethoxysilane or trichlorosilane is preferred.
The product 4, 6-dichloro-2-propylthio-5-aminopyrimidine is obtained through the operations of neutralization, water washing, extraction, acidification, crystallization and other separation and purification.
The invention has the beneficial effects that: according to the invention, a silane compound is adopted as a reducing agent for nitro reduction, and nitro is reduced in the presence of organic alkali to prepare the 4, 6-dichloro-2-propylthio-5-aminopyrimidine compound, so that substances with high cost, such as noble metal, active metal and the like, which are easy to cause environmental pollution, are not used for nitro reduction, the operation with high dangerousness of using hydrogen, high pressure and the like is avoided, the reduction reaction process is easy to control, the yield is high, the method is suitable for industrial production, and the 4, 6-dichloro-2-propylthio-5-aminopyrimidine product synthesized by adopting the process has few impurities, and the quality meets the production requirement of ticagrelor bulk drugs.
Drawings
FIG. 1 is a GC spectrum of dimethyl 2-nitromalonate.
FIG. 2 is a GC spectrum of dimethyl 2-nitromalonate.
FIG. 3 is an HPLC chart of 5-nitro-2 thiobarbituric acid.
FIG. 4 is an HPLC chart of 4, 6-dihydroxy-2-propylsulfanyl-5-nitropyrimidine.
FIG. 5 is a schematic illustration of 4, 6-dichloro-2-propylsulfanyl-5-nitropyrimidine 1 H-NMR spectrum.
FIG. 6 is a mass spectrum of 4, 6-dichloro-2-propylsulfanyl-5-nitropyrimidine.
FIG. 7 is an HPLC chart of 4, 6-dichloro-2-propylsulfanyl-5-nitropyrimidine.
FIG. 8 is a diagram of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine 1 H-NMR spectrum.
FIG. 9 is a mass spectrum of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine.
FIG. 10 is an HPLC chart of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine.
FIG. 11 is an HPLC chart of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine.
FIG. 12 is an HPLC chart of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine.
Detailed Description
The following description of the present invention is given by way of example only and is not to be construed as limiting the invention.
EXAMPLE 1 (nitration) Synthesis of dimethyl 2-nitromalonate
150g of dimethyl malonate is added into a 1000ml three-port reaction bottle, stirring is started, the temperature is controlled to be about 10 ℃ under ice-water bath, 240g of 60% nitric acid is slowly added into the three-port reaction bottle through a constant-pressure dropping funnel, and the temperature is kept at 5-10 ℃ for reaction for 24 hours after the nitric acid is added.
And performing central control detection by using GC, wherein the reaction qualification is that the dimethyl malonate is less than or equal to 1 percent. After the reaction is qualified, 200ml of 10% saline solution is added at 5-10 ℃, and then 300ml of ethyl acetate is used for extraction for 2 times. The ethyl acetate phases were combined and washed with 300ml of 10% aqueous sodium carbonate solution and 300ml of water, respectively.
The ethyl acetate phase separated off was dried with anhydrous sodium sulfate under stirring for 2 hours and filtered off with suction. The filtrate is distilled off at normal pressure to obtain ethyl acetate, then reduced pressure distillation is carried out, and fractions 104-106 ℃ (2 mmHg) are collected to obtain 144g (theoretical yield 201 g) of dimethyl 2-nitromalonate, the yield is 72%, and the purity is 98.7% (GC, normalization, as shown in figure 1).
EXAMPLE 2 (nitration) Synthesis of dimethyl 2-nitromalonate
150g of dimethyl malonate is added into a 1000ml three-port reaction bottle, stirring is started, the temperature is controlled to be about 10 ℃ under ice-water bath, 160g of 80% nitric acid is slowly added into the three-port reaction bottle through a constant-pressure dropping funnel, and the temperature is kept at 5-10 ℃ for reaction for 12h after the nitric acid is added.
And performing central control detection by using GC, wherein the reaction qualification is that the dimethyl malonate is less than or equal to 1 percent. After the reaction is qualified, 200ml of 10% saline solution is added at 5-10 ℃, and then 300ml of ethyl acetate is used for extraction for 2 times. The ethyl acetate phases were combined and washed with 300ml of 10% aqueous sodium carbonate solution and 300ml of water, respectively.
The ethyl acetate phase separated off was dried with anhydrous sodium sulfate under stirring for 2 hours and filtered off with suction. The filtrate was distilled off at normal pressure to give ethyl acetate, and then distilled under reduced pressure, and the fraction was collected at 104 ℃ -106 ℃ (2 mmHg) to give 163g (theoretical yield 201 g) of dimethyl 2-nitromalonate, yield 81%, purity 98.4% (GC, normalized, as shown in fig. 2).
EXAMPLE 3 Synthesis of 5-nitro-2-thiobarbituric acid (cyclization reaction)
Into a 500ml dry three-port reaction flask, 150ml of anhydrous methanol was added, and 32.25g of thiourea was added under stirring, followed by dissolution and then addition of dimethyl 2-nitromalonate. At room temperature, 75g of 30% sodium methoxide methanol solution is slowly added dropwise, the temperature is raised to reflux after the addition, the reflux reaction is carried out for 10 hours, the TLC detection reaction is carried out, and after the reaction is completed, the reflux is stopped, and the temperature is reduced. Under stirring, adding 30% hydrochloric acid to adjust the pH to 6-7 at the temperature below 30 ℃, precipitating white solid, cooling to 0 ℃, stirring for 1 hour, filtering to obtain white solid, and rinsing the filter cake with water for 2 times. The filter cake was dried in vacuo (65 ℃ C.) to give 32.1g (34.7 g of theory) of 5-nitro-2-thiobarbituric acid in 93% yield and 98.8% purity (HPLC, normalized, see FIG. 3).
EXAMPLE 4 (nucleophilic substitution reaction) Synthesis of 4, 6-dihydroxy-2-propylsulfanyl-5-nitropyrimidine
150ml of methanol and 100g of 20% NaOH solution are added into a 500ml three-port reaction bottle, 45g of 5-nitro-2-thiobarbituric acid is added under stirring, then 35.05g of bromopropane is added dropwise from a constant pressure dropping funnel at 20-25 ℃, after the dropwise addition is finished, the reaction is stirred at room temperature for 10h, TLC (thin layer chromatography) detection reaction is carried out, and the raw material point disappears to terminate the reaction.
Slowly adding 30% hydrochloric acid dropwise into a reaction bottle at a temperature below 25 ℃ to adjust the pH to 6-7, precipitating a large amount of white solid, cooling to 0 ℃, stirring for 1 hour for crystallization, suction filtering, rinsing a filter cake with distilled water, and vacuum drying (65 ℃ temperature) the filter cake to obtain 46.4g (55 g of theoretical yield) of white solid product with a yield of 84% and a purity of 78.1% (HPLC, normalization, as shown in figure 4).
EXAMPLE 5 (Chlorination) Synthesis of 4, 6-dichloro-2-propylsulfanyl-5-nitropyrimidine
A dry 250ml three-necked flask was filled with nitrogen to replace air, 100g of phosphorus oxychloride was then added, 35g of 4, 6-dihydroxy-5-nitro-2-propylsulfanyl pyrimidine was added under stirring, the temperature was raised to 110 ℃, the reaction was stirred for 10 hours, TLC was monitored to monitor the reaction, and the reaction was stopped after the raw material disappeared.
Most of phosphorus oxychloride is distilled off under reduced pressure, the residue is cooled to room temperature, 250ml of dichloromethane is added, stirring is carried out until the residue is dissolved, an ice water bath is cooled to 10 ℃, 100ml of water is slowly added under stirring to hydrolyze the rest phosphorus oxychloride, then 10% NaOH aqueous solution is used for regulating the pH value to 6-7, stirring is carried out for 30min, standing and layering are carried out, the aqueous phase is extracted for 1 time by 100ml of dichloromethane, and the organic phases are combined.
The organic phase was dried over anhydrous sodium sulfate, filtered, and the dichloromethane solution was concentrated to dryness by distillation. Recrystallizing the product with ethyl acetate, and vacuum drying (65 ℃ C.) to obtain white 4, 6-dichloro-2-propylsulfanyl-5-nitropyrimidine 38g (theoretical yield 40.6 g) 1 The H-NMR spectrum is shown in FIG. 5, and the mass spectrum is shown in FIG. 6. Yield 94%, purity 99.0% (HPLC, normalized, fig. 7).
EXAMPLE 6 (nitroreduction reaction) Synthesis of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine
To a 500ml dry round bottom flask, 150ml of anhydrous dichloromethane was added under nitrogen protection, 32.5g of 4, 6-dichloro-5-nitro-2-propylsulfanylpyrimidine was added at room temperature and stirred to dissolve, then 90g of Diisopropylethylamine (DIPEA) was added and stirred uniformly.
Cooling to-5deg.C, and dropwise adding HSiCl under stirring 3 69g in 50ml of anhydrous dichloromethane, the reaction temperature is controlled below 0 ℃ during the dripping process, and the dripping is completed in about 60 minutes. After the addition of trichlorosilane was completed, the reaction was stirred at 0 ℃ for 18 hours, the progress of the reaction was checked by TLC, and the reaction was terminated by disappearance of the starting material.
After the reaction is completed, 200ml of saturated sodium bicarbonate aqueous solution is dripped at the temperature of 0 ℃ to decompose excessive trichlorosilane, and the mixture is stirred for 30 minutes after the dripping is completed, so that the pH value is measured to be 8-9. The reaction mixture was extracted with 200ml×3 with ethyl acetate, the ethyl acetate phases were combined, dried over anhydrous sodium sulfate overnight, filtered, and the solvent was distilled off from the filtrate under reduced pressure to dryness to give a crude product. Recrystallizing the crude product with isopropanol, and vacuum drying to obtain 22.2g (theoretical yield 28.9 g) of white 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine 1 The H-NMR spectrum is shown in FIG. 8, and the mass spectrum is shown in FIG. 9. Yield 76.8%, purity 99.6% (HPLC, normalized, shown in fig. 10).
EXAMPLE 7 (nitroreduction reaction) Synthesis of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine
To a 500ml dry round bottom flask, 150ml of anhydrous dichloromethane was added under nitrogen protection, 32.5g of 4, 6-dichloro-5-nitro-2-propylsulfanylpyrimidine was added at room temperature and stirred to dissolve, then 71g of anhydrous Triethylamine (TEA) was added and stirred uniformly.
Cooling to-5deg.C, and dropwise adding HSiCl under stirring 3 69g of a solution in 50ml of anhydrous dichloromethane, the reaction temperature being controlled below 0℃during the dropwise addition, it taking about 90 minutes to finish the dropwise addition. After the addition of trichlorosilane was completed, the reaction was stirred at 0 ℃ for 18 hours, the progress of the reaction was checked by TLC, and the reaction was terminated by disappearance of the starting material.
After the reaction is finished, 200ml of saturated sodium bicarbonate aqueous solution is dripped at the temperature of 0 ℃ to decompose excessive trichlorosilane, the mixture is stirred for 30 minutes after the dripping is finished, and the pH value is measured to be 8-9. The reaction mixture was extracted with 200ml×3 with ethyl acetate, the ethyl acetate phases were combined, dried over anhydrous sodium sulfate overnight, filtered, and the solvent was distilled off from the filtrate under reduced pressure to dryness to give a crude product. The crude product was recrystallized from isopropanol and dried in vacuo to give 20.8g (28.9 g of theory) of off-white 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine in 72.0% yield and 98.3% purity (HPLC, normalization, FIG. 11).
EXAMPLE 8 (nitroreduction reaction) Synthesis of 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine
To a 500ml dry round bottom flask, 150ml of anhydrous dichloromethane was added under nitrogen protection, 32.5g of 4, 6-dichloro-5-nitro-2-propylthiopyrimidine was added at room temperature and stirred to dissolve, then 90g of anhydrous Diisopropylethylamine (DIPEA) was added and stirred uniformly.
Reducing the temperature to-5 ℃, and dropwise adding trimethoxysilane (HSi (OMe)) under stirring 3 ) 65g of the solution in 50ml of anhydrous dichloromethane are added dropwise, the reaction temperature is controlled below 0 ℃ during the dropwise addition, and the dropwise addition is completed in about 90 minutes. After the trimethoxysilane was added dropwise, the reaction was stirred at 0℃for 18 hours, and the progress of the reaction was checked by TLC to terminate the reaction after the disappearance of the starting material.
After the reaction, 200ml of saturated sodium bicarbonate aqueous solution is added dropwise at 0 ℃ to decompose excess trimethoxysilane, and then stirring is carried out for 30 minutes, so that the pH is measured to be 8-9. The reaction mixture was extracted with 200ml×3 of ethyl acetate, the ethyl acetate phases were combined, dried over anhydrous sodium sulfate overnight, and filtered. The filtrate was distilled off under reduced pressure to dryness to give a crude product. The crude product was recrystallized from isopropanol and dried in vacuo to give 19.2g (28.9 g of theory) of off-white 4, 6-dichloro-2-propylsulfanyl-5-aminopyrimidine in 66.4% yield and 98.5% purity (HPLC, normalization, FIG. 12).
The present invention is described in detail with reference to the above embodiments. It should be noted that the above embodiments are merely illustrative of the invention. Numerous alternatives and modifications of the present invention will be devised by those skilled in the art without departing from the spirit and nature of the invention, which should be construed as being within the scope of the present invention.
Claims (10)
1. A synthesis method of 4, 6-dichloro-2-propylthio-5-aminopyrimidine is characterized in that an organosilane compound is used as a reducing agent for the nitro reduction on 4, 6-dichloro-2-propylthio-5-nitropyrimidine, and the nitro reduction is carried out in an organic solvent in the presence of organic alkali to prepare 4, 6-dichloro-2-propylthio-5-aminopyrimidine.
2. The method of claim 1, wherein the organosilane compound is a trisubstituted silane compound.
3. The synthetic method according to claim 2, wherein the organosilane compound comprises triethoxysilane, 1, 3-tetramethyldisiloxane, trichlorosilane, triethylsilane, trimethoxysilane, trimethylsilane or triphenylsilane.
4. The synthetic method of claim 1 wherein the organic base is a nitrogen-containing organic base.
5. The method of synthesis according to claim 4, wherein the organic base comprises 4-N, N-lutidine, N-dimethylaniline, triethylamine, trimethylamine, triisopropylamine or diisopropylethylamine.
6. The synthetic method of claim 1 wherein the organic solvent is an inert aprotic solvent.
7. The method of synthesis according to claim 6, wherein the organic solvent comprises benzene, toluene, xylene, chlorobenzene, dichloromethane, dichloroethane, dioxane, tetrahydrofuran, N-dimethylformamide or acetonitrile.
8. The synthesis method according to claim 1, wherein the reaction temperature is-20 ℃ to 80 ℃.
9. The method according to claim 8, wherein the reaction temperature is-10 ℃ to 30 ℃.
10. The synthesis method according to claim 1, further comprising a post-treatment process: terminating the reaction process, extracting to remove impurities, crystallizing and recrystallizing for refining.
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