CN105949135A - Synthetic method of selexipag - Google Patents
Synthetic method of selexipag Download PDFInfo
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- CN105949135A CN105949135A CN201610303627.3A CN201610303627A CN105949135A CN 105949135 A CN105949135 A CN 105949135A CN 201610303627 A CN201610303627 A CN 201610303627A CN 105949135 A CN105949135 A CN 105949135A
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- CN
- China
- Prior art keywords
- isopropyl
- aminobutoxy
- tertbutyloxycarbonyl
- solvent
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- 229960003841 selexipag Drugs 0.000 title abstract description 4
- QXWZQTURMXZVHJ-UHFFFAOYSA-N selexipag Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(C)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 QXWZQTURMXZVHJ-UHFFFAOYSA-N 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 31
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006467 substitution reaction Methods 0.000 claims abstract description 15
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- VUGNCPVAXWZTOL-UHFFFAOYSA-N 5-chloro-2,3-diphenylpyrazine Chemical compound C=1C=CC=CC=1C1=NC(Cl)=CN=C1C1=CC=CC=C1 VUGNCPVAXWZTOL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 10
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 58
- -1 [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl Chemical group 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 19
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 7
- 230000004044 response Effects 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical group [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 5
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 150000002118 epoxides Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 239000007983 Tris buffer Substances 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims 1
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 abstract 1
- 239000000376 reactant Substances 0.000 description 26
- 238000003756 stirring Methods 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 239000007787 solid Substances 0.000 description 11
- 238000002390 rotary evaporation Methods 0.000 description 10
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 238000000746 purification Methods 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 208000002815 pulmonary hypertension Diseases 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 102000009079 Epoprostenol Receptors Human genes 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 108091006335 Prostaglandin I receptors Proteins 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- MPNXSZJPSVBLHP-UHFFFAOYSA-N 2-chloro-n-phenylpyridine-3-carboxamide Chemical compound ClC1=NC=CC=C1C(=O)NC1=CC=CC=C1 MPNXSZJPSVBLHP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 1
- 229960003065 bosentan Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
- C07D241/20—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of selexipag. According to the method, 4-[(t-butyloxycarboryl)(isopropyl) amino]-1-butanol and tert-butyl bromoacetate are subjected to a condensation reaction, and obtained 4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl] tert-butyl acetate is subjected to a hydrolysis reaction under an alkaline reaction; obtained 4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl] acetic acid and methanesulfonamide are subjected to a condensation reaction; obtained 2-[4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl]-N-(methylsulfonyl) acetamide is subjected to a deprotection reaction under an acid condition, obtained 2-[4-(isopropyl) amino butoxyl]-N-(methylsulfonyl) acetamide and 5-chloro-2,3-diphenyl pyrazine are subjected to a substitution reaction, and the finished product selexipag is obtained. The method has a reasonable and concise process route and is environment-friendly and suitable for industrial production, the operation is simplified, and the cost is relatively low.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, be specifically related to a kind of new drug Sai Lexipa for treating pulmonary hypertension
Synthetic method.
Background technology
The chemistry entitled 2-[4-(5,6-of selectivity non-prostanoid IP prostacyclin receptor agonist Sai Lexipa (Selexipag)
Diphenyl pyrazine-2-base) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, its chemical structural formula is:
Sai Lexipa is pulmonary hypertension (PAH) the treatment new drug of Actelion biopharmaceutical company of Switzerland research and development, in 2015
Obtain FDA approval the end of the year, and just start the additive treatment after Primary Care as patients with pulmonary hypertension and promote, it is contemplated that list first year energy
Enough realizing the income from sales of 200,000,000 dollars, 2020 sales forecasts reach more than 600,000,000 dollars.Pulmonary hypertension be a kind of chronic,
The pulmonary disease progressively deteriorated, is characterized in that abnormal hypertension occurs in pulmonary artery, patient's daily routines can be caused tired out.Due to the heart
Blood is transported to pulmonary by the influential point of viscera more hardy, and this disease can frequently result in fatefulue heart failure, and patient may premature death
Or need lung transplantation.The Ip prostacyclin receptor agonism agent medicine that Sai Lexipa is administered orally as a kind of selectivity, with other with ring
Prostaglandin path is target spot, must suck or the medicine of intravenous administration is compared, and the most convenient, can relax blood
Tube wall smooth muscle, expands blood vessel, reduces pulmonary artery pressure.
Patent WO2011017612, document " Journal ofMedicinal Chemistry 2015, Vol.58, p.7128-7137. " and
" p.6692-6704. " Bioorganic and Medicinal Chemistry 2007, Vol.15 reports and a kind of prepares Sai Lexipa's
Synthetic route, its process route is as follows:
This synthetic route is raw material with 5-chloro-2,3-diphenyl pyrazine and 4-(isopropylamino)-n-butyl alcohol, by replacement, coupling,
The multistep reactions such as condensation, make the continuous superposition of functional group, prepare target product Sai Lexipa.Due to 4-(isopropylamino)-n-butyl alcohol
As raw material, its structure has-NH and-OH group so that the substitution reaction of the first step produces the competitive secondary anti-of diverse location
Should, introduce impurity, intermediate down and the quality of product and purifying process are all adversely affected, cause operation complicated numerous
Trivial, it is unfavorable for amplifying and produces and Industry Promotion, it is therefore necessary to explore that technological process is short, simple to operate, with low cost and mat
Synthetic method with the Sai Lexipa of applicable industrialized production.
Summary of the invention
For the deficiencies in the prior art and defect, it is an object of the invention to provide the synthetic method of a kind of Sai Lexipa.
In order to realize foregoing invention purpose, the technical solution used in the present invention is:
The synthetic route of described Sai Lexipa is
Specifically comprising the following steps that of the synthetic method of Sai Lexipa
(1) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared: by 4-[(tertbutyloxycarbonyl) (isopropyl)
Amino]-n-butyl alcohol and bromo-acetic acid tert-butyl quaternary ammonium salt phase transfer catalyst, base reagent, solvent, water composition system in contract
Close reaction, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate；
(2) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared: by [4-(tertbutyloxycarbonyl) (isopropyl) amino fourth oxygen
Base] tert-butyl acetate puts in the system being made up of base reagent, solvent and water, and be hydrolyzed reaction, obtains [4-(tertiary butyloxycarbonyl
Base) (isopropyl) Aminobutoxy] acetic acid；
(3) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared: by [4-(tertiary butyloxycarbonyl
Base) (isopropyl) Aminobutoxy] acetic acid and methylsulfonamides condensing agent, solvent composition system in carry out condensation reaction, obtain
2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide；
(4) prepare Sai Lexipa: by 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, throw
Enter in the system being made up of the solvent of trifluoroacetic acid and deprotection reaction, carry out deprotection reaction, obtain 2-[4-(isopropyl)
Aminobutoxy]-N-(mesyl) acetamide；Again by 2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide and 5-
Chloro-2,3-diphenyl pyrazine carries out substitution reaction in the system of the solvent composition of acid binding agent alkali and substitution reaction, obtains Sai Lexi
Handkerchief.
Preferably, the quaternary ammonium salt phase transfer catalyst described in step (1) is tetrabutylammonium chloride, tetrabutyl ammonium bromide, the tetrabutyl
Ammonium iodide, 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, methyl tricapryl ammonium chloride, ten
Dialkyl group trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride；Described base reagent is potassium hydroxide, sodium hydroxide, hydrogen-oxygen
Change lithium, potassium carbonate, sodium carbonate, cesium carbonate or lithium carbonate；Described solvent is dichloromethane, 1,2-dichloroethanes, chloroform, first
Benzene, methyl tertiary butyl ether(MTBE) or acetonitrile；Wherein, 4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol, bromo-acetic acid tert-butyl, season
Mol ratio between ammonium salt phase transfer catalyst, base reagent, solvent, water is 1.0: (1.1～1.5): (0.02～0.05): (1.4～1.8):
(10.0～25.0): (5.0～10.0).
Preferably, the base reagent described in step (2) is sodium hydroxide, potassium hydroxide, Lithium hydrate or Cesium hydrate.；Described
Solvent is methanol, ethanol, isopropanol, normal propyl alcohol, the tert-butyl alcohol or n-butyl alcohol；Wherein, [4-(tertbutyloxycarbonyl) (isopropyl) amino
Butoxy] tert-butyl acetate, base reagent, solvent, mol ratio between water be 1.0: (1.1～1.4): (10.0～25.0): (5.0～10.0).
Preferably, the condensing agent described in step (3) is N, N '-carbonyl dimidazoles, N, N '-dicyclohexylcarbodiimide, N, N '-
DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 1-hydroxy benzo triazole, 1,8-diaza are double
Ring [5.4.0]-ten one-7-alkene, BTA-N, N, N ', N '-tetramethylurea hexafluorophosphate, O-BTA-N, N, N ', N '-
Tetramethylurea Tetrafluoroboric acid ester, 2-(7-azo BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, hexafluorophosphoric acid benzo
Triazol-1-yl-epoxide tripyrrole alkyl phosphorus or BTA-1-base epoxide three (dimethylamino) phosphorus hexafluorophosphate；Described
Solvent be oxolane, dichloromethane, 1,2-dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide,
Methyl tertiary butyl ether(MTBE) or 1,4-dioxane；Wherein, [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, sulfonyloxy methyl
Mol ratio between amine, condensing agent, solvent is 1.0: (1.1～1.4): (1.1～1.6): (10.0～25.0).
Preferably, the solvent of the deprotection reaction described in step (4) is methanol, ethanol, dichloromethane, ethyl acetate, tetrahydrochysene
Furan, isopropanol or dioxane；Described acid binding agent alkali be N, N-diisopropylethylamine, triethylamine, diethylamine, trimethylamine,
Pyridine, piperidines, DMAP, 2,6-lutidines, aniline, N, N-dimethylaniline, N, N-diethylaniline, three
2-aminopropane., tri-n-butylamine, tetramethyl guanidine, N-methylmorpholine or N-ethylmorpholine；The solvent of described substitution reaction be methanol,
Ethanol, the tert-butyl alcohol, isopropanol or oxolane；Wherein, 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(methylsulfonyl
Base) acetamide, trifluoroacetic acid, the solvent of deprotection reaction, 5-chloro-2,3-diphenyl pyrazine, acid binding agent alkali, substitution reaction molten
Mol ratio between agent is 1.0: (1.1～1.4): (25.0～75.0): (1.1～1.3): (2.0～2.5): (10.0～25.0).
Preferably, the temperature of the condensation reaction described in step (1) is 20～40 DEG C, and the response time is 1～5 hour；Step (2)
The temperature of described hydrolysis is 20～80 DEG C, and the response time is 1～8 hour；The temperature of the condensation reaction described in step (3)
Being 70～110 DEG C, the response time is 16～36 hours；The temperature of the deprotection reaction described in step (4) is 50～80 DEG C, remove-insurance
Protecting the response time is 4～10 hours, and the temperature of described substitution reaction is 80～120 DEG C, and the substitution reaction time is 6～24 hours.
The synthetic method of a kind of Sai Lexipa of the present invention, first with 4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol and
Bromo-acetic acid tert-butyl is raw material, by condensation, hydrolysis, again condensation reaction, prepares N-(mesyl) acetamide side chain
Compound, then deprotection chloro-with 5-2,3-diphenyl pyrazine carries out substitution reaction, prepares Sai Lexipa, this route methods
I.e. starting to avoid the purification introducing pyrazine mother nucleus structure, beneficially intermediate too early and avoiding by-product to produce.
The technical scheme that the present invention provides has following technical effect that one, only makees routinely after having reacted due to each step
Post processing and purification are without column chromatography, and impurity is less, controlled, can directly carry out next step reaction, therefore simplify
Operation, the most each step can obtain higher yield；Its two, process route initiation material and the reagent used of the present invention are easy
, the technical scheme of synthetic reaction is reasonable, can produce the use demand meeting crude drug in a large number, it is adaptable to industrialized production；
Its three, owing to pollutant will not be produced in preparation process, thus environmental protection effect can be embodied.
In a word, the method process route is reasonable, operation is succinct, reagent is easy to get and total recovery is high and is satisfied industrialization and amplifies life
Produce the environmental protection effect requiring and embodying excellence.
Detailed description of the invention
Embodiment 1
A) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared:
4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol (20.0g, 0.09mol) and bromo-acetic acid tert-butyl (21.1g, 0.11mol)
Be dissolved in dichloromethane (90mL), add tetrabutylammonium chloride (0.72g, 2.6mmol), potassium hydroxide (7.3g, 0.13mol) and
Water (12.0g), reactant mixture 25 DEG C stirring reaction 2 hours, reactant liquor vacuum rotary steam is concentrated to dryness, and adds ethyl acetate extraction
Taking, magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, ethanol and isopropyl alcohol mixed solvent recrystallization, obtains [4-(tertbutyloxycarbonyl) (isopropyl)
Aminobutoxy] tert-butyl acetate, light yellow oil (26.6g), yield 89.0%, the reaction equation of this step is as follows:
B) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate (26.0g, 0.075mol) is dissolved in methanol (50mL),
Add sodium hydroxide solution (NaOH=3.3g, 0.08mol；Water 9.0g), it is heated to 80 DEG C and reacts 6 hours, be down to room temperature, warp
Later process and purification, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (20.7g), yield 95.0%, this step
Rapid reaction equation is as follows:
C) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (20.0g, 0.07mol) and N, N '-carbonyl dimidazoles (14.0g,
0.09mol) it is dissolved in oxolane (70mL), stirring, add methylsulfonamides (7.9g, 0.08mol), reactant mixture 90 DEG C
Stirring is reacted 18 hours, and reactant liquor concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry,
Recrystallizing methanol, obtains 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, off-white color solid
(21.2g), yield 83.7%, the reaction equation of this step is as follows:
D) prepare Sai Lexipa: 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide (20.0g,
0.055mol) and be dissolved in methanol (110mL), adding trifluoroacetic acid (6.8g, 0.06mol), 65 DEG C of stirring reactions 6 hours are to instead
Should be complete, reactant liquor is added drop-wise to the water (200mL) of stirring, is cooled to 0 DEG C of crystallize 3 hours, filters, obtains midbody compound
(2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide), is then dissolved in methanol (40mL), adds 5-chloro-2,3-
Diphenyl pyrazine (16.0g, 0.06mol), DIPEA (15.5g, 0.12mol), reactant mixture 100 DEG C stirring
Reacting 8 hours, reactant liquor is down to room temperature, adds water (40mL), is cooled to-10 DEG C of crystallizes 3 hours, filters, get Sai Lexi
Handkerchief, white solid (25.0g), yield 92.3%, the reaction equation of this step is as follows:
Embodiment 2
A) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared:
4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol (23.0g, 0.10mol) and bromo-acetic acid tert-butyl (25.2g, 0.13mol)
It is dissolved in 1,2-dichloroethanes (110mL), add tetrabutyl ammonium bromide (1.1g, 3.5mmol), sodium hydroxide (6.4g, 0.16mol)
With water (14.0g), reactant mixture 30 DEG C stirring reaction 3 hours, reactant liquor vacuum rotary steam is concentrated to dryness, and adds ethyl acetate
Extraction, magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, ethanol and isopropyl alcohol mixed solvent recrystallization, obtains [4-(tertbutyloxycarbonyl) (isopropyl
Base) Aminobutoxy] tert-butyl acetate, light yellow oil (30.3g), yield 88.2%, the same embodiment of reaction equation of this step
1；
B) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate (30.0g, 0.09mol) is dissolved in ethanol (85mL), adds
Enter potassium hydroxide solution (KOH=5.7g, 0.10mol；Water 12g), it is heated to 75 DEG C and reacts 7 hours, be down to room temperature, pass through
Post processing and purification, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, off-white color solid (23.5g), yield
93.7%, the reaction equation of this step is with embodiment 1；
C) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (23.0g, 0.08mol) and N, N '-dicyclohexylcarbodiimide
(22.1g, 0.11mol) is dissolved in chloroform (120mL), stirring, adds methylsulfonamides (9.8g, 0.10mol), reactant mixture
80 DEG C of stirrings are reacted 19 hours, and reactant liquor concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is extremely
Dry, recrystallizing methanol, obtain 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, off-white color is solid
Body (24.8g), yield 85.0%, the reaction equation of this step is with embodiment 1；
D) prepare Sai Lexipa: 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide (24.0g,
0.065mol) and be dissolved in ethanol (160mL), adding trifluoroacetic acid (9.0g, 0.08mol), 70 DEG C of stirring reactions 7 hours are to instead
Should be complete, reactant liquor is added drop-wise to the water (260mL) of stirring, is cooled to 0 DEG C of crystallize 3 hours, filters, obtains midbody compound
(2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide), is then dissolved in ethanol (90mL), adds 5-chloro-2,3-
Diphenyl pyrazine (21.8g, 0.08mol), triethylamine (14.9g, 0.15mol), reactant mixture 100 DEG C stirring reaction 18 hours,
Reactant liquor is down to room temperature, adds water (40mL), is cooled to-10 DEG C of crystallizes 3 hours, filters, get Sai Lexipa, white solid
(29.6g), yield 91.0%, the reaction equation of this step is with embodiment 1.
Embodiment 3
A) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared:
4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol (12g, 0.05mol) and bromo-acetic acid tert-butyl (12.1g, 0.06mol)
It is dissolved in chloroform (70mL), adds tetrabutylammonium iodide (0.5g, 1.3mmol), Lithium hydrate (1.7g, 0.07mol) and water (6.5g),
Reactant mixture 20 DEG C stirring reaction 4 hours, reactant liquor vacuum rotary steam is concentrated to dryness, and adds ethyl acetate extraction, and magnesium sulfate is done
Dry, concentrated by rotary evaporation is the most dry, ethanol and isopropyl alcohol mixed solvent recrystallization, obtains [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]
Tert-butyl acetate, light yellow oil (15.6g), yield 86.8%, the reaction equation of this step is with embodiment 1；
B) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate (15.0g, 0.04mol) is dissolved in isopropanol (40mL),
Add lithium hydroxide solution (LiOH=1.3g, 0.05mol；Water 6.0g), it is heated to 70 DEG C and reacts 8 hours, be down to room temperature, warp
Later process and purification, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, off-white color solid (11.7g), yield
93.0%, the reaction equation of this step is with embodiment 1；
C) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (11.0g, 0.04mol) and 1-(3-dimethylamino-propyl)-3-ethyl
Carbodiimide (8.3g, 0.05mol) is dissolved in acetonitrile (40mL), stirring, adds methylsulfonamides (5.1g, 0.05mol), reaction
95 DEG C of mixture stirring reaction 22 hours, reactant liquor concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, rotation
Steaming is concentrated to dryness, recrystallizing methanol, obtains 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide,
Off-white color solid (11.7g), yield 84.2%, the reaction equation of this step is with embodiment 1；
D) prepare Sai Lexipa: 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide (11.0g,
0.03mol) and be dissolved in dichloromethane (60mL), add trifluoroacetic acid (4.4g, 0.04mol), 50 DEG C of stirring reactions 10 hours
To reaction completely, reactant liquor is added drop-wise to the water (120mL) of stirring, is cooled to 0 DEG C of crystallize 3 hours, filters, obtains intermediate
Compound (2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide), is then dissolved in the tert-butyl alcohol (40mL), adds 5-
Chloro-2,3-diphenyl pyrazine (9.6g, 0.036mol), DMAP (8.1g, 0.07mol), reactant mixture 110 DEG C stirs
Mixing reaction 14 hours, reactant liquor is down to room temperature, adds water (15mL), is cooled to-10 DEG C of crystallizes 3 hours, filters, obtains match
Le Xipa, white solid (13.5g), yield 90.5%, the reaction equation of this step is with embodiment 1.
Embodiment 4
A) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared:
4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol (15.0g, 0.065mol) and bromo-acetic acid tert-butyl (17.7g, 0.09mol)
It is dissolved in toluene (70mL), adds 4-butyl ammonium hydrogen sulfate (0.88g, 2.6mmol), potassium carbonate (15.2g, 0.11mol) and water
(9.5g), reactant mixture 40 DEG C stirring reaction 1.5 hours, reactant liquor vacuum rotary steam is concentrated to dryness, and adds ethyl acetate extraction,
Magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, ethanol and isopropyl alcohol mixed solvent recrystallization, obtains [4-(tertbutyloxycarbonyl) (isopropyl) amino
Butoxy] tert-butyl acetate, light yellow oil (19.6g), yield 87.5%, the reaction equation of this step is with embodiment 1；
B) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate (19.0g, 0.055mol) is dissolved in the tert-butyl alcohol (60mL),
Add cesium hydroxide solution (CsOH=11.1g, 0.07mol；Water 8.0g), it is heated to 75 DEG C and reacts 6.5 hours, be down to room temperature,
Through post processing and purification, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, off-white color solid (15.0g), receive
Rate 94.2%, the reaction equation of this step is with embodiment 1；
C) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (15.0g, 0.05mol) and 1,8-diazabicyclo [5.4.0]-ten one
-7-alkene (9.5g, 0.06mol) is dissolved in toluene (80mL), stirring, adds methylsulfonamides (5.7g, 0.06mol), and reaction is mixed
Compound 105 DEG C stirring reaction 16 hours, reactant liquor concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and rotation is steamed
It is concentrated to dryness, recrystallizing methanol, obtains 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, class
White solid (16.6g), yield 87.3%, the reaction equation of this step is with embodiment 1；
D) prepare Sai Lexipa: 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide (16.0g,
0.04mol) and be dissolved in ethyl acetate (130mL), add trifluoroacetic acid (5.7g, 0.05mol), 80 DEG C of stirring reactions 5 hours
To reaction completely, reactant liquor is added drop-wise to the water (150mL) of stirring, is cooled to 0 DEG C of crystallize 3 hours, filters, obtains intermediate
Compound (2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide), is then dissolved in isopropanol (50mL), adds 5-
Chloro-2,3-diphenyl pyrazine (13.5g, 0.05mol), N, N-dimethylaniline (12.2g, 0.10mol), reactant mixture 95 DEG C stirring
Reacting 12 hours, reactant liquor is down to room temperature, adds water (40mL), is cooled to-10 DEG C of crystallizes 3 hours, filters, get Sai Le
Western handkerchief, white solid (19.7g), yield 91.0%, the reaction equation of this step is with embodiment 1.
Claims (9)
1. the synthetic method of Yi Zhong Sai Lexipa, it is characterised in that described method comprises the steps:
(1) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared: by 4-[(tertbutyloxycarbonyl) (isopropyl)
Amino]-n-butyl alcohol and bromo-acetic acid tert-butyl quaternary ammonium salt phase transfer catalyst, base reagent, solvent, water composition system in contract
Close reaction, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate；
(2) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared: by [4-(tertbutyloxycarbonyl) (isopropyl) amino fourth oxygen
Base] tert-butyl acetate puts in the system being made up of base reagent, solvent and water, and be hydrolyzed reaction, obtains [4-(tertiary butyloxycarbonyl
Base) (isopropyl) Aminobutoxy] acetic acid；
(3) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared: by [4-(tertiary butyloxycarbonyl
Base) (isopropyl) Aminobutoxy] acetic acid and methylsulfonamides condensing agent, solvent composition system in carry out condensation reaction, obtain
2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide；
(4) prepare Sai Lexipa: by 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, throw
Enter in the system being made up of the solvent of trifluoroacetic acid and deprotection reaction, carry out deprotection reaction, obtain 2-[4-(isopropyl)
Aminobutoxy]-N-(mesyl) acetamide；Again by 2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide and 5-
Chloro-2,3-diphenyl pyrazine carries out substitution reaction in the system of the solvent composition of acid binding agent alkali and substitution reaction, obtains Sai Lexi
Handkerchief.
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the quaternary ammonium salt described in step (1)
Phase transfer catalyst is tetrabutylammonium chloride, tetrabutyl ammonium bromide, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, benzyl three second
Ammonium chloride, benzyl triethyl ammonium bromide, methyl tricapryl ammonium chloride, Dodecyl trimethyl ammonium chloride or CPC
Ammonium chloride；Described base reagent is potassium hydroxide, sodium hydroxide, Lithium hydrate, potassium carbonate, sodium carbonate, cesium carbonate or carbon
Acid lithium；Described solvent is dichloromethane, 1,2-dichloroethanes, chloroform, toluene, methyl tertiary butyl ether(MTBE) or acetonitrile；Wherein, 4-[(uncle
Butoxy carbonyl) (isopropyl) amino]-n-butyl alcohol, bromo-acetic acid tert-butyl, quaternary ammonium salt phase transfer catalyst, base reagent, solvent, water it
Between mol ratio be 1.0: (1.1～1.5): (0.02～0.05): (1.4～1.8): (10.0～25.0): (5.0～10.0).
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the base reagent described in step (2)
For sodium hydroxide, potassium hydroxide, Lithium hydrate or Cesium hydrate.；Described solvent be methanol, ethanol, isopropanol, normal propyl alcohol,
The tert-butyl alcohol or n-butyl alcohol；Wherein, [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate, base reagent, solvent,
Mol ratio between water is 1.0: (1.1～1.4): (10.0～25.0): (5.0～10.0).
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the condensing agent described in step (3)
For N, N '-carbonyl dimidazoles, N, N '-dicyclohexylcarbodiimide, N, N '-DIC, 1-(3-dimethylamino third
Base)-3-ethyl carbodiimide, 1-hydroxy benzo triazole, 1,8-diazabicyclo [5.4.0]-ten one-7-alkene, BTA
-N, N, N ', N '-tetramethylurea hexafluorophosphate, O-BTA-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester, 2-(7-azo
BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl phosphorus or
BTA-1-base epoxide three (dimethylamino) phosphorus hexafluorophosphate；Described solvent be oxolane, dichloromethane,
1,2-dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide, methyl tertiary butyl ether(MTBE) or 1,4-dioxane；
Wherein, the mol ratio between [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, methylsulfonamides, condensing agent, solvent
It is 1.0: (1.1～1.4): (1.1～1.6): (10.0～25.0).
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the deprotection described in step (4)
The solvent of reaction is methanol, ethanol, dichloromethane, ethyl acetate, oxolane, isopropanol or dioxane；Described ties up
Acid agent alkali is N, N-diisopropylethylamine, triethylamine, diethylamine, trimethylamine, pyridine, piperidines, DMAP, 2,6-
Lutidines, aniline, N, N-dimethylaniline, N, N-diethylaniline, Tris(isopropylamine)., tri-n-butylamine, tetramethyl guanidine, N-
Methyl morpholine or N-ethylmorpholine；The solvent of described substitution reaction is methanol, ethanol, the tert-butyl alcohol, isopropanol or oxolane；
Wherein, 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, trifluoroacetic acid, deprotection reaction
Solvent, 5-chloro-2,3-diphenyl pyrazine, acid binding agent alkali, substitution reaction solvent between mol ratio be 1.0: (1.1～1.4):
(25.0～75.0): (1.1～1.3): (2.0～2.5): (10.0～25.0).
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the condensation described in step (1) is anti-
The temperature answered is 20～40 DEG C, and the response time is 1～5 hour.
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the hydrolysis described in step (2) is anti-
The temperature answered is 20～80 DEG C, and the response time is 1～8 hour.
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the condensation described in step (3) is anti-
The temperature answered is 70～110 DEG C, and the response time is 16～36 hours.
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the deprotection described in step (4)
The temperature of reaction is 50～80 DEG C, and the deprotection reaction time is 4～10 hours, and the temperature of described substitution reaction is 80～120 DEG C,
The substitution reaction time is 6～24 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107915770A (en) * | 2016-10-11 | 2018-04-17 | 联宁（苏州）生物制药有限公司 | A kind of antibody drug conjugates intermediate and preparation method thereof |
| CN108069914A (en) * | 2016-11-17 | 2018-05-25 | 江苏艾立康药业股份有限公司 | A kind of preparation method of West pa lattice crystal form |
| CN108440421A (en) * | 2018-05-14 | 2018-08-24 | 湖南华腾制药有限公司 | A kind of deuterated Sai Lexipa and preparation method thereof |
| CN108558653A (en) * | 2018-05-14 | 2018-09-21 | 湖南华腾制药有限公司 | The preparation method of Sai Lexipa intermediates and Sai Lexipa |
| CN108774182A (en) * | 2018-07-11 | 2018-11-09 | 湖南华腾制药有限公司 | A kind of process for purification of Sai Lexipa |
| CN109384734A (en) * | 2017-08-14 | 2019-02-26 | 上海科胜药物研发有限公司 | A kind of preparation method of Sai Erxipa intermediate |
| CN112939877A (en) * | 2019-12-11 | 2021-06-11 | 南京理工大学 | Synthesis method of diphenylpyrazine derivative |
| CN113717115A (en) * | 2021-08-27 | 2021-11-30 | 湖北石河医药科技有限公司 | Preparation method of celecoxib intermediate and application of celecoxib intermediate in preparation of celecoxib |
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| CN108069914A (en) * | 2016-11-17 | 2018-05-25 | 江苏艾立康药业股份有限公司 | A kind of preparation method of West pa lattice crystal form |
| CN109384734A (en) * | 2017-08-14 | 2019-02-26 | 上海科胜药物研发有限公司 | A kind of preparation method of Sai Erxipa intermediate |
| CN109384734B (en) * | 2017-08-14 | 2023-04-11 | 上海科胜药物研发有限公司 | Preparation method of Selsemipa intermediate |
| CN108440421A (en) * | 2018-05-14 | 2018-08-24 | 湖南华腾制药有限公司 | A kind of deuterated Sai Lexipa and preparation method thereof |
| CN108558653A (en) * | 2018-05-14 | 2018-09-21 | 湖南华腾制药有限公司 | The preparation method of Sai Lexipa intermediates and Sai Lexipa |
| CN108774182A (en) * | 2018-07-11 | 2018-11-09 | 湖南华腾制药有限公司 | A kind of process for purification of Sai Lexipa |
| CN112939877A (en) * | 2019-12-11 | 2021-06-11 | 南京理工大学 | Synthesis method of diphenylpyrazine derivative |
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