CN106496201A - A kind of preparation method of avanaphil crude drug - Google Patents
A kind of preparation method of avanaphil crude drug Download PDFInfo
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- CN106496201A CN106496201A CN201610934462.XA CN201610934462A CN106496201A CN 106496201 A CN106496201 A CN 106496201A CN 201610934462 A CN201610934462 A CN 201610934462A CN 106496201 A CN106496201 A CN 106496201A
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- chloro
- methoxy
- methanol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000003814 drug Substances 0.000 title claims abstract description 18
- 229940079593 drug Drugs 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 73
- 238000004458 analytical method Methods 0.000 claims abstract description 20
- 238000001514 detection method Methods 0.000 claims abstract description 18
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 12
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 239000000047 product Substances 0.000 claims description 50
- OCNMSDZALRAYEX-UHFFFAOYSA-N (3-chloro-4-methoxyphenyl)methanamine Chemical class COC1=CC=C(CN)C=C1Cl OCNMSDZALRAYEX-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 238000000746 purification Methods 0.000 claims description 33
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 235000019257 ammonium acetate Nutrition 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 19
- 239000012043 crude product Substances 0.000 claims description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- -1 ethyl ester pyrimidines Chemical class 0.000 claims description 16
- 125000003375 sulfoxide group Chemical group 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 208000035126 Facies Diseases 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 11
- 238000013517 stratification Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 238000004440 column chromatography Methods 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 10
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 9
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004494 ethyl ester group Chemical group 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000012264 purified product Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 5
- 235000015177 dried meat Nutrition 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000010583 slow cooling Methods 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- 239000004952 Polyamide Substances 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 239000012190 activator Substances 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 3
- 239000004519 grease Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229920002647 polyamide Polymers 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- CGKQZIULZRXRRJ-UHFFFAOYSA-N Butylone Chemical compound CCC(NC)C(=O)C1=CC=C2OCOC2=C1 CGKQZIULZRXRRJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- RHMTZMHPIDIFRE-UHFFFAOYSA-N n-chloro-1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CNCl)C=C1 RHMTZMHPIDIFRE-UHFFFAOYSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical class N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims 4
- 150000001412 amines Chemical class 0.000 claims 2
- 239000005909 Kieselgur Substances 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 238000013019 agitation Methods 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000004575 stone Substances 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 18
- 238000012544 monitoring process Methods 0.000 abstract description 14
- 239000013067 intermediate product Substances 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 230000018044 dehydration Effects 0.000 abstract 1
- 238000006297 dehydration reaction Methods 0.000 abstract 1
- 230000000977 initiatory effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- 230000008569 process Effects 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000004064 recycling Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 101150098694 PDE5A gene Proteins 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- KPHYZXNSRFAWKM-UHFFFAOYSA-N methanesulfonic acid pyrimidin-2-ylmethanamine Chemical compound CS(O)(=O)=O.NCc1ncccn1 KPHYZXNSRFAWKM-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- RZJRJXONCZWCBN-UHFFFAOYSA-N octadecane Chemical compound CCCCCCCCCCCCCCCCCC RZJRJXONCZWCBN-UHFFFAOYSA-N 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MYLBTCQBKAKUTJ-UHFFFAOYSA-N 7-methyl-6,8-bis(methylsulfanyl)pyrrolo[1,2-a]pyrazine Chemical compound C1=CN=CC2=C(SC)C(C)=C(SC)N21 MYLBTCQBKAKUTJ-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- POMDBLUWYDPJHC-UHFFFAOYSA-N N-(pyrimidin-2-ylmethyl)pyrimidine-2-carboxamide Chemical compound N1=C(N=CC=C1)CNC(=O)C1=NC=CC=N1 POMDBLUWYDPJHC-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960000307 avanafil Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010960 commercial process Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229940038384 octadecane Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 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
- 229940046921 stendra Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to medical synthesis technical field, discloses a kind of preparation method of avanaphil crude drug.Preparation method of the present invention is with intermediate MI as initiation material, the condensation reaction of oxidized reaction and L proline, hydrolysis, dehydration condensation obtain avanaphil successively, for the problem that existing avanaphil preparation method lacks monitoring and analysis method, the invention provides a set of effective monitoring and detection method, it is capable of the quality of effective control intermediate product and end-product, each step purifying method be adjusted simultaneously after is particularly suitable for industrialized great production so that the purity of intermediate product and end-product reaches higher level.
Description
Technical field
The present invention relates to medical synthesis technical field, particularly relates to a kind of preparation side of avanaphil crude drug
Method.
Background technology
Avanaphil (Avanafil) is to authorize the exploitation of Vivus companies of the U.S. by Japanese Tanabe Mitsubishi Pharmaceutical Co
For treating the medicine of male erectile dysfunction, list in the U.S. in the approval of the 27 Nikkei U.S. FDA of April in 2012, trade name
For Stendra.The medicine is a kind of orally quick-acting high selectivity PDE5 (PDE-5) inhibitor.
Avanaphil is white or off-white color crystalline powder, without special odor.This product is easily held in glacial acetic acid,
Dissolve in 0.1mol/L hydrochloric acid solutions, slightly soluble, insoluble in water in ethanol.Avanaphil CAS：330784-47-9, in chirality
The heart：One, molecular formula：C23H26ClN7O3, molecular weight：483.95,160 DEG C -165 DEG C of fusing point, structural formula is shown in formula I：
The synthetic method of avanaphil is more, and Chinese patent CN104003981A discloses that a kind of route is shorter, each step is anti-
More conventional synthetic route is answered, but in the patented technology, lacks the detection method for the reaction of each step, and respectively walk finished product
Detection method.In commercial process, each step product needed reaches certain purity requirement can carry out next step
Reaction, can otherwise affect the quality of subsequent reactions product, purge process is brought compared with burden.
Although patent CN104003981A discloses specific course of reaction and means of purification, but it is not disclosed how
The method of detection reaction process, reaction process suitable termination have no definite foundation, while the intermediate product purity of each step is not draped over one's shoulders yet
Dew, this process may be only available for laboratory research, and be really applied to industrialized production and also lack maturation condition.Mesh
Before, not yet there is relevant report with regard to quality analysiss in avanaphil crude drug building-up process and the control method country, particularly
Quality analysiss and control method for patent CN104003981A synthetic route.In addition, the patent is in means of purification
Shortcomings, it is impossible to improve the purity of intermediate product and finished product to greatest extent.
Content of the invention
In view of this, it is an object of the invention to provide a kind of preparation method of avanaphil crude drug so that the preparation
Increase quality monitoring method and analysis method to intermediate product and end-product avanaphil in method, beneficial to industrialized production in
Real-time monitoring and control.
Another kind of purpose of the present invention is to provide a kind of preparation method of avanaphil crude drug so that the preparation method
Optimal improvements are obtained to the purifying process of intermediate product and end-product, improve purity after purification.
To achieve these goals, the present invention provides following technical scheme：
A kind of preparation method of avanaphil crude drug, including：
The oxidized reaction of step 1,2- methyl mercapto -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines obtains 2- first
Sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidine crude products, then purified product；
Step 2, step 1 product 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl esters after purification are phonetic
Pyridine, under conditions of acid binding agent is present, carries out condensation reaction with L- dried meat ammonia alcohol, obtains (S) -2- (2- methylol -1- pyrrolidines
Base) -4- (3- chloro-4-methoxy benzylamines) -5- Ethyl formate pyrimidine crude products, then purified product；
Step 3, step (2) product (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxies after purification
Benzylamine) -5- Ethyl formate pyrimidines, in the basic conditions, (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- are obtained through hydrolysis
Chloro-4-methoxy benzylamine) -5- pyrimidinecarboxylic acid crude products, then purified product；
Step 4, step (3) product (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxies after purification
Benzylamine) -5- pyrimidinecarboxylic acids, amidatioon is carried out under conditions of alkalescence condition and activator, condensing agent, catalyst are present, obtain
Final products (S) -2- [2- (methylol) -1- pyrrolidinyls] -4- [(3- chloro-4-methoxy benzyls) amino] -5- [N- (2 pyrimidines
Ylmethyl) carbamoyl] pyrimidine, i.e. avanaphil crude product, then purification end-product；
Wherein, the reaction of step 1-4 is monitored reaction end with HPLC and carries out quality analysiss to product, and HPLC is with octadecane
Base silane key and silica gel are filler, with Spirit of Mindererus .-methanol or methanol-water as mobile phase, Detection wavelength 265nm, and column temperature
30-35 DEG C, flow velocity 0.5-1.0ml/min.
Intermediate product and the reaction monitoring method of end-product and lacking for mass analysis method be there is no for the reaction scheme
Fall into, the invention provides a set of monitoring and analysis method, be able to can control effectively when industrialized great production is carried out, protect
Card obtains qualified products.
Wherein, preferably, in the step 1 and step 2 HPLC with 0.3-0.5% Spirit of Mindererus .-methanol or methanol-
Water is mobile phase, and when reaction end is detected, 0.3-0.5% Spirit of Mindererus. is 20 with the volume ratio of methanol:80, first alcohol and water
Volume ratio be 70:30；When quality analysiss are carried out to product, 0.3-0.5% Spirit of Mindererus. is 30 with the volume ratio of methanol:
70, the volume ratio of first alcohol and water is 70:30.
Preferably, HPLC is with 0.3-0.5% Spirit of Mindererus .-methanol as mobile phase, whole in detection reaction in the step 3
During point, 0.3-0.5% Spirit of Mindererus. is 30 with the volume ratio of methanol:70；When quality analysiss are carried out to product, 0.3-0.5%
Spirit of Mindererus. is 35 with the volume ratio of methanol:65.
Preferably, in the step 4 HPLC with 0.3-0.5% Spirit of Mindererus .-methanol or methanol-water as mobile phase,
When detecting reaction end and carrying out quality analysiss to product, 0.3-0.5% Spirit of Mindererus. is 30 with the volume ratio of methanol:
70, the volume ratio of first alcohol and water is 70:30.
On the basis of the above, the present invention has also carried out adjusting and optimizing to the purification process of each intermediate product and end-product, carries
The purity of high product after purification.
Preferably, purification is described in step 1：
2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidine crude products are washed with sodium bicarbonate solution
Washing twice, stratification, sodium chloride solution washing being added to by organic, organic purified water that is added to is washed by stratification, quiet
Layering is put, organic faciess is collected and is dried, filter, filter cake is washed with dichloromethane, and filtrate reduced in volume obtains grease product, i.e.,
For 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines after purification.
Preferably, purification is described in step 2：
(S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- Ethyl formate pyrimidine crude products
Sodium bicarbonate solution is added to stir stratification, lower floor's organic faciess are washed with sodium chloride solution, then use purification water washing, quiet
Layering is put, organic faciess are dried, filtering and concentrating is subsequently adding methyl tertiary butyl ether(MTBE) and is heated to reflux, filtered, filtrate stirring is slowly cold
To 0 ± 5 DEG C of crystallize, white powder is filtered to obtain；
The white powder is dissolved with dichloromethane, then column chromatography, merge organic faciess concentration after the washing of column chromatography solvent,
Recrystallization solvent heating for dissolving is added, to 0 ± 5 DEG C, stirred crystallization is filtered slow cooling, obtain white powder, as after purification
(S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- Ethyl formate pyrimidines.
Wherein, the column chromatography is preferably with silica gel, aluminium oxide, and polyamide or kieselguhr are column chromatography solvent described in inserts
Preferably dichloromethane, chloroform, methylene bromide, dichloroethanes, tetrahydrofuran, DMF, acetone, acetic acid
One or more in ethyl ester, petroleum ether etc.；The recrystallization solvent is preferably ether, butyl ether, butyl oxide, n-butyl ether,
One or more in methyl tertiary butyl ether(MTBE), ethyl acetate, petroleum ether, normal hexane etc..
Preferably, purification is described in step 3：
By (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acid crude product mistakes
Filter, filtrate cool to 25 ± 5 DEG C, are slowly added to acid solution, control temperature at 30 ± 5 DEG C, to system pH<3, then stirred
Filter, gained solid are beaten with purified water, are filtered, are subsequently adding solvent refluxing, and heat filtering obtains white powder, and drying under reduced pressure is obtained
To (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acids after purification.
Wherein, the acid solution is preferably dilute hydrochloric acid, dilute sulfuric acid, acetic acid, sodium acetate, phosphoric acid, and boric acid, in citric acid solution
One or more；The solvent is preferably one or more in methanol, ethanol, ethyl acetate, petroleum ether etc..
Preferably, purification is described in step 4：
Ethyl acetate is added in avanaphil crude product, is stirred, is slowly added to purified water, reaction system slowly heats up
To 25 ± 5 DEG C, charging is stirred after finishing, and is filtered；Filter cake adds purified water to be beaten, and filters, after solids with methanol backflow dissolving, slowly
0-10 DEG C is cooled to, stirred crystallization is filtered, and pressure is dried to obtain avanaphil after purification.
After purification, the product in step 1 can reach more than 98% purity, step to purification process after the present invention is improved
In 2, product purity is not less than product in 98%, step 3 and is not less than final product list in 99.5%, step 4 miscellaneous no more than 0.1%,
Always miscellaneous be less than 0.4%, purity is more than 99.6%；And the purity that existing patent CN104003981A respectively walks product is below this
Bright.
From above technical scheme, the present invention lacks monitoring with analysis method for existing avanaphil preparation method
Problem, there is provided a set of effective monitoring and detection method, is capable of the quality of effective control intermediate product and end-product, with
When be adjusted after each step purifying method so that the purity of intermediate product and end-product reaches higher level, be particularly suitable for industry
Change big production.
Description of the drawings
Fig. 1 show step 1 reaction monitoring HPLC spectrograms of the present invention；
Fig. 2 show step 1 of the present invention and step 2 reaction monitoring HPLC spectrograms；
Fig. 3 show step 2 reaction monitoring HPLC spectrograms of the present invention；
Fig. 4 show step 2 product analysis HPLC spectrograms of the present invention；
Fig. 5 show step 3 reaction monitoring HPLC spectrograms of the present invention；
Fig. 6 show step 3 product analysis HPLC spectrograms of the present invention；
Fig. 7 show step 4 reaction monitoring HPLC spectrograms of the present invention；
Fig. 8 show step 4 product analysis HPLC spectrograms of the present invention；
Fig. 9 show step 4 product analysis HPLC spectrograms of the present invention；
Figure 10 show step 1 product nuclear magnetic spectrogram of the present invention；
Figure 11 show step 2 product nuclear magnetic spectrogram of the present invention；
Figure 12 show step 3 product nuclear magnetic spectrogram of the present invention；
Figure 13 show step 4 product nuclear magnetic spectrogram of the present invention；
Figure 14 show reaction mechanism mechanism of reaction figure of the present invention.
Specific embodiment
The embodiment of the invention discloses a kind of preparation method of avanaphil crude drug, those skilled in the art can use for reference
Present disclosure, is suitably modified technological parameter realization.Specifically, all similar replacements and change are to this area skill
It is it will be apparent that they are considered as being included in the present invention for art personnel.A kind of avanaphil raw material of the present invention
The preparation method of medicine is described by preferred embodiment, and related personnel substantially can be without departing from present invention, spirit
With preparation method as herein described is modified in scope or suitably change and combine, realize and apply the technology of the present invention.
The present invention prepares avanaphil process referring to Fig. 1, and specific course of reaction can also refer to patent CN104003981A
In reactional equation Formulas I and embodiment 1, the present invention in substantially flow process as follows
1) -5- carboxylic acid, ethyl ester pyrimidines are oxidized reacts for intermediate-MI, 2- methyl mercapto -4- (3- chloro-4-methoxy benzylamines)
Arrive intermediate-M II, 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines, during using HPLC as
Reaction end is monitored, and intermediate-M II can be detected not as finished product, directly carry out next step reaction；
2) intermediate-M II, 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines are in acid binding agent
Under conditions of presence, carry out condensation reaction with L- dried meat ammonia alcohol, during monitored using HPLC as reaction end, reaction terminates, post
Chromatography carries out remove impurity, then carries out solvent recrystallization, obtains intermediate-M III, (S) -2- (2- methylol -1- pyrrolidinyls) -4-
(3- chloro-4-methoxy benzylamines) -5- Ethyl formate pyrimidines；
3) intermediate-M III, (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- formic acid
Ethyl ester pyrimidine, in the basic conditions, through hydrolysis obtain intermediate-M IV, during using HPLC as reaction end monitor, (S)-
2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acids；
4) intermediate-M IV, (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidines
Formic acid, carries out amidatioon under conditions of alkalescence condition and activator, condensing agent, catalyst are present, during using HPLC as
Reaction end is monitored, and obtains final products AV, (S) -2- [2- (methylol) -1- pyrrolidinyls] -4- [(3- chloro-4-methoxy benzyls
Base) amino] -5- [N- (2 Pyrimidylmethyl) carbamoyl] pyrimidine, i.e. avanaphil finished product.
In preparation method of the present invention, in step 1,2- methyl mercaptos -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl esters are phonetic
Pyridine and oxidant metachloroperbenzoic acid (m-CPBA), hydrogen peroxide, peracetic acid, benzoyl peroxide, dibenzoyl peroxide
Deng one or more reactions, inventory is 0.55-0.65 times, and reaction dissolvent is dichloromethane, chloroform, methylene bromide, two
Ethyl chloride, tetrahydrofuran, DMF, acetone etc., reaction temperature are -10-0 DEG C, and the response time is 2-5 hours,
Speed of agitator is 150-200rpm, obtains 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines, yield
Scope：100%-110%；
In step 2,2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl esters pyrimidine is having depositing for acid binding agent
Under, acid binding agent is triethylamine, diethylamine, DMF, Feldalat NM, Sodium ethylate, sodium hydride, potassium carbonate, carbonic acid
One or more in sodium, pyridine etc., are condensed with L- dried meat ammonia alcohol, and inventory is 0.30-0.40 times, and reaction dissolvent is dichloro
Methane, chloroform, methylene bromide, dichloroethanes, tetrahydrofuran, DMF, acetone etc., reaction temperature is
20-30 DEG C, the response time is 5.5-6 hours, and speed of agitator is 150-200rpm, and recrystallization temperature is -5-5 DEG C, analyses crystal time
For 2-4 hours, column chromatography inserts are silica gel, aluminium oxide, polyamide, kieselguhr etc., and column chromatography solvent is dichloromethane, trichlorine
In methane, methylene bromide, dichloroethanes, tetrahydrofuran, DMF, acetone, ethyl acetate, petroleum ether etc. one
Kind or several, recrystallization solvent is ether, butyl ether, butyl oxide, n-butyl ether, methyl tertiary butyl ether(MTBE), ethyl acetate, petroleum ether, just
One or more in hexane etc., obtain (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5-
Ethyl formate pyrimidine, yield spectra：45%-70%；
Step 1 products therefrom 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl esters pyrimidine is viscous fluid
Body, is not solidified, and continues reaction by being evaporated off after partial solvent；Reaction can be merged into a step and be connected by step 1 and step 2
Continuous reaction；
(S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- formic acid second in the step 3
Ester pyrimidine is in the basic conditions, diethylamine, triethylamine, diisopropyl base ethamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate,
One or more in sodium carbonate, potassium carbonate, pyridine etc. are hydrolyzed, and inventory is 1.3-2.0 times, and reaction dissolvent is that diformazan is sub-
Sulfone, acetone, dichloromethane, tetrahydrofuran etc., reaction temperature be 25-35 DEG C, the response time be 2.5-3.5 hours, speed of agitator
For 200-250rpm, it is dilute hydrochloric acid to adjust acid used by pH value, dilute sulfuric acid, acetic acid, sodium acetate, phosphoric acid, boric acid, in citric acid etc.
Plant or several, adjust pH<3, the solvent of backflow is methanol, ethanol, ethyl acetate, and one or more in petroleum ether etc., during backflow
Between for 2-6 hours, obtain (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acids,
Yield spectra：80%-100%；
(S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acids in step 4；
It is diethylamine in the basic conditions, triethylamine, diisopropyl base ethamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate,
Potassium carbonate, pyridine one or more, inventory be 1-1.3 times, catalyst be I-hydroxybenzotriazole (HOBT), inventory 0.4-
0.7 times, aminomethyl pyrimidine mesylate, inventory are 0.6-0.8 times, and condensing agent is 1- ethyls-(3- dimethylaminopropyl)
Carbodiimide hydrochloride (EDCI), inventory are 0.5-0.7 times, reaction dissolvent dimethyl sulfoxide, acetone, dichloromethane, tetrahydrochysene furan
Mutter, DMF etc., reaction temperature are 20-30 DEG C, and the response time is 12-36 hours, and speed of agitator is 150-
200rpm, recrystallisation solvent are methanol, and crystallize temperature is 0-10 DEG C, and the crystallize time is more than 15 hours, obtains (S) -2- [2-
(methylol) -1- pyrrolidinyls] -4- [(3- chloro-4-methoxy benzyls) amino] -5- [N- (2 Pyrimidylmethyl) carbamyls
Base] pyrimidine, i.e. avanaphil raw material finished product, yield spectra：50%-80%.
Intermediate-MI in the present invention is existing known compound, can prepare according to the following reaction mechanism mechanism of reaction：
Additionally, the three wastes of the present invention are environmentally friendly, the recyclable recycling of all multi-solvents in reaction, such as each reaction dissolvent are returned
Receive and can utilize hypergravity rectifying device, the recyclable recycling of the dichloromethane in step 1, the dichloromethane excessively used by post in step 2
The recyclable recycling of methyl tertiary butyl ether(MTBE) used by alkane and recrystallization, the recyclable recycling of the ethanol of the beating in step 3, step
Recyclable recycling of the methanol of recrystallization etc. in 4.
Just a kind of preparation method of avanaphil crude drug provided by the present invention is described further below.
Embodiment 1：The preparation of 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines
By 2- methyl mercapto -4- (3- chloro-4-methoxy benzylamines), (intermediate-MI, Fig. 1, during reservation for -5- carboxylic acid, ethyl ester pyrimidines
Between 16.671) 12.0Kg and dichloromethane 134.0Kg add reactor, stirring, dissolving；Controlling reaction temperature is -5 ± 5 DEG C, delays
The slow dichloromethane solution for adding m-CPBA6.9Kg and 178.0Kg；After charging is finished, with 0.3% Spirit of Mindererus .-methanol
(20:80) it is mobile phase, Detection wavelength 265nm；Column temperature：30 DEG C, flow velocity：1.0ml/min, HPLC monitor reaction end.(without in
During mesosome-MI peaks, it is considered as reaction completely；If reaction is not completely, then extend the response time.) reaction finish (Fig. 2), reactant liquor
Washed twice with sodium bicarbonate solution 132.0kg, stratification separates organic faciess；Sodium chloride solution 168.0kg washings are added,
Stratification, separates organic faciess；120.0kg purification water washings, stratification is added to collect organic faciess；Anhydrous sodium sulfate drying,
Filter, filter cake is washed with a small amount of dichloromethane；Filtrate reduced in volume, obtains grease 2- first sulfoxide group -4- (the chloro- 4- methoxies of 3-
Base benzylamine) -5- carboxylic acid, ethyl ester pyrimidines (intermediate-MII), 13.1Kg, yield 109%, purity ＞ 98%.
Nucleus magnetic hydrogen spectrum HNMR：δ 1.40 (t, J=5.68Hz, J=11.36Hz, 3H), 2.88 (s, 3H), 3.89 (s, 3H),
4.39 (q, J=5.68Hz, J=11.36Hz, 2H), 4.70 (dd, J=1.88Hz, J=4.52Hz, 2H), 6.90 (d, J=
6.72Hz, 1H), 7.24 (dd, J=1.60Hz, J=6.72Hz, 1H), 7.37 (d, J=1.60Hz, 1H), 8.81 (brs, 1H),
8.91 (s, 1H)；Show to be obtained 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines (intermediate -
MII, Figure 10).
Embodiment 2：(S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- Ethyl formates
The preparation of pyrimidine
By 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines, (intermediate-MII, Fig. 2 retain
Time, 5.882) 13.0kg, dichloromethane 64.0kg added reactor dissolving；0 ± 5 DEG C of reaction system of control, is slowly added to L- dried meat
The mixed solution of ammonia 3.9kg, triethylamine 3.9kg and dichloromethane 6.5kg；After having fed, then it is warming up to 25 ± 5 DEG C of reactions；
With 0.3% Spirit of Mindererus .-methanol (20:80) it is mobile phase, Detection wavelength 265nm；Column temperature：30 DEG C, flow velocity：1.0ml/min,
HPLC monitors reaction end.(during without intermediate-MII peaks, it is considered as reaction completely；If reaction is not completely, then when extending reaction
Between.) after completion of the reaction (Fig. 3), add sodium bicarbonate solution 71.5kg, stir, stratification, lower floor's organic faciess chlorination
Sodium solution 65.0kg is washed, then purifies water washing with 65.0kg, stratification；Organic faciess 4.6kg anhydrous sodium sulfate dryings, mistake
Filter concentration.Add 130.0kg methyl tertiary butyl ether(MTBE)s to be heated to reflux, filter, filtrate stirring is slowly cooled to 0 ± 5 DEG C of crystallize, filters
White powder.250.0kg dichloromethane and above-mentioned white powder is added in reactor, and completely, 13.0kg silica gel is too fast for dissolving
Fast post, silica gel are washed with q. s. methylene chloride, merge organic faciess concentration.130.0kg methyl tertiary butyl ether(MTBE) heating for dissolving is added, is delayed
0 ± 5 DEG C is cooled to slowly, and stirred crystallization is filtered, obtains white powder (S) -2- (2- methylol -1- pyrrolidinyls) -4- (the chloro- 4- of 3-
Methoxybenzylamine) -5- Ethyl formate pyrimidines, with 0.3% Spirit of Mindererus.-methanol (30:70) it is mobile phase, Detection wavelength
265nm；Column temperature：30 DEG C, flow velocity：1.0ml/min, HPLC detection finished product (intermediate-MIII, Fig. 4, retention time 12.848),
55 ± 5 DEG C of drying under reduced pressure obtain 6.85kg, yield 53%, purity >=98%.
Nucleus magnetic hydrogen spectrum HNMR：δ 1.33 (t, J=7.12Hz, J=14.24Hz, 3H), 1.67 (m, 1H), 1.91 (m, 2H),
2.12 (m, 1H), 3.73 (m, 4H), 3.88 (s, 3H), 4.26 (Abq, J=7.08Hz, J=14.20Hz, 2H), 4.59 (d, J=
4.92Hz, 2H), 6.60 (brs, 1H), 6.88 (d, J=8.40Hz, 1H), 7.19 (Abq, J=1.76Hz, J=8.40Hz,
1H), 7.36 (d, J=1.76Hz, 1H), 8.54 (s, 1H), 8.65 (brs, 1H)；Show (S) -2- (2- methylol -1- pyrroles are obtained
Cough up alkyl) -4- (3- chloro-4-methoxy benzylamines) -5- Ethyl formate pyrimidines (intermediate-MIII, Figure 11).
Embodiment 3：(S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acids
Preparation
By (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- Ethyl formate pyrimidines (in
Mesosome-MIII) 6.7kg, DMSO 29.5kg add reactor in, open stirring and dissolving, by temperature of reaction system control 30 ± 5
DEG C, 8.7kg10% sodium hydrate aqueous solutions are slowly added to, gentle heat release is reacted, with 0.3% Spirit of Mindererus .-methanol (30:70)
For mobile phase, Detection wavelength 265nm；Column temperature：30 DEG C, flow velocity：1.0ml/min, HPLC monitor reaction end.(without intermediate-
During MIII peaks, it is considered as reaction completely；If reaction completely, is not then added sodium hydroxide solution and extends the response time.) reacted
After finishing (Fig. 5), filter；Filtrate is cooled to 25 ± 5 DEG C, 20% aqueous citric acid solution 40.2kg is slowly added to, temperature, inspection is controlled
Survey system pH<3；Charging is finished, stirring, is filtered, and solid is beaten at 30 ± 10 DEG C with 67.0kg purified water, is filtered；Add
67.0kg alcohol refluxs, heat filtering obtain white powder；Wet product in 55 ± 5 DEG C of drying under reduced pressure, obtain (S) -2- (2- methylols -
1- pyrrolidinyls) (3.505) intermediate-MIV, Fig. 6, retention time do -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acids
Dry product 6.24kg, yield 93%, with 0.3% Spirit of Mindererus .-methanol (35:65) it is mobile phase, Detection wavelength 265nm；Column temperature：
30 DEG C, flow velocity：1.0ml/min, HPLC detect finished product, purity >=99.5%.
Nucleus magnetic hydrogen spectrum HNMR (Figure 10)：δ 1.94 (m, 4H), 3.34 (m, 1H), 3.51 (m, 2H), 3.61 (m, 1H), 3.82
(s, 3H), 4.10 (m, 1H), 4.56 (d, J=4.9Hz, 2H), 7.08 (d, J=8.4Hz, 1H), 7.29 (d9, J=8.3Hz,
1H), 7.41 (d, J=4.6Hz, 1H), 8.45 (d, J=4.8Hz, 1H), 8.67 (d, J=5.0Hz, 1H)；Show to be obtained (S)-
2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acids (intermediate-MIV, Figure 12).
Embodiment 4：(S) -2- [2- (methylol) -1- pyrrolidinyls] -4- [(3- chloro-4-methoxy benzyls) amino] -5-
The preparation of [N- (2 Pyrimidylmethyl) carbamoyl] pyrimidine (avanaphil crude drug)
DMF 48.8kg are put into reactor, S is added) -2- (2- methylol -1- pyrrolidinyls) -4- (the chloro- 4- methoxies of 3-
Base benzylamine) -5- pyrimidinecarboxylic acids (intermediate-MIV) 6.1kg, aminomethyl pyrimidine mesylate 3.8kg stirrings；Add HOBT
2.9kg, EDCI 3.4kg, diisopropyl ethyl amine 6.7kg, while control feed temperature at 20 ± 5 DEG C；It is anti-that charging finishes control
20 ± 5 DEG C are answered, is reacted 24 ± 12 hours, with 0.3% Spirit of Mindererus .-methanol (30:70) it is mobile phase, Detection wavelength 265nm；
Column temperature：30 DEG C, flow velocity：1.0ml/min, HPLC monitoring reaction.(when intermediate-MIV residuals are less than 0.05%, it is considered as reaction
Completely.) reaction finish (Fig. 7), to reactant liquor add 2.75kg ethyl acetate, stir；79.3kg purified water is slowly added to,
Reaction system is to slowly warm up to 25 ± 5 DEG C；Charging is finished, stirring, is filtered；Plus 30 ± 10 DEG C of beating of 61.0kg purified water, filter,
Obtain avanaphil crude product.After with the dissolving of 146.0kg methanol eddies, to less than 10 DEG C, stirred crystallization is filtered slow cooling；55
± 5 DEG C of drying under reduced pressure obtain 4.08kg (S) -2- [2- (methylol) -1- pyrrolidinyls] -4- [(3- chloro-4-methoxy benzyls) ammonia
Base] -5- [N- (2 Pyrimidylmethyl) carbamoyl] pyrimidine (avanaphil crude drug) finished product, yield 67%, with 0.3% vinegar
Acid ammonium solution-methanol (30:70) it is mobile phase, Detection wavelength 265nm；Column temperature：30 DEG C, flow velocity：1.0ml/min, HPLC are detected
(Fig. 8, retention time is 10.088) or with methanol-water (70 for finished product:30) it is mobile phase, Detection wavelength 265nm；Column temperature：30 DEG C, stream
Speed：1.0ml/min, HPLC detection finished product (Fig. 9, retention time 10.222), purity ＞ 99.6%.
Nucleus magnetic hydrogen spectrum HNMR (Figure 10)：δ 2.00 (m, 4H), 3.59 (m, 4H), 3.70 (dd, J=4.8Hz, 1H), 3.84
(s, 3H), 4.20 (t, J=4.8Hz, 1H), 4.57 (s, 2H), 4.69 (s, 2H), 6.99 (d, 1H), 7.23 (dd, J=2.1Hz,
J=8.4Hz, 1H), 7.33 (t, J=2.1Hz, 1H), 7.36 (d, J=4.8Hz, 1H), 8.43 (s, 1H), 8.73 (d, J=
4.8Hz, 2H)；(S) [(2 is phonetic for N- for -5- for -2- [2- (methylol) -1- pyrrolidinyls] -4- [(3- chloro-4-methoxy benzyls) amino]
Piperidinyl methyl) carbamoyl] pyrimidine (AV, Figure 13), i.e. avanaphil crude drug.
Embodiment 5：The purity detecting of intermediate product and end-product in existing preparation method
With in patent CN104003981A embodiment 1,2-4 one step process as control, (react equivalent to the present invention by wherein the 2nd step
Step 1+ step 2 is reacted), each step product purity after purification is detected, is followed successively by：
2nd step, intermediate-MII purity are 85.7%, and intermediate-MIII purity is 91.6%；
3rd step, intermediate-MIV purity are 90.4%；
4th step, avanaphil crude drug purity are 92.2%.
According to above-mentioned data, the purity of the corresponding step products of the contrast present invention is, it is apparent that the method for the present invention can
To significantly improve the purity of each intermediate product and end-product.
The above is only intended to understand the method for the present invention and its core concept, it is noted that for the art
Those of ordinary skill for, under the premise without departing from the principles of the invention, some improvement and modification can be carried out to the present invention,
These improvement and modification also fall into the protection domain of right of the present invention.
Claims (13)
1. a kind of preparation method of avanaphil crude drug, it is characterised in that include：
The oxidized reaction of step 1,2- methyl mercapto -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines obtains 2- first sulfoxides
Base -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidine crude products, then purified product；
Step 2, step 1 product 2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines after purification,
Under conditions of acid binding agent is present, condensation reaction is carried out with L- dried meat ammonia alcohol, obtain (S) -2- (2- methylol -1- pyrrolidinyls) -4-
(3- chloro-4-methoxy benzylamines) -5- Ethyl formate pyrimidine crude products, then purified product；
Step 3, step (2) product (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzyls after purification
Amine) -5- Ethyl formate pyrimidines, in the basic conditions, (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- are obtained through hydrolysis
Chloro-4-methoxy benzylamine) -5- pyrimidinecarboxylic acid crude products, then purified product；
Step 4, step (3) product (S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzyls after purification
Amine) -5- pyrimidinecarboxylic acids, amidatioon is carried out under conditions of alkalescence condition and activator, condensing agent, catalyst are present, obtain most
Finished product (S) -2- [2- (methylol) -1- pyrrolidinyls] -4- [(3- chloro-4-methoxy benzyls) amino] -5- [N- (2 pyrimidine radicals
Methyl) carbamoyl] pyrimidine, i.e. avanaphil crude product, then purification end-product；
Wherein, the reaction of step 1-4 is monitored reaction end with HPLC and carries out quality analysiss to product, and HPLC is with octadecyl silicon
Alkane key and silica gel are filler, with Spirit of Mindererus .-methanol or methanol-water as mobile phase, Detection wavelength 265nm, and column temperature 30-35
DEG C, flow velocity 0.5-1.0ml/min.
2. preparation method according to claim 1, it is characterised in that HPLC is with 0.3-0.5% in the step 1 and step 2
Spirit of Mindererus .-methanol or methanol-water are mobile phase, 0.3-0.5% Spirit of Mindererus. and methanol when reaction end is detected
Volume ratio is 20:80, the volume ratio of first alcohol and water is 70:30；When quality analysiss are carried out to product, 0.3-0.5% ammonium acetates
Solution is 30 with the volume ratio of methanol:70, the volume ratio of first alcohol and water is 70:30.
3. preparation method according to claim 1, it is characterised in that HPLC is molten with 0.3-0.5% ammonium acetates in the step 3
Liquid-methanol as mobile phase, when reaction end is detected, 0.3-0.5% Spirit of Mindererus. is 30 with the volume ratio of methanol:70；To producing
When thing carries out quality analysiss, 0.3-0.5% Spirit of Mindererus. is 35 with the volume ratio of methanol:65.
4. preparation method according to claim 1, it is characterised in that HPLC is molten with 0.3-0.5% ammonium acetates in the step 4
Liquid-methanol or methanol-water are mobile phase, the 0.3-0.5% ammonium acetates when detecting reaction end and carrying out quality analysiss to product
Solution is 30 with the volume ratio of methanol:70, the volume ratio of first alcohol and water is 70:30.
5. preparation method according to claim 1, it is characterised in that purification is described in step 1：
2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidine crude products are washed two with sodium bicarbonate solution
Secondary, stratification is added to sodium chloride solution washing by organic, and stratification is added to purified water washing by organic, stands and divide
Layer, collects organic faciess and dries, filter, and filter cake is washed with dichloromethane, and filtrate reduced in volume obtains grease product, as pure
2- first sulfoxide group -4- (3- chloro-4-methoxy benzylamines) -5- carboxylic acid, ethyl ester pyrimidines after change.
6. preparation method according to claim 1, it is characterised in that purification is described in step 2：
(S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- Ethyl formate pyrimidines crude product is added
Sodium bicarbonate solution stirs stratification, and lower floor's organic faciess are washed with sodium chloride solution, then use purification water washing, stands point
Layer, organic faciess is dried, filtering and concentrating, is subsequently adding methyl tertiary butyl ether(MTBE) and is heated to reflux, and is filtered, and filtrate stirring is slowly cooled to 0
± 5 DEG C of crystallizes, filter to obtain white powder；
The white powder is dissolved with dichloromethane, then column chromatography, merge organic faciess concentration, add after the washing of column chromatography solvent
Recrystallization solvent heating for dissolving, to 0 ± 5 DEG C, stirred crystallization is filtered, obtains white powder slow cooling, (S) as after purification-
2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- Ethyl formate pyrimidines.
7. preparation method according to claim 6, it is characterised in that the column chromatography is with silica gel, aluminium oxide, polyamide or silicon
Diatomaceous earth is inserts.
8. preparation method according to claim 6, it is characterised in that the column chromatography solvent is dichloromethane, chloroform,
One kind in methylene bromide, dichloroethanes, tetrahydrofuran, DMF, acetone, ethyl acetate, petroleum ether etc. or
Two or more.
9. preparation method according to claim 6, it is characterised in that the recrystallization solvent is ether, butyl ether, butyl oxide,
One or more in n-butyl ether, methyl tertiary butyl ether(MTBE), ethyl acetate, petroleum ether, normal hexane etc..
10. preparation method according to claim 1, it is characterised in that purification is described in step 3：
(S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acids crude product is filtered, filter
Liquid cools to 25 ± 5 DEG C, is slowly added to acid solution, controls temperature at 30 ± 5 DEG C, to system pH<3, then agitation and filtration, gained
Solid is beaten with purified water, is filtered, is subsequently adding solvent refluxing, and heat filtering obtains white powder, and drying under reduced pressure is obtained after purification
(S) -2- (2- methylol -1- pyrrolidinyls) -4- (3- chloro-4-methoxy benzylamines) -5- pyrimidinecarboxylic acids.
11. preparation methoies according to claim 10, it is characterised in that the acid solution is dilute hydrochloric acid, dilute sulfuric acid, acetic acid,
Sodium acetate, phosphoric acid, boric acid, one or more in citric acid solution.
12. preparation methoies according to claim 10, it is characterised in that the solvent is methanol, ethanol, ethyl acetate, stone
One or more in oily ether etc..
13. preparation methoies according to claim 1, it is characterised in that purification is described in step 4：
Ethyl acetate is added in avanaphil crude product, is stirred, is slowly added to purified water, reaction system is to slowly warm up to 25
± 5 DEG C, charging is stirred after finishing, and is filtered；Filter cake adds purified water to be beaten, and filters, after solids with methanol backflow dissolving, slow cooling
To 0-10 DEG C, stirred crystallization is filtered, and pressure is dried to obtain avanaphil after purification.
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| CN108658872A (en) * | 2018-05-03 | 2018-10-16 | 无锡富泽药业有限公司 | A kind of preparation method of avanaphil intermediate |
| CN109438421A (en) * | 2018-11-13 | 2019-03-08 | 扬州市三药制药有限公司 | A kind of polishing purification method of avanaphil intermediate |
| CN111208232A (en) * | 2020-01-20 | 2020-05-29 | 山东省药学科学院 | Analysis method of related substances in avanafil and preparation thereof |
| CN115304585A (en) * | 2022-08-23 | 2022-11-08 | 江苏恒沛药物科技有限公司 | Preparation method of avanafil |
| CN118777452A (en) * | 2024-06-21 | 2024-10-15 | 北京沃邦医药科技有限公司 | A method for detecting impurity G of avanafil |
| CN119039235A (en) * | 2024-08-20 | 2024-11-29 | 湖北省医药工业研究院有限公司 | Method for synthesizing avanafil, intermediate and application |
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| CN108658872A (en) * | 2018-05-03 | 2018-10-16 | 无锡富泽药业有限公司 | A kind of preparation method of avanaphil intermediate |
| CN109438421A (en) * | 2018-11-13 | 2019-03-08 | 扬州市三药制药有限公司 | A kind of polishing purification method of avanaphil intermediate |
| CN111208232A (en) * | 2020-01-20 | 2020-05-29 | 山东省药学科学院 | Analysis method of related substances in avanafil and preparation thereof |
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| CN118777452A (en) * | 2024-06-21 | 2024-10-15 | 北京沃邦医药科技有限公司 | A method for detecting impurity G of avanafil |
| CN119039235A (en) * | 2024-08-20 | 2024-11-29 | 湖北省医药工业研究院有限公司 | Method for synthesizing avanafil, intermediate and application |
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