CN110790753B - Ealaprilin p-toluenesulfonate, and preparation method and application thereof - Google Patents
Ealaprilin p-toluenesulfonate, and preparation method and application thereof Download PDFInfo
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- CN110790753B CN110790753B CN201911126445.3A CN201911126445A CN110790753B CN 110790753 B CN110790753 B CN 110790753B CN 201911126445 A CN201911126445 A CN 201911126445A CN 110790753 B CN110790753 B CN 110790753B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 155
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000003379 elimination reaction Methods 0.000 claims abstract description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 11
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims abstract description 8
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical class C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 chroman compound Chemical class 0.000 claims description 186
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 170
- 238000006243 chemical reaction Methods 0.000 claims description 158
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 144
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 114
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 100
- 239000003960 organic solvent Substances 0.000 claims description 94
- 238000006640 acetylation reaction Methods 0.000 claims description 71
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 69
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 68
- 239000012074 organic phase Substances 0.000 claims description 68
- 238000000034 method Methods 0.000 claims description 64
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 60
- 238000001035 drying Methods 0.000 claims description 59
- 239000007787 solid Substances 0.000 claims description 56
- 238000001816 cooling Methods 0.000 claims description 51
- 238000001914 filtration Methods 0.000 claims description 50
- 238000005406 washing Methods 0.000 claims description 47
- 238000010992 reflux Methods 0.000 claims description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 39
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 38
- 239000002841 Lewis acid Substances 0.000 claims description 34
- 150000007517 lewis acids Chemical class 0.000 claims description 34
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 29
- 238000010520 demethylation reaction Methods 0.000 claims description 28
- 238000006460 hydrolysis reaction Methods 0.000 claims description 28
- 230000021736 acetylation Effects 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 26
- 229960001082 trimethoprim Drugs 0.000 claims description 26
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
- 239000000047 product Substances 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 19
- 239000012071 phase Substances 0.000 claims description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 17
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 claims description 17
- 238000006722 reduction reaction Methods 0.000 claims description 17
- 238000007363 ring formation reaction Methods 0.000 claims description 17
- 239000012065 filter cake Substances 0.000 claims description 15
- 238000006386 neutralization reaction Methods 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 14
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 claims description 14
- 229960001208 eplerenone Drugs 0.000 claims description 14
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 14
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 13
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 13
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- 238000001953 recrystallisation Methods 0.000 claims description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 150000008282 halocarbons Chemical class 0.000 claims description 10
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 9
- 239000012346 acetyl chloride Substances 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 6
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 6
- 235000019260 propionic acid Nutrition 0.000 claims description 6
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 6
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical class C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 claims description 4
- 230000008033 biological extinction Effects 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- PVFTVTSMZMQOLM-UHFFFAOYSA-N cyclopropane;formaldehyde Chemical compound O=C.C1CC1 PVFTVTSMZMQOLM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 150000002825 nitriles Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000003158 alcohol group Chemical group 0.000 claims 2
- 230000001954 sterilising effect Effects 0.000 claims 2
- 238000004659 sterilization and disinfection Methods 0.000 claims 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 description 145
- 238000004128 high performance liquid chromatography Methods 0.000 description 94
- 238000003756 stirring Methods 0.000 description 76
- 239000000243 solution Substances 0.000 description 48
- 229940125898 compound 5 Drugs 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 230000000052 comparative effect Effects 0.000 description 32
- 238000004809 thin layer chromatography Methods 0.000 description 32
- HWJPWWYTGBZDEG-UHFFFAOYSA-N 5-[(2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)methyl]pyrimidine-2,4-diamine Chemical compound C=12C=CC(C3CC3)OC2=C(OC)C(OC)=CC=1CC1=CN=C(N)N=C1N HWJPWWYTGBZDEG-UHFFFAOYSA-N 0.000 description 26
- 229910052757 nitrogen Inorganic materials 0.000 description 24
- 229940125782 compound 2 Drugs 0.000 description 22
- 238000010438 heat treatment Methods 0.000 description 21
- 239000008346 aqueous phase Substances 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 238000000967 suction filtration Methods 0.000 description 16
- CERYEPWGELTBEI-UHFFFAOYSA-N C1(CC1)C1OC2=C(C(=CC(=C2C(C1)=O)CC=1C(=NC(=NC=1)N)N)OC)OC Chemical compound C1(CC1)C1OC2=C(C(=CC(=C2C(C1)=O)CC=1C(=NC(=NC=1)N)N)OC)OC CERYEPWGELTBEI-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 14
- 229940126214 compound 3 Drugs 0.000 description 14
- 238000001514 detection method Methods 0.000 description 14
- 239000005457 ice water Substances 0.000 description 14
- 239000002994 raw material Substances 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- LEDWOUJPDAFDRJ-UHFFFAOYSA-N 1-[6-[(2,4-diaminopyrimidin-5-yl)methyl]-2-hydroxy-3,4-dimethoxyphenyl]ethanone Chemical compound NC1=NC=C(C(=N1)N)CC1=C(C(=C(C(=C1)OC)OC)O)C(C)=O LEDWOUJPDAFDRJ-UHFFFAOYSA-N 0.000 description 11
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 10
- 238000010791 quenching Methods 0.000 description 9
- 230000000171 quenching effect Effects 0.000 description 9
- FLXHQHPYGDVCDP-UHFFFAOYSA-N C1(CC1)C1OC2=C(C(=CC(=C2C(C1)O)CC=1C(=NC(=NC=1)N)N)OC)OC Chemical compound C1(CC1)C1OC2=C(C(=CC(=C2C(C1)O)CC=1C(=NC(=NC=1)N)N)OC)OC FLXHQHPYGDVCDP-UHFFFAOYSA-N 0.000 description 8
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 8
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
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- 229920006395 saturated elastomer Polymers 0.000 description 6
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- USLKCMBGQFYUFI-UHFFFAOYSA-N dichloromethane;tribromoborane Chemical compound ClCCl.BrB(Br)Br USLKCMBGQFYUFI-UHFFFAOYSA-N 0.000 description 4
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 description 4
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- 230000001376 precipitating effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
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- UXRXKBGRKRYPCP-UHFFFAOYSA-N n-[2-acetamido-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-4-yl]acetamide Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(NC(C)=O)=NC=2)NC(C)=O)=C1 UXRXKBGRKRYPCP-UHFFFAOYSA-N 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- HEMYPJHWBDDJGB-UHFFFAOYSA-N 1-[6-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3,4-trimethoxyphenyl]ethanone Chemical compound NC1=NC=C(C(=N1)N)CC1=C(C(=C(C(=C1)OC)OC)OC)C(C)=O HEMYPJHWBDDJGB-UHFFFAOYSA-N 0.000 description 2
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- 241000191967 Staphylococcus aureus Species 0.000 description 2
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- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 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 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- ZDWYFWIBTZJGOR-UHFFFAOYSA-N bis(trimethylsilyl)acetylene Chemical group C[Si](C)(C)C#C[Si](C)(C)C ZDWYFWIBTZJGOR-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001843 chromanes Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000012910 preclinical development Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses elaprine p-toluenesulfonate, and a preparation method and application thereof. The invention discloses a preparation method of elaprine p-toluenesulfonate shown as a formula 7a, which comprises the following steps: in an aprotic solvent, under the action of p-toluenesulfonic acid, carrying out elimination reaction on chroman compounds shown in formula 6 to obtain elaprine p-toluenesulfonic acid shown in formula 7 a; the aprotic solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide and dimethylsulfoxide. The preparation method of elaprine by using the elaprine p-toluenesulfonate as an intermediate has the advantages of more economical reagent, short route, high yield, low preparation cost and simple post-treatment, and is suitable for industrial production.
Description
Technical Field
The invention relates to elaprine p-toluenesulfonate and a preparation method and application thereof.
Background
The chemical name of the elaprine (English name: ilaprim) is as follows: 5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine, formula 7:
iclaprim, a dihydrofolate reductase inhibitor developed by Motif Bio, was marketed by the FDA in 2018 as a therapeutic for acute bacterial skin and skin structure infection (abssi) indications. Iclaprim is currently in phase II clinical trials as a drug for the treatment of hospital-acquired bacterial pneumonia (HABP). In addition, staphylococcus aureus lung infections are currently in preclinical development as a drug for the treatment of cystic fibrosis patients.
In regulatory terms, iclaprim has been awarded by the FDA in the united states for qualified infectious disease product Qualification (QIDP) and rapid passage. In addition, the FDA has also awarded Iclaprim the orphan drug status for the treatment of staphylococcus aureus lung infections in cystic fibrosis patients.
At present, the main synthesis method in the preparation method of elaprine is as follows:
the method comprises the following steps: (CN 101115743A)
In this route, starting from the compound 1 trimethoprim, by protecting the amino group, where R represents-C (CH) 3 ) 3 or-CH (CH) 3 ) 2 Then carrying out Friedel-crafts acetylation and selective demethylationAnd (3) performing aldol condensation, ring closing, reduction and hydrolysis reaction after elimination to prepare the elaprine. The method has a plurality of defects, the reaction route is long, and the yield is only 4 percent (the yield of the step of preparing the compound 14 without the compound 13 is not written in the patent). And each step in the preparation of compounds 9 to 13 requires column chromatography for purification, which is not suitable for industrial production.
The second method comprises the following steps: (CN 1092194C)
In the route, a compound 16 and bis (trimethylsilyl) acetylene are used as starting materials to prepare a compound 17, wherein the two raw materials are expensive, and a large amount of expensive catalyst cerium (III) chloride heptahydrate is needed in the process of preparing a compound 18 by reducing carbonyl by the compound 17. Moreover, the compound 20 needs to be prepared by mitsnobu reaction, the reaction condition is severe, the yield is extremely low, and the post-treatment is difficult. In conclusion, the route has high cost, low yield and complex operation, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects that in the existing synthesis method of the elaprine, a reagent with high price is needed, the cost is high, the post-treatment is complex, the route is long, the yield is low, the method is not suitable for industrial production and the like, and provides the elaprine p-toluenesulfonate and the preparation method and application thereof.
The invention provides an elaprine p-toluenesulfonate shown as a formula 7a,
the invention also provides a preparation method of the eplerenone p-toluenesulfonate shown in the formula 7a, which comprises the following steps: in an aprotic solvent, under the action of p-toluenesulfonic acid (such as p-toluenesulfonic acid monohydrate), the chroman compound shown as the formula 6 is subjected to elimination reaction to obtain the elaprine p-toluenesulfonic acid salt shown as the formula 7 a;
the aprotic solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide and dimethyl sulfoxide;
in the preparation method of the eplerenone p-toluenesulfonate shown in the formula 7a, the aprotic solvent is preferably a mixed solvent of tetrahydrofuran and dimethyl sulfoxide (the volume ratio of tetrahydrofuran to dimethyl sulfoxide is, for example, 3:1), tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide or dimethyl sulfoxide.
In the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the amount of the aprotic solvent can be the amount conventionally used in the field for such elimination reaction, and preferably, the volume-to-mass ratio of the aprotic solvent to the chroman compound shown in the formula 6 is in the range of 4 to 15ml/g (e.g. 4ml/g, 5.4ml/g, 10ml/g and 11.8 ml/g).
In the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the p-toluenesulfonic acid can be used in an amount which is conventional in the field of such elimination reaction, preferably, the molar ratio of the p-toluenesulfonic acid to the chroman compound shown in the formula 6 is (0.5-3): 1 (for example, 1:1, 1.5.
In the method for preparing the elaprine p-toluenesulfonate represented by the formula 7a, the temperature of the elimination reaction may be a temperature commonly used in the art for such elimination reaction, and the temperature of 60 to 100 ℃ (e.g., 66 ℃,80 ℃) is particularly preferable in the present invention.
In the preparation method of the esloprine p-toluenesulfonate shown in the formula 7a, the progress of the elimination reaction can be monitored according to a detection method (such as TLC, HPLC or GC) which is conventional in the art, and is generally used as an end point of the reaction when the chroman compound shown in the formula 6 disappears, and the time of the elimination reaction is preferably 0.5 to 15 hours (such as 1 hour, 3 hours, 5 hours and 15 hours), and more preferably 0.5 to 2 hours (such as 1 hour).
In the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, after the elimination reaction is finished, part or all of the obtained product exists in the form of the elaprine p-toluenesulfonate shown in the formula 7a (as can be understood by those skilled in the art, the "part or all" is determined by the amount of p-toluenesulfonic acid, and when the molar ratio of the p-toluenesulfonic acid to the chroman compound shown in the formula 6 is less than an equivalent, part of the product preferably exists in the form of the elaprine p-toluenesulfonate shown in the formula 7 a).
In the preparation method of elaprine p-toluenesulfonate shown in formula 7a, the elimination reaction may further include a post-treatment operation, and the post-treatment method and conditions may be those conventional in the art for the elimination reaction, such as cooling to precipitate a solid, filtering, and drying. Or adding halogenated hydrocarbon solvent (such as dichloromethane), washing the organic phase with water, precipitating solid, filtering, and drying.
In the invention, the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a can also comprise the following steps: in an organic solvent, under the action of a reducing reagent, carrying out a reduction reaction on a chromanone compound shown in a formula 5 and/or a salt of the chromanone compound shown in the formula 5 to obtain a chromane compound shown in a formula 6;
the reducing reagent is sodium borohydride and/or potassium borohydride;
in the preparation method of the chromane compound shown in the formula 6, the salt of the chromane compound shown in the formula 5 is formed by the chromane compound shown in the formula 5 and acid in a molar ratio of 1:1, and the acid can be organic acid or inorganic acid which is conventional in the field and can form salt. The acid is particularly preferably acetic acid and/or propionic acid, and further preferably acetic acid.
In the preparation method of the chroman compound shown in the formula 6, the organic solvent can be a solvent commonly used in the reduction reaction in the field, and methanol and/or ethanol are particularly preferred, and methanol is further preferred.
In the preparation method of the chromane compounds shown in the formula 6, the dosage of the organic solvent can be the conventional dosage in the field of reduction reaction, and preferably, the dosage range of the volume-to-mass ratio of the organic solvent to the chromanone compounds shown in the formula 5 and/or the salts of the chromanone compounds shown in the formula 5 is 5-25ml/g (for example, 19.1ml/g and 20 ml/g).
In the preparation method of the chroman compound shown in the formula 6, the amount of the reducing agent can be the amount conventionally used in the reduction reaction in the field, and preferably, the molar ratio of the reducing agent to the chromanone compound shown in the formula 5 is (0.5-2): 1 (e.g., 0.5; the molar ratio of the reducing reagent to the salt of the chromanone compound shown in the formula 5 is (1.5-2): 1 (e.g. 1.5.
In the preparation method of the chroman compound shown in the formula 6, the temperature of the reduction reaction can be the temperature commonly used in the reduction reaction in the field, and the temperature is particularly preferably-15 ℃ to 30 ℃, and further preferably 20 ℃ to 30 ℃.
In the preparation method of the chroman compounds represented by the formula 6, the progress of the reduction reaction can be monitored according to detection methods (such as TLC, HPLC or GC) which are conventional in the art, and generally used as the end point of the reaction when the raw material disappears, and the time of the reduction reaction is preferably 0.5-3 hours (such as 2.5 hours).
In the preparation method of the chroman-type compound shown in the formula 6, the reduction reaction may further include a post-treatment operation, and the post-treatment method and conditions may be conventional in the art, and in the present invention, the following post-treatment steps are preferably included: removing the solvent (e.g., evaporating to dryness), washing (e.g., washing with water), filtering, and recrystallizing (e.g., in an alcoholic solvent and water).
In the preparation method of the chroman compound shown in formula 6, in the post-treatment of the reduction reaction, preferably, the filtering step further includes the following steps: the filter cake is refluxed (e.g. 2-4h, for example 3 h) with an alcoholic solvent (e.g. methanol) and after refluxing the solvent is removed (e.g. concentrated in vacuo).
In the preparation method of the chroman compounds shown in the formula 6, the recrystallization method can be a method which is conventional in the field in the post-treatment of the reduction reaction, and the invention particularly preferably performs recrystallization in a mixture of an alcohol solvent (such as methanol and ethanol) and water (the volume ratio of the alcohol solvent to the water is 5:1, for example).
In the invention, the preparation method of the chroman compound shown as the formula 6 can also comprise the following steps: step (1): in an organic solvent, in the presence of alkali and acid, carrying out aldol condensation-ring closure reaction on a phenol compound shown as a formula 4 and cyclopropane formaldehyde as shown in the specification to obtain a tetrahydropyranone substance; the tetrahydropyranone substance comprises a chromanone compound shown as a formula 5 and the acid;
optionally, further comprising step (2): carrying out neutralization reaction on the tetrahydropyranone substance obtained in the step (1) and alkali as shown in the specification to obtain a chromanone compound shown in a formula 5;
in the preparation method of the chromanone compound shown in the formula 5, in the step (1), the organic solvent can be a conventional organic solvent in the aldol condensation-ring closure reaction in the field; preferably a nitrile solvent (e.g., acetonitrile).
In the preparation method of the chromanone compound shown in the formula 5, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the aldol condensation-ring closure reaction in the field so as not to influence the reaction; the volume-mass ratio of the organic solvent to the phenol compound shown in the formula 4 can be 8ml/g-20ml/g (for example, 10ml/g-15 ml/g).
In the preparation method of the chromanone compound shown in the formula 5, in the step (1), the alkali can be the alkali which is conventional in the aldol condensation-ring closure reaction in the field; for example, organic bases, in the present invention are preferably pyrrolidine and/or piperidine, more preferably pyrrolidine.
In the preparation method of the chromanone compound shown in the formula 5, the molar ratio of the base to the phenol compound shown in the formula 4 is preferably 1:1-2:1 (for example, 1.45.
In the preparation method of the chromanone compound shown in formula 5, in step (1), the acid may be an acid conventional in the art, such as an organic acid, preferably acetic acid and/or propionic acid in the present invention, more preferably acetic acid,
in the preparation method of the chromanone compound shown in the formula 5, in the step (1), the molar ratio of the acid to the phenol compound shown in the formula 4 can be 0.5.
In the preparation method of the chromanone compound shown in the formula 5, in the step (1), the molar ratio of the cyclopropanecarboxaldehyde to the phenol compound shown in the formula 4 is preferably 1:1-2:1 (for example, 1.2.
In the preparation method of the chromanone compound shown in the formula 5, in the step (1), the temperature of the aldol condensation-ring closure reaction may be a temperature conventional in the field of the aldol condensation-ring closure reaction, and in the present invention, is preferably 0 ℃ to 50 ℃ (for example, room temperature of 10 ℃ to 30 ℃).
In the preparation method of the chromanone compound shown in the formula 5, in the step (1), the progress of the aldol condensation-ring closure reaction can be detected by a conventional monitoring method (such as TLC, HPLC or NMR) in the art, and the disappearance or no longer reaction of the phenol compound shown in the formula 4 is generally used as a reaction end point. The reaction time may be 20 to 40 hours.
In the preparation method of the chromanone compound shown in the formula 5, the conditions of the aldol condensation-ring closure reaction can be carried out according to the conditions in the ring closure reaction in the field except the conditions specifically described above.
In one embodiment of the present invention, the tetrahydropyranone compound is composed of the chromanone compound represented by the formula 5 and the acid.
In the present invention, in the tetrahydropyranone compound, a part or all of the chromanone compound represented by the formula 5 and the acid preferably exist in the form of "a salt of the chromanone compound represented by the formula 5" (as will be understood by those skilled in the art, the "part or all" is determined by the amount of the acid used; when the molar ratio of the acid to the phenol compound represented by the formula 4 is less than an equivalent, a part of the chromanone compound represented by the formula 5 and the acid preferably exist in the form of "a salt of the chromanone compound represented by the formula 5"). Wherein, the salt of the benzodihydropyrone compound shown in the formula 5 is preferably the salt formed by the benzodihydropyrone compound shown in the formula 5 and the acid in a molar ratio of 1:1.
In the preparation method of the chromanone compound shown in the formula 5, in the step (2), the operation and conditions of the neutralization reaction can be the operation and conditions which are conventional in the neutralization reaction in the field.
In the preparation method of the chromanone compound shown in the formula 5, in the step (2), the base can be a base which is conventional in the neutralization reaction in the field, such as an alkali metal carbonate (such as sodium carbonate and/or potassium carbonate) and/or an alkali metal bicarbonate (such as sodium bicarbonate and/or potassium bicarbonate). The base may be used in a form conventional in this type of neutralization reaction in the art, for example, in the form of an aqueous solution of the base, for example, a saturated sodium carbonate solution.
The preparation method of the chromanone compound shown in the formula 5 can further comprise post-treatment, and preferably, the post-treatment comprises the following steps: after the aldol condensation-ring closure reaction is finished, filtering and drying a reaction system to obtain the tetrahydropyranone substance;
and/or after the neutralization reaction is finished, filtering and drying a reaction system to obtain the chromanone compound shown as the formula 5.
In the present invention, the preparation method of the chromanone compound shown in formula 5 may further include the following scheme 1 or scheme 2:
the method 1 comprises the following steps of carrying out acetylamino hydrolysis reaction on a phenol compound shown as a formula 8 in an organic solvent in the presence of alkali to obtain the phenol compound shown as a formula 4;
the scheme 2 comprises the following steps of carrying out selective demethylation reaction on an acetophenone compound shown as a formula 3 in an organic solvent in the presence of Lewis acid to obtain a phenol compound shown as a formula 4;
in the scheme 1, the organic solvent can be an organic solvent which is conventional in the field of such an acetamido hydrolysis reaction, and the invention is preferably an alcoholic solvent, such as one or more of methanol, ethanol, and isopropanol, and more preferably methanol.
In the scheme 1, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the acetamido hydrolysis reaction in the field, so as not to influence the reaction; the volume mass ratio of the organic solvent to the phenolic compound shown in the formula 8 is preferably 5ml/g-20ml/g (for example 10ml/g-15 ml/g).
In scheme 1, the base may be a base conventional in the hydrolysis reaction of acetylamino group of this type in the art; the present invention is preferably an alkali metal carbonate, such as sodium carbonate and/or potassium carbonate.
In the scheme 1, the molar ratio of the base to the phenolic compound represented by the formula 8 is preferably 0.1 to 1:1 (e.g. 0.1 to 0.5.
In said scheme 1, the temperature of said acetylamino group hydrolyzing reaction may be a temperature conventional in this type of acetylamino group hydrolyzing reaction in the art, and the present invention is preferably 60 ℃ to 82 ℃ (for example 65 ℃ to 70 ℃).
In the scheme 1, the progress of the acetamido hydrolysis reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the end point of the reaction is generally determined by the disappearance or no longer reaction of the phenolic compound shown in the formula 8. The reaction time may be 0.5 to 2 hours.
In scheme 1, the hydrolysis of the acetamido group can be carried out under the same conditions as those in the hydrolysis of the acetamido group in the art except as specifically described above.
In the embodiment 1, the preparation method may further include a post-treatment, and the post-treatment includes the following steps: after the acetylamino hydrolysis reaction is finished, crystallizing the reaction system (for example, in an ice bath), filtering, washing with water, and drying to obtain the phenol compound shown as the formula 4.
In scheme 2, the organic solvent can be an organic solvent conventional in such selective demethylation reactions in the art; preferably a halogenated hydrocarbon solvent (e.g., dichloromethane and/or chloroform).
In the scheme 2, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the selective demethylation reaction in the field, so that the reaction is not influenced; the volume-mass ratio of the organic solvent to the acetophenone compound shown in formula 3 can be 8ml/g-25ml/g (for example, 10ml/g-20 ml/g).
In the scheme 2, the lewis acid is preferably boron tribromide and/or boron trichloride. The Lewis acid may be used in a form conventional in the art, for example, as a solution in the organic solvent (again, for example, a 1mol/L solution of boron tribromide in methylene chloride).
In the scheme 2, the molar ratio of the lewis acid to the acetophenone compound shown in the formula 3 is preferably 1:1-2:1 (e.g. 1.2.
In scheme 2, the temperature of the selective demethylation reaction can be any temperature conventional in the art for such selective demethylation reactions, and the present invention is preferably from-15 ℃ to 35 ℃ (e.g., -6 ℃ to 30 ℃).
In the scheme 2, the Lewis acid is preferably added dropwise (for example, at-8 ℃) to the acetyl compound represented by the formula 2 and the organic solvent.
In the scheme 2, the progress of the selective demethylation reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance or no longer reaction of the acetophenone compound shown in the formula 3 is generally used as the reaction endpoint. The reaction time may be 2 to 5 hours.
In scheme 2, the conditions for the selective demethylation reaction can be performed according to the conditions in the art for such selective demethylation reaction, except as specifically described above.
In the scheme 2, the preparation method can further comprise post-treatment, and the post-treatment comprises the following steps: after the selective demethylation reaction is finished, the reaction system is subjected to extraction and extinction (for example, methanol is used), concentration (for example, in vacuum) and recrystallization (for example, in ethanol) to obtain the phenol compound shown in the formula 4.
In the above scheme 1, the method may further include scheme a, where the scheme a may include the following steps: in an organic solvent, in the presence of Lewis acid, performing selective demethylation reaction on the acetyl compound shown as the formula 2 as shown in the specification to obtain the phenol compound shown as the formula 8;
in the scheme A, the organic solvent can be an organic solvent which is conventional in the selective demethylation reaction in the field; preferably a halogenated hydrocarbon solvent (e.g., dichloromethane and/or chloroform).
In the scheme A, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the selective demethylation reaction in the field, so that the reaction is not influenced; the volume-mass ratio of the organic solvent to the acetyl compound shown in the formula 2 can be 8ml/g-20ml/g (for example, 10ml/g-15 ml/g).
In the above-mentioned scheme a, the lewis acid is preferably boron tribromide and/or boron trichloride. The lewis acid may be used in a form conventional in the art; for example, in the form of a solution of the organic solvent (e.g., a 1mol/L solution of boron tribromide in methylene chloride).
In the embodiment a, the molar ratio of the lewis acid to the acetyl compound shown in formula 2 may be 1:1-2:1 (e.g. 1.2.
In scheme A, the temperature of the selective demethylation reaction may be that conventional in the art for such selective demethylation reactions, and the present invention is preferably from-15 ℃ to 35 ℃ (e.g., -8 ℃ to 30 ℃).
In the scheme A, the Lewis acid is preferably dripped (for example, at-8 ℃) into the acetyl compound shown in the formula 2 and the organic solvent.
In the scheme A, the progress of the selective demethylation reaction can be detected by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and the disappearance or no longer reaction of the acetyl compound shown in the formula 2 is generally used as the reaction end point. The reaction time may be 10 to 20 hours.
In the scheme A, the conditions of the selective demethylation reaction can be performed according to the conditions in the selective demethylation reaction in the field except the conditions specifically described above.
In the scheme A, the method also comprises post-treatment, wherein the post-treatment comprises the following steps: after the selective demethylation reaction is finished, the reaction system is extracted and extinguished (for example, ice water is used for extraction and extinction), the pH is adjusted to about 6 (for example, saturated sodium carbonate aqueous solution is used), and the phenol compound shown in the formula 8 can be obtained through filtration and recrystallization (for example, in isopropanol).
In the scheme 2, the method can further comprise a scheme B, and the scheme B can comprise the following steps; in an organic solvent, in the presence of alkali, performing the following acetylamino hydrolysis reaction on an acetyl compound shown as a formula 2 to obtain an acetophenone compound shown as a formula 3;
in the embodiment B, the organic solvent may be an organic solvent commonly used in the field of such an acetamido hydrolysis reaction, and the present invention is preferably an alcohol solvent, such as one or more of methanol, ethanol, and isopropanol, and more preferably methanol.
In the scheme B, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the acetamido hydrolysis reaction in the field, so that the reaction is not influenced; the volume mass ratio of the organic solvent to the acetyl compound shown in the formula 2 is preferably 5ml/g-15ml/g (for example 9ml/g-11 ml/g).
In scheme B, the base may be a base conventional in this type of acetylamino hydrolysis reaction in the art; the present invention is preferably an alkali metal carbonate, such as sodium carbonate and/or potassium carbonate.
In the embodiment B, the molar ratio of the base to the acetyl compound represented by the formula 2 is preferably 0.1 to 1:1 (e.g. 0.1 to 0.7.
In the embodiment B, the temperature of the hydrolysis reaction of the acetamido group can be the temperature conventional in the field of such hydrolysis reaction of the acetamido group, and the temperature of the invention is preferably 60 ℃ to 82 ℃ (for example 65 ℃ to 70 ℃).
In the scheme B, the progress of the acetamido hydrolysis reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance or no longer reaction of the acetyl compound represented by the formula 2 is generally used as the reaction endpoint. The reaction time may be 0.5 to 2 hours.
In the above-mentioned embodiment B, the respective conditions of the hydrolysis reaction of the acetylamino group may be carried out according to the conditions in the hydrolysis reaction of the acetylamino group as described in the art except those specifically mentioned above.
In the scheme B, the method also comprises post-treatment, wherein the post-treatment comprises the following steps: after the acetylamino hydrolysis reaction is finished, crystallizing a reaction system (such as in ice bath), filtering, washing with water, and drying to obtain the acetophenone compound shown in the formula 3.
In the scheme A or the scheme B, the following scheme a or scheme B can be further included:
the scheme a comprises the following steps: carrying out acetylation reaction on trimethoprim shown in a formula 1 and an acetylation reagent in an organic solvent in the presence of Lewis acid to obtain an acetyl compound shown in a formula 2;
the scheme b comprises the following steps: in an organic solvent, in the presence of Lewis acid, acetylating an acetamide compound shown as a formula 1a and an acetylating reagent to obtain an acetylate compound shown as a formula 2;
in the scheme a, the organic solvent can be an organic solvent which is conventional in such acetylation reaction in the field, and the invention is preferably a halogenated hydrocarbon solvent, such as chloroform, one or more of dichloromethane and dichloroethane, and more preferably chloroform.
In the scheme a, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the acetylation reaction in the field, so that the reaction is not influenced; the volume-mass ratio of the organic solvent to the trimethoprim as shown in the formula 1 can be 5ml/g-15ml/g (for example, 8ml/g-10 ml/g).
In the scheme a, the acetylation reagent can be an acetylation reagent which is conventional in the acetylation reaction in the field; in the present invention, acetyl chloride and/or acetic anhydride are preferred, and acetic anhydride is more preferred.
In the embodiment a, the molar ratio of the acetylation reagent to the trimethoprim shown in the formula 1 is preferably 3:1-6:1 (for example, 4:1-5:1).
In scheme a, the lewis acid may be a lewis acid conventional in this type of acetylation reaction in the art; tin tetrachloride is preferred.
In the scheme a, the molar ratio of the Lewis acid to the trimethoprim shown in the formula 1 is preferably 1:1-3:1 (for example 2:1-3:1).
In scheme a, the temperature of the acetylation reaction may be a temperature conventional in the art for such acetylation reactions, and the temperature of the present invention is preferably 25 ℃ to 85 ℃ (e.g., 60 ℃ to 65 ℃).
In the scheme a, the progress of the acetylation reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the termination point of the reaction is generally determined when the trimethoprim shown in the formula 1 disappears or no longer reacts. The reaction time may be 1 to 5 hours.
In the scheme a, the acetylation reaction conditions can be performed according to the conditions in the acetylation reaction in the art except the conditions specifically described above.
In the scheme a, the method can also comprise post-treatment, and the post-treatment comprises the following steps: after the acetylation reaction is finished, the reaction system is subjected to extraction (for example, ice water extraction), liquid separation to obtain an organic phase and an aqueous phase, water washing of the organic phase, extraction of the aqueous phase with an organic solvent (the organic solvent may be chloroform), pH adjustment of the combined organic phase to 7-8 (for example, saturated aqueous sodium carbonate solution), liquid separation to obtain an organic phase, water washing of the organic phase, organic phase drying (for example, anhydrous sodium sulfate), filtration, concentration (for example, vacuum), and recrystallization (for example, recrystallization in ethylene glycol monomethyl ether) to obtain the acetyl compound represented by the formula 2.
In scheme b, the organic solvent may be an organic solvent conventionally used in such acetylation reaction in the art, and the present invention is preferably a halogenated hydrocarbon solvent, such as chloroform, one or more of dichloromethane and dichloroethane, and more preferably chloroform.
In the scheme b, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the acetylation reaction in the field, so that the reaction is not influenced; the volume mass ratio of the organic solvent to the acetamide compound shown in the formula 1a can be 5ml/g-15ml/g (for example, 8ml/g-10 ml/g).
In the scheme b, the acetylation reagent can be an acetylation reagent which is conventional in the acetylation reaction in the field; in the present invention, acetyl chloride and/or acetic anhydride are preferred, and acetic anhydride is more preferred.
In the embodiment b, the molar ratio of the acetylation reagent to the acetamide compound represented by formula 1a is preferably 1.5 to 4:1 (e.g., 2:1).
In scheme b, the lewis acid may be a lewis acid conventional in this type of acetylation reaction in the art; tin tetrachloride is preferred.
In the embodiment b, the molar ratio of the Lewis acid to the acetamide compound shown in the formula 1a is preferably 1:1-3:1 (e.g. 2:1-3:1).
In said scheme b, the temperature of said acetylation reaction may be a temperature conventional in such acetylation reactions in the art, and the present invention is preferably 25 ℃ to 85 ℃ (e.g., 60 ℃ to 65 ℃).
In the scheme b, the progress of the acetylation reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the end point of the reaction is generally determined when the acetamide compound shown in the formula 1a disappears or does not react any more. The reaction time may be 1 to 5 hours.
In the scheme b, the acetylation reaction conditions can be performed according to the conditions in the acetylation reaction in the art except those specifically mentioned above.
In the scheme b, the method also comprises post-treatment, wherein the post-treatment comprises the following steps: after the acetylation reaction is finished, the reaction system is subjected to extraction and quenching (ice water), liquid separation to obtain an organic phase and a water phase, water washing of the organic phase, organic solvent extraction of the water phase (for example, the organic solvent can be chloroform), pH adjustment of the combined organic phase to 7-8 (for example, a saturated sodium carbonate aqueous solution), liquid separation to obtain an organic phase, water washing of the organic phase, drying (for example, anhydrous sodium sulfate), filtration, concentration (for example, vacuum), and recrystallization (for example, recrystallization in ethylene glycol monomethyl ether is used) to obtain the acetyl compound shown in the formula 2.
In the scheme b, the method can further comprise a scheme c, and the scheme c can comprise the following steps: in an organic solvent, under the action of an acetylation reagent, carrying out acetylation reaction on trimethoprim shown in a formula 1 to obtain an acetamide compound shown in a formula 1 a;
in the scheme c, the organic solvent can be a solvent commonly used in the acetylation reaction in the field, and toluene is particularly preferred in the invention.
In the embodiment c, the amount of the organic solvent may be the amount conventionally used in chemical reactions in the art, and preferably, the volume-to-mass ratio of the organic solvent to the trimethoprim shown in formula 1 is in the range of 5-20ml/g (e.g. 9 ml/g).
In the scheme c, the acetylation reagent can be conventional acetylation reagent in the art, and acetic anhydride and/or acetyl chloride are preferred in the invention.
In the scheme c, the amount of the acetylation reagent can be the conventional amount in the field of such acetylation reaction, and preferably, the molar ratio of the acetylation reagent to the trimethoprim shown in formula 1 is (2-5): 1 (for example, 2:1, 4:1, 5:1).
In the scheme c, the temperature of the acetylation reaction can be the temperature commonly used in the acetylation reaction in the field, and the temperature is particularly preferably 100-110 ℃.
In the scheme c, the progress of the acetylation reaction can be monitored according to the conventional detection method in the art (such as TLC, HPLC or GC), and is generally used as the end point of the reaction when the trimethoprim shown in the formula 1 disappears, and the acetylation reaction time is preferably 1-3 hours (such as 1.5 hours).
In the scheme c, the acetylation reaction may further include a post-treatment operation, and the post-treatment method and conditions may be those conventional in the art for such acetylation reaction, and in the present invention, the following post-treatment steps are preferably included: crystallizing (for example, standing the reaction system to room temperature for crystallization), filtering, and drying.
In the scheme c, in the post-treatment step of the acetylation reaction, the crystallization method and conditions may be those conventional in the art, and the present invention particularly preferably performs crystallization by standing after cooling to room temperature.
The invention also provides an application of the eplerenone p-toluenesulfonate shown in the formula 7a, wherein the application comprises a method for preparing the eplerenone shown in the formula 7 from the eplerenone p-toluenesulfonate shown in the formula 7a, and the method comprises the following steps of: under the action of alkali, performing neutralization reaction on the tosylate by the elaprine shown in the formula 7a to obtain the elaprine shown in the formula 7;
in the application of the esloprine p-toluenesulfonate shown in formula 7a, the method and conditions for the neutralization reaction can be those conventional in the art for such neutralization reactions. For example, the salt of elaprine p-toluenesulfonate shown in formula 7a is mixed with an aqueous solution of the base (e.g., a saturated aqueous solution of sodium carbonate).
In the application of the elaprine p-toluenesulfonate shown in the formula 7a, the base can be a base commonly used in the field for such neutralization reaction, such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like, and the invention particularly preferably adopts sodium carbonate, especially saturated sodium carbonate aqueous solution.
In the application of the esloprine p-toluenesulfonate shown in the formula 7a, the neutralization reaction may further include a post-treatment operation, and the post-treatment method and conditions may be those conventional in the art for such neutralization reaction, such as filtration and drying.
In the invention, the concentrated sulfuric acid refers to a sulfuric acid aqueous solution with the mass fraction of 95-98%.
In the present invention, the room temperature means 10 to 30 ℃.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: by using the elaprine p-toluenesulfonate shown in the formula 7a as an intermediate, the elaprine can be prepared with high purity, column chromatography is not required, and post-treatment is simple.
The preparation method of elaprine by using the elaprine intermediate provided by the invention has the advantages of more economical reagents, short route, high yield, low preparation cost and simple post-treatment, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
Example 1
Preparation of Compound 1a (N, N' - (5- (3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Adding compound 1 (100.0g, 344.5 mmol), acetic anhydride (176g, 1710.4 mmol) and 900ml of toluene into a reaction bottle, heating and refluxing for reaction for 1.5h, cooling to room temperature, standing for crystallization, performing suction filtration, drying to obtain 109.0g of white solid 1a, wherein the yield is 84.5%, the purity is 98.72% through HPLC detection at the temperature of mp.201-203 ℃, 1 H-NMR(400MHz, CDCl 3 ).δ(ppm):10.41(s,1H),10.09(s,1H),8.36(s,1H),6.48(s,1H),6.34(s,2H),3.84(s, 2H),3.71(s,6H),3.61(s,3H),2.16(s,6H)。
example 2
Preparation of Compound 1a (N, N' - (5- (3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
To a reaction flask were added compound 1 (100.1g, 344.8mmol), acetyl chloride (98.1ml, 1379.6mmol) and 900mlToluene, heating, refluxing and stirring for 1.5h, cooling to room temperature, standing for crystallization, performing suction filtration and drying to obtain 104.0g of white solid 1a, wherein the yield is 80.6%, the purity is 98.70% by HPLC (high performance liquid chromatography) detection at the temperature of mp.201-203 ℃, 1 H-NMR(400MHz, CDCl 3 ).δ(ppm):10.41(s,1H),10.09(s,1H),8.36(s,1H),6.48(s,1H),6.34(s,2H),3.84(s, 2H),3.71(s,6H),3.61(s,3H),2.16(s,6H)。
example 3
Preparation of Compound 1a (N, N' - (5- (3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Adding the compound 1 (100.0 g,344.5 mmol), acetic anhydride (70.3 g,688.5 mmol) and 900ml toluene into a reaction bottle, heating and refluxing for reaction for 1.5h, cooling to room temperature, standing for crystallization, performing suction filtration and drying to obtain 102.8g of white solid 1a with the yield of 71.7 percent, the purity of 98.62 percent detected by HPLC (high performance liquid chromatography) at the temperature of mp.201-203 ℃, 1 H-NMR(400MHz, CDCl 3 ).δ(ppm):10.41(s,1H),10.09(s,1H),8.36(s,1H),6.48(s,1H),6.34(s,2H),3.84(s, 2H),3.71(s,6H),3.61(s,3H),2.16(s,6H)。
example 4
Preparation of compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Adding the compound 1a (99.9g, 266.8mmol), acetic anhydride (55.5g, 544.4mmol) and 1000ml dichloroethane into a reaction bottle, slowly adding tin tetrachloride (62ml, 537.8mmol) under stirring, heating, refluxing for 5h, cooling to room temperature, pouring the reaction liquid into 600ml of ice water, stirring for 20min, separating, washing the organic phase twice with 50ml of water, combining the water phases, extracting the water phase for 4 times with 50ml of dichloroethane, combining the organic phases, washing the organic phase with saturated sodium carbonate solution to pH value of about 7, washing the organic phase for 1 time with 50ml of water, drying with anhydrous sodium sulfate, filtering, vacuum concentrating, recrystallizing ethylene glycol monomethyl ether to obtain 87.2g of the compound 2 with yield of 78.5%. mp.204-206 deg.C, and its purity is 96.24% by HPLC detection; 1 H-NMR(400 MHz,CDCl 3 ).δ(ppm):10.03(s,1H),9.20(s,1H),8.41(s,1H),7.26(s,1H),6.34(s,1H),3.95 (s,3H),3.84(s,3H),3.76(s,3H),3.68(s,2H),2.60(s,3H),2.48(s,3H),2.48(s,3H)；MS (ESI+):m/z,417([M+H] + )。
example 5
Preparation of Compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diethylamide)
Adding compound 1a (100.0g, 267.1mmol), acetic anhydride (55.4g, 544.3mmol) and 1000ml of chloroform into a reaction flask, slowly adding tin tetrachloride (62ml, 537.8mmol) under stirring, heating, refluxing for 2 hours, cooling to room temperature, pouring the reaction liquid into 600ml of ice water, stirring for 20 minutes, separating, washing the organic phase twice by 50ml of water, combining the aqueous phases, extracting the aqueous phase for 4 times by 50ml of chloroform, combining the organic phases, washing the organic phase by saturated sodium carbonate to pH of about 7, washing the organic phase for 1 time by 50ml of water, drying by anhydrous sodium sulfate, filtering, vacuum concentrating, recrystallizing by 200ml of ethylene glycol monomethyl ether to obtain 101.3g of compound 2, wherein the yield is 91.2%. mp.204-206 ℃; the purity of the product is 96.25% by HPLC detection; 1 H-NMR(400MHz, CDCl 3 ).δ(ppm):10.03(s,1H),9.20(s,1H),8.41(s,1H),7.26(s,1H),6.34(s,1H),3.95(s,3H), 3.84(s,3H),3.76(s,3H),3.68(s,2H),2.60(s,3H),2.48(s,3H),2.48(s,3H)；MS(ESI+):m/z, 417([M+H] + )。
example 6
Preparation of compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Adding the compound 1a (100.1g, 267.4mmol), acetyl chloride (76.0ml, 1006.9mmol) and 1000ml chloroform into a reaction bottle, slowly adding tin tetrachloride (62ml, 537.8mmol) under stirring, heating, refluxing for 1.5h, cooling to room temperature, pouring the reaction liquid into 600ml ice water, stirring for 20min, separating, washing the organic phase twice with 50ml water, combining the water phases, washing the water phase 4 times with 50ml chloroform, combining the organic phases, washing the organic phase with a saturated sodium carbonate solution to pH value of about 7, washing the organic phase 1 time with 50ml water, drying with anhydrous sodium sulfate, filtering, concentrating under vacuum, and recrystallizing with 200ml ethylene glycol monomethyl ether to obtain 99.3g of the compound 2 with yield of 89.3%. mp.204-206 ℃; the purity of the product is 96.75 percent by HPLC detection; 1 H-NMR(400 MHz,CDCl 3 ).δ(ppm):10.03(s,1H),9.20(s,1H),8.41(s,1H),7.26(s,1H),6.34(s,1H),3.95 (s,3H),3.84(s,3H),3.76(s,3H),3.68(s,2H),2.60(s,3H),2.48(s,3H),2.48(s,3H)；MS (ESI+):m/z,417([M+H] + )。
example 7
Preparation of compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Adding compound 1 (trimethoprim) (10.02g, 34.52mmol), acetic anhydride (17.06 g, 167.11mmol) and 100ml of chloroform into a 250ml reaction bottle, adding tin tetrachloride (8.00ml, 68.36mmol) under stirring, carrying out reflux reaction for 1h, detecting the raw materials by TLC, cooling to room temperature, pouring the reaction liquid into 50ml of ice water, stirring for 6mins, carrying out liquid separation, washing the organic phase by 5ml of water for 3 times, combining the aqueous phases, extracting the aqueous phases by 5ml of chloroform for 3 times, combining the organic phases, adjusting the pH of saturated sodium carbonate aqueous solution to 7-8, carrying out liquid separation, washing the organic phase by 5ml of water for 1 time, drying by anhydrous sodium sulfate, filtering, carrying out vacuum concentration, recrystallizing ethylene glycol monomethyl ether to obtain 13.30g of a product, wherein the yield is 92.63%. mp.203-205 deg.C; purity by HPLC was 96.72%. 1 H-NMR(300MHz,CDCl 3 )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H), 6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19 (s,3H)；MS(ESI + ):m/z,417([M+H] + ).
Example 8
Preparation of compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Adding compound 1 (trimethoprim) (10.00g, 34.45mmol), acetyl chloride (9.80 ml, 138.57mmol) and 100ml chloroform into a 250ml reaction bottle, adding tin tetrachloride (8.00ml, 68.36mmol) under stirring, refluxing for 1h, cooling to room temperature, pouring the reaction solution into 50ml ice water, stirring for 6mins, separating, washing the organic phase with 5ml water for 3 times, combining the aqueous phases, extracting the aqueous phase with 5ml chloroform for 3 times, combining the organic phases, adjusting the pH value to 7-8 by using saturated sodium carbonate aqueous solution, separating, washing the organic phase with 5ml water for 1 time, and adding anhydrous sulfuric acidSodium drying, filtering, vacuum concentrating, and recrystallizing with ethylene glycol monomethyl ether to obtain 12.98g product with 90.58% yield. mp.203-205 ℃; purity was 95.52% by HPLC. 1 H- NMR(300MHz,CDCl 3 )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95 (s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H)；MS (ESI + ):m/z,417([M+H] + ).
Example 9
Preparation of compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Adding compound 1 (trimethoprim) (10.00g, 34.45mmol), acetic anhydride (17.06 g, 167.11mmol) and 100ml chloroform into a 250ml reaction bottle, adding tin tetrachloride (5.30ml, 45.29mmol) under stirring, refluxing for 1h, cooling to room temperature, pouring the reaction liquid into 50ml ice water, stirring for 6mins, separating, washing the organic phase for 3 times by 5ml water, combining the aqueous phases, extracting the aqueous phase for 3 times by 5ml chloroform, combining the organic phases, adjusting the pH value to 7-8 by saturated sodium carbonate aqueous solution, separating the aqueous phase for 1 time by 5ml water, drying by anhydrous sodium sulfate, filtering, vacuum concentrating, recrystallizing ethylene glycol monomethyl ether to obtain 12.08g of product, wherein the yield is 84.30%. mp.203-205 ℃; the purity was 95.61% by HPLC. 1 H-NMR(300 MHz,CDCl 3 )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95(s,3H),3.84 (s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H)；MS(ESI + ):m/z,417 ([M+H] + ).
Example 10
Preparation of compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Adding compound 1 (trimethoprim) (10.00g, 34.45mmol), acetic anhydride (17.04 g, 166.90mmol) and 100ml chloroform into a 250ml reaction bottle, adding stannic chloride (12.00ml, 68.36mmol) under stirring, refluxing for 1h, cooling to room temperature, pouring the reaction liquid into 50ml ice water, stirring for 6mins, separating, washing the organic phase with 5ml water for 3 times, combining the water phase, extracting the water phase with 5ml chloroform for 3 times, combining the organic phases, adjusting the pH value to 7-8 with saturated sodium carbonate aqueous solution, separating, washing the organic phase with 5ml water for 1 time, and separating anhydrousDrying with sodium sulfate, filtering, vacuum concentrating, and recrystallizing with ethylene glycol monomethyl ether to obtain 10.96g of product with yield of 76.48%. mp.203-205 deg.C; purity by HPLC was 95.67%. 1 H- NMR(300MHz,CDCl 3 )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95 (s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H)；MS (ESI + ):m/z,417([M+H] + ).
Example 11
Preparation of compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Adding compound 1 (trimethoprim) (10.00g, 34.45mmol), acetic anhydride (17.03 g, 166.80mmol) and 100ml dichloromethane into a 250ml reaction bottle, adding tin tetrachloride (8.00ml, 102.54mmol) under stirring, refluxing for 1h, cooling to room temperature, pouring the reaction liquid into 50ml ice water, stirring for 6mins, separating, washing the organic phase with 5ml water for 3 times, combining the water phases, extracting the water phases with 5ml chloroform for 3 times, combining the organic phases, adjusting the pH value to 7-8 with saturated sodium carbonate aqueous solution, separating, drying with anhydrous sodium sulfate for 1 time, filtering, concentrating in vacuum, recrystallizing ethylene glycol monomethyl ether to obtain 12.93g of product with the yield of 90.23%. mp.203-205 deg.C; the purity was 95.72% by HPLC. 1 H- NMR(300MHz,CDCl 3 )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95 (s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H)；MS (ESI + ):m/z,417([M+H] + ).
Example 12
Preparation of compound 3 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2,3,4-trimethoxyphenyl) ethanone)
Adding compound 2 (65.00g, 156.25mmol), potassium carbonate (15.090g, 109.35mmol) and 600ml methanol into a reaction bottle, stirring and refluxing for 1.5h, stopping heating, cooling to room temperature, placing in an ice bath, stirring slowly, crystallizing, filtering, washing with water, and drying to obtain 47.00g white solid compound 3, yield 90.5%, mp.121-123 deg.C; purity by HPLC was 97.22%. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):7.28(s,1H),6.66(s,1H),6.12,(s, 2H),5.70(s,2H),3.82(s,3H),3.75(d,6H,4Hz),3.42(s,2H),2.29(s,3H).
Example 13
Preparation of compound 3 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2,3,4-trimethoxyphenyl) ethanone)
Adding compound 2 (65.01g, 156.49mmol), potassium carbonate (15.091g, 109.36mmol) and 600ml of ethanol into a reaction bottle, heating and refluxing for reaction for 1.5h, stopping heating, cooling to room temperature, placing in an ice bath, stirring slowly, stirring for crystallization, performing suction filtration, washing with water, and drying to obtain 45.00g of white solid compound 3, wherein the yield is 86.7 percent, and the mp.121-123 ℃; purity by HPLC 97.32%. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):7.28(s,1H),6.66(s,1H),6.12, (s,2H),5.70(s,2H),3.82(s,3H),3.75(d,6H,4Hz),3.42(s,2H),2.29(s,3H).
Example 14
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
Adding the compound 3 (30.00g and 90.36mmol) and 600ml of dichloromethane into a 1L reaction bottle, cooling to-6 ℃ by an ice salt bath, slowly dropwise adding 135.5ml of boron tribromide dichloromethane solution of 1mol/L, and raising the temperature to room temperature after the addition to react for 5 hours. Cooling to 0 ℃, quenching with 300ml of methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 25.50g of white solid compound 4 with a yield of 88.74%. mp.217 ℃; the purity was 96.10% by HPLC. 1 H-NMR(300MHz, CDCl 3 )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H), 3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI + ):m/z,319([M+H] + ).
Example 15
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
Adding the compound 3 (20.01g, 60.27mmol) and 200ml of chloroform into a 500ml reaction bottle, cooling to-6 ℃ by an ice salt bath, slowly dropwise adding 90.5ml of a 1mol/L boron tribromide dichloromethane solution, and raising the temperature to room temperature for reaction for 5 hours after the addition is finished. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 16.02g of white solid compound 4 with a yield of 83.58%. mp.217 ℃; purity by HPLC was 96.08%. 1 H-NMR(400MHz,CDCl 3 ) δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s, 3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI + ):m/z,319([M+H] + ).
Example 16
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
A250 ml reaction flask was charged with Compound 3 (10.02g, 30.18mmol) and 100ml chloroform, cooled to-6 ℃ in an ice salt bath, and 45.3ml of a 1mol/L solution of boron trichloride in methylene chloride was added dropwise thereto, and the mixture was allowed to warm to room temperature for 5 hours. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 7.88g of white solid compound 4 with a yield of 82.10%. mp.217 ℃; purity by HPLC was 96.13%. 1 H-NMR(400MHz,CDCl 3 )δ (ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s, 3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI + ):m/z,319([M+H] + ).
Example 17
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
A500 ml reaction flask was charged with compound 3 (10.11g, 30.45mmol) and 200ml of dichloromethane, cooled to-6 ℃ in an ice salt bath, and 45.7ml of a 1mol/L solution of boron trichloride in dichloromethane was added dropwise thereto, and the mixture was allowed to warm to room temperature for 5 hours. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 7.96g of white solid compound 4 with a yield of 82.20%. mp.217 ℃; HPLC detection of its purityThe degree was 96.09%. 1 H-NMR(400MHz,CDCl 3 ) δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s, 3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI + ):m/z,319([M+H] + ).
Example 18
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
Adding the compound 3 (30.00g and 90.36mmol) and 600ml of dichloromethane into a 1L reaction bottle, cooling to-6 ℃ by an ice salt bath, slowly dropwise adding 108.5ml of boron tribromide dichloromethane solution of 1mol/L, and raising the temperature to room temperature after the addition to react for 5 hours. Cooling to 0 deg.c, quenching in 300ml methanol, stirring for 1 hr, vacuum concentrating the dry solvent, and re-crystallizing in ethanol to obtain 21.73g white solid compound 4 in 75.62% yield. mp.217 ℃; purity by HPLC was 96.19%. 1 H-NMR(300MHz, CDCl 3 )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H), 3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI + ):m/z,319([M+H] + ).
Example 19
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
Adding the compound 3 (30.00g and 90.36mmol) and 600ml of dichloromethane into a 1L reaction bottle, cooling to-6 ℃ through an ice salt bath, slowly and dropwise adding 153.5ml of boron tribromide dichloromethane solution of 1mol/L, and raising the temperature to room temperature after the addition to react for 5 hours. Cooling to 0 deg.c, quenching in 300ml methanol, stirring for 1 hr, vacuum concentrating the dry solvent, and re-crystallizing in ethanol to obtain 24.73g white solid compound 4 in 86.06% yield. mp.217 ℃; the purity was 96.10% by HPLC. 1 H-NMR(300MHz, CDCl 3 )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H), 3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI + ):m/z,319([M+H] + ).
Example 20
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
A250 ml reaction flask is added with the compound 3 (10.00g, 30.12mmol) and 100ml chloroform, cooled to-6 ℃ by an ice salt bath, added with 51.5ml of 1mol/L boron trichloride dichloromethane solution dropwise, and heated to room temperature for reaction for 5 hours after the addition. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 7.83g of white solid compound 4 with a yield of 81.75%. mp.217 ℃; purity by HPLC was 96.25%. 1 H-NMR(400MHz,CDCl 3 )δ (ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s, 3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI + ):m/z,319([M+H] + ).
Example 21
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
A250 ml reaction flask is added with the compound 3 (10.00g, 30.12mmol) and 100ml chloroform, cooled to-6 ℃ by an ice salt bath, added with 46.5ml of 1mol/L boron trichloride dichloromethane solution dropwise, and heated to room temperature for reaction for 5 hours after the addition. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 7.58g of white solid compound 4 with a yield of 79.14%. mp.217 ℃; the purity was 96.21% by HPLC. 1 H-NMR(400MHz,CDCl 3 )δ (ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s, 3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI + ):m/z,319([M+H] + ).
Example 22
Preparation of compound 8 (N, N' - (5- (2-acetyl-3-hydroxy-4,5-dimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
To the reaction flask were added compound 2 (10.005g, 24.050mmol) and 100ml dichloromethane and the ice salt bath was cooled to-8 ℃. A dichloromethane solution of boron tribromide (36ml, 36.000mmol) is slowly added dropwise, and after 1h of reaction, the temperature is raised to room temperature for 19h of reaction. The reaction solution was poured into 90ml of ice water and saturated with carbonAdjusting the pH value of the sodium acid aqueous solution to about 6, performing suction filtration, and recrystallizing filter cake isopropanol to obtain 8.730g of the compound 8 with the yield of 90.336%. mp 203-205 ℃; the purity was 97.53% by HPLC. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):11.22(s,1H),8.94(s,1H),8.38(s,1H),6.83(s, 1H),6.19(s,1H),3.90(s,3H),3.77(s,5H),2.69(s,3H),2.50(s,3H),2.19(s,3H).
Example 23
Preparation of compound 8 (N, N' - (5- (2-acetyl-3-hydroxy-4,5-dimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Compound 2 (10.000g, 24.038mmol) and 100ml dichloromethane were added to the reaction flask and the temperature of the ice salt bath was lowered to-8 ℃. A dichloromethane solution (36ml, 36.000mmol) of boron trichloride is slowly added dropwise, and after 1h of reaction, the temperature is raised to room temperature for reaction for 15h. The reaction solution was poured into 90ml of ice water, the pH of the saturated aqueous solution of sodium carbonate was adjusted to about 6, and suction filtration was carried out. Recrystallization of the cake from isopropanol afforded 8.700g of compound 8 in 90.023% yield. mp.203-205 ℃; purity by HPLC was 97.49%. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):11.22(s,1H),8.94(s,1H),8.38(s,1H),6.83 (s,1H),6.19(s,1H),3.90(s,3H),3.77(s,5H),2.69(s,3H),2.50(s,3H),2.19(s,3H).
Example 24
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
Adding the compound 8 (5.000g, 12.438mmol), potassium carbonate (0.172g, 1.244mmol) and 50ml of methanol into a reaction bottle, heating and refluxing for 1.5h, stopping heating, cooling to room temperature, placing in an ice bath, stirring slowly, crystallizing, filtering, washing with water, and drying to obtain 3.901g of a white solid compound 4 with a yield of 98.63% and a temperature of mp.121-123 ℃. Purity by HPLC was 98.97%. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s, 1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)； MS(ESI + ):m/z,319([M+H] + ).
Example 25
Preparation of compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.01g, 12.58mmol), cyclopropanecarboxaldehyde (1.07g, 15.29 mmol) and 40ml acetonitrile were added to a 100ml reaction flask, and pyrrolidine (1.34g, 18.87mol) and acetic acid (1.13g, 18.83 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36 hours, filtered with suction, and dried to give 4.57g of an acetate salt of off-white solid compound 5, with an yield of 84.28%, mp168-171 ℃. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):7.13(s,1H),6.49(s,1H), 6.31(s,2H),5.92(s,2H),3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),2.78-2.85(m,1H), 2.64-2.69(m,1H),1.89(s,3H),1.19-1.25(m,1H)0.53-0.63(m,2H),0.45-0.51(m,1H),0.37- 0.43(m,1H)；MS(ESI + ):m/z,373([M+H] + ).
Acetate salt of compound 5 (4.57g, 10.63mmol) was stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 3.93g of off-white solid in 84.23% yield. mp.152-155 ℃; purity was 96.13% by HPLC. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):7.18(s,1H),6.47(s,1H),6.11,(s,2H),5.63(s,2H), 3.91-3.99(m,2H),3.77-3.85(m,1H),3.76(s,3H),3.70(s,3H),2.79-2.83(m,1H),2.65-2.69 (m,1H),1.20-1.24(m,1H),0.55-0.62(m,2H),0.47-0.48(m,1H),0.40-0.41(m,1H)；MS(ESI + ): m/z,371([M+H] + )。
Example 26
Preparation of compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
A250 ml reaction flask is added with compound 4 (11.00g, 34.59mmol), cyclopropanecarboxaldehyde (3.63g, 51.86 mmol) and 110ml acetonitrile, slowly dropwise adding pyrrolidine (3.68g, 51.83mmol) and propionic acid (2.557 g, 34.56 mmol) under stirring, stirring at room temperature for 36h, filtering and drying to obtain the propionic salt of compound 5, stirring in saturated sodium carbonate solution for 1h, and drying to obtain 11.11g of compound 5 with the yield of 86.81%. mp.152-155 ℃; purity by HPLC was 96.15%.
Example 27
Preparation of compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
A100 ml reaction flask was charged with compound 4 (4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00 mmol) and 40ml acetonitrile, and piperidine (1.55g, 18.22mmol) and acetic acid (1.12g, 18.67 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered with suction, and dried to give 4.68g of an acetate salt of compound 5 as a white-like solid with an yield of 86.52%.
Acetate salt of compound 5 (4.68g, 10.88mmol) was stirred in saturated sodium carbonate solution for 1h, filtered, and dried to give 4.02g off-white solid in 86.38% yield. mp.152-155 ℃; purity by HPLC was 96.17%.
Example 28
Preparation of compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
A100 ml reaction flask was charged with compound 4 (4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.08g, 15.429 mmol) and 40ml acetonitrile, and piperidine (1.57g, 18.44mmol) and propionic acid (1.38g, 18.67 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered to give the propionate salt of compound 5, stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 3.98g of an off-white solid with a yield of 85.52%. mp.152-155 ℃; the purity was 96.11% by HPLC.
Example 29
Preparation of Compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00 mmol) and 40ml acetonitrile were added to a 100ml reaction flask, and pyrrolidine (1.35g, 19.01mol) and acetic acid (1.51g, 25.17 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36 hours, filtered under suction, and dried to give 4.57g of an acetate salt of compound 5 as a white-like solid with an yield of 84.28%.
Acetate salt of compound 5 (4.54g, 10.56mmol) was stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 3.91g off-white solid in 84.01% yield. mp.152-155 ℃; the purity was 96.11% by HPLC.
Example 30
Preparation of compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
A100 ml reaction flask was charged with compound 4 (4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00 mmol) and 40ml acetonitrile, and pyrrolidine (1.36g, 19.15mol) and acetic acid (0.75g, 12.50 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered, stirred in a saturated sodium carbonate solution for 1h, filtered and dried to give 3.23 g as a white solid in a total yield of 78.5% (based on compound 4, 12.58 mmol). mp.152-155 ℃; purity by HPLC was 96.25%.
Example 31
Preparation of compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00 mmol) and 40ml acetonitrile were added to a 100ml reaction flask, pyrrolidine (1.34g, 18.87mol) and acetic acid (0.38g, 6.33 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered, dried, stirred in saturated sodium carbonate solution for 1h, filtered, dried, and recrystallized from ethanol to give 2.82g of an off-white solid with a yield of 60.59%. mp.152-155 ℃; the purity was 96.01% by HPLC.
Example 32
Preparation of compound 6 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-ol)
Adding compound 5 (4.00g, 10.81mmol) and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.21g, 5.56mmol),reacting for 2.5h at room temperature, evaporating methanol to dryness, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, and recrystallizing with ethanol and water (the volume ratio of the ethanol to the water is 5:1) to obtain 3.88g of a white solid compound 6, wherein the yield is 96.48%. mp.211-213 deg.C; the purity of the product is 99.23% by HPLC detection; 1 H- NMR(400MHz,CDCl3).δ(ppm):7.49(s,1H),6.17-6.2(d,3H),5.58-5.64(m,3H),4.93-4.94 (d,1H),3.78-3.82(d,1H),3.63(s,3H),3.62(s,3H),3.53-3.57(m,1H),2.24-2.28(m,1H),1.96- 2.02(m,1H),1.34-1.37(m,1H)，0.49-0.1(d,2H),0.31-0.36(m,2H)；MS(ESI+):m/z,373 ([M+H]+)。
example 33
Preparation of Compound 6 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-ol)
Adding the compound 5 (4.00g, 10.81mmol) and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.40g, 10.58mmol), reacting at room temperature for 2.5h, evaporating the methanol to dryness, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, and recrystallizing with ethanol and water to obtain 3.90g of a white solid compound 6 with the yield of 96.98%. mp.211-213 deg.C; the purity was 99.21% by HPLC.
Example 34
Preparation of compound 6 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-ol)
Adding the compound 5 (4.00g, 10.81mmol) and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.29g, 7.67mmol), reacting at room temperature for 2.5h, evaporating the methanol, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, vacuum concentrating, recrystallizing ethanol and water to obtain 3.89g of a white solid compound 6, wherein the yield is 96.73%. mp.211-213 deg.C; the purity was 99.25% by HPLC.
Example 35
Preparation of compound 6 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-ol)
Adding acetate (4.00g, 9.30mmol) of the compound 5 and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.53g, 14.02mmol), reacting for 2.5h at room temperature, concentrating in vacuum, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, and recrystallizing ethanol and water to obtain 3.18g of a white solid compound 6 with the yield of 91.90. mp.211-213 deg.C; the purity was 99.19% by HPLC.
Example 36
Preparation of compound 6 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-ol)
Adding acetate (4.00g, 9.30mmol) of the compound 5 and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.70g, 18.52mmol), reacting at room temperature for 2.5h, concentrating in vacuum, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, and recrystallizing ethanol and water to obtain 3.20g of a white solid compound 6 with the yield of 92.47%. mp.211-213 deg.C; the purity was 99.23% by HPLC.
Example 37
Preparation of compound 6 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-ol)
Adding acetate (4.00g, 9.30mmol) of the compound 5 and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.60g, 15.87mmol), reacting at room temperature for 2.5h, concentrating in vacuum, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, and recrystallizing ethanol and water to obtain 3.17g of a white solid compound 6 with the yield of 91.61. mp.211-213 deg.C; the purity was 99.27% by HPLC.
Example 38
Preparation of compound 6 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-ol)
Adding the compound 5 (7.85g, 18.26mmol) and 150ml of ethanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.69g, 26.46mmol), reacting for 2.5h at room temperature, concentrating in vacuum, adding 70ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, recrystallizing ethanol and water to obtain 6.71g of a white solid compound 6, wherein the yield is 85.02%. mp.211-213 deg.C; purity by HPLC was 99.24%.
Example 39
Preparation of compound 6 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-ol)
Adding the compound 5 (4.00g, 10.81mmol) and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding potassium borohydride (0.76g, 14.09mmol), reacting at room temperature for 2.5h, concentrating in vacuum, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, recrystallizing ethanol and water to obtain 3.78g of a white solid compound 6, wherein the yield is 93.99%. mp.211-213 deg.C; the purity was 99.26% by HPLC.
Example 40
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (2.01g, 5.40mmol and HPLC purity of 99.23%) and 20ml of tetrahydrofuran into a reaction bottle, adding paratoluenesulfonic acid monohydrate (1.54g and 8.10 mmol) under stirring, heating and refluxing for reaction for 1h, detecting by TLC that no raw material is remained, cooling to room temperature, precipitating a large amount of white solid, filtering, and drying to obtain 2.54g of paratoluenesulfonic acid salt of a white solid compound 7, wherein the yield is 89.27%, and mp.208 ℃; the purity of the product is 99.91% by HPLC detection; 1 H- NMR(400MHz,CDCl 3 ).δ(ppm):8.06(b,2H),7.45-7.49(m,3H),7.10-7.12(d,2H),6.85(s, 1H),6.47(s,1H),6.39-6.42(m,1H),5.75-5.78(m,1H),4.24-4.27(m,1H),3.74(s,3H),-3.72 (s,3H),3.57(b,2H),2.28(s,3H),1.12-1.20(m,1H),0.29-0.54(m,4H)，MS(ESI+):m/z,355 ([M+H] + )。
the p-toluenesulfonate salt of Compound 7 (2.54g, 4.83 mmol) was stirred in a saturated sodium carbonate solution for 1h, filtered off with suction and dried to give 1.71g of the white solid compound 7 in a total yield of 89.40%. mp.215 ℃; the purity of the product is 99.96% by HPLC detection; 1 H-NMR(400MHz,CDCl 3 ).δ(ppm):7.07(s,1H),6.45-6.46(d,1H),6.42(s,1H),6.19 (s,2H),5.70-5.72(m,1H),5.68(s,2H),4.24-4.26(m,1H),3.70(s,3H),3.71(s,3H),3.52(d, 2H),1.11-1.15(m,1H),0.43-0.51(m,2H),0.35-0.39(m,1H),0.30-0.33(m,1H)；MS(ESI+): m/z,355([M+H] + )。
example 41
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (2.00g, 5.38mmol and HPLC purity of 99.23%) and 8ml of dimethyl sulfoxide into a reaction bottle, adding paratoluenesulfonic acid monohydrate (1.54g, 8.10 mmol) under stirring, reacting at 80 ℃ for 1h, detecting by TLC that basically no raw material is left, cooling to room temperature, adding dichloromethane, washing a dichloromethane phase for 5 times by water, precipitating a large amount of white solid from a dichloromethane layer, filtering, and drying to obtain 2.53g of paratoluenesulfonic acid salt of compound 7 as a white solid, wherein the yield is 89.36 percent and mp.208 ℃; HPLC purity 99.92%.
P-toluenesulfonate (2.53g, 4.81mmol) of the compound 7 was stirred in a saturated sodium carbonate solution for 1 hour, filtered by suction, and dried to obtain 1.70g of a white solid compound 7 with a total yield of 89.32%. mp.215 ℃; the purity was 99.95% by HPLC.
Example 42
Preparation of Compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding a compound 6 (2.00g, 5.38mmol, and the HPLC purity is 99.23%) and 20ml of methyltetrahydrofuran into a reaction bottle, adding paratoluenesulfonic acid monohydrate (1.55g, 8.15mmol) under stirring, reacting at 80 ℃ for 1h, detecting by TLC that no raw material is remained basically, cooling to room temperature, adding dichloromethane, washing a dichloromethane phase for 5 times, chromatographing a large amount of white solid by dichloromethane, filtering, and drying to obtain 2.50g of paratoluenesulfonic acid salt of a white solid compound 7, wherein the yield is 88.30 percent and mp.208 ℃; HPLC purity 99.94%.
P-toluenesulfonate salt of compound 7 (2.50g, 4.75mmol) was stirred in saturated sodium carbonate solution for 1h, filtered under suction, and dried to give 1.69g of white solid compound 7 with a total yield of 88.80%. mp.215 ℃; purity by HPLC was 99.96%.
Example 43
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (2.00g, 5.38mmol, HPLC purity 99.23%) and 20ml of acetone into a reaction bottle, adding paratoluenesulfonic acid monohydrate (1.53g, 8.04mmol) under stirring, reacting at 80 ℃ for 1h, detecting by TLC that no raw material is remained basically, cooling to room temperature, adding dichloromethane, washing a dichloromethane phase for 5 times, precipitating a large amount of white solid from a dichloromethane layer, filtering, drying to obtain 2.52g of paratoluenesulfonic acid salt of compound 7 as a white solid, wherein the yield is 89.01%, and mp. ℃; HPLC purity 99.95%.
P-toluenesulfonate salt (2.52g, 4.79mmol) of the compound 7 is stirred in a saturated sodium carbonate solution for 1 hour, filtered by suction and dried to obtain 1.70g of a white solid compound 7 with a total yield of 89.32%. mp.215 ℃; the purity was 99.97% by HPLC.
Example 44
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (2.01g, 5.40mmol, HPLC purity 99.23%) and 20ml of dimethylformamide into a reaction bottle, adding p-toluenesulfonic acid monohydrate (1.53g, 8.04mmol) under stirring, reacting at 80 ℃ for 1h, detecting by TLC that no raw material is basically left, cooling to room temperature, adding dichloromethane, washing a dichloromethane phase for 5 times, performing dichloromethane chromatography to obtain a large amount of white solid, filtering, and drying to obtain 2.49g of p-toluenesulfonic acid salt of compound 7 as a white solid, wherein the yield is 87.51%, and mp.208 ℃; HPLC purity 99.96%.
P-toluenesulfonate (2.49g, 4.73mmol) of the compound 7 was stirred in a saturated sodium carbonate solution for 1 hour, filtered by suction, and dried to obtain 1.67g of a white solid compound 7 with a total yield of 87.30%. mp.215 ℃; the purity was 99.96% by HPLC.
Comparative example 1
Preparation of compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
Compound 1a (2.576g, 6.888mmol), acetic anhydride (3.510g, 34.438mmol) and 20ml of chloroform were charged in a 50ml reaction vessel, and aluminum trichloride (2.230g, 16.724mmol) was slowly added thereto under stirring, and the reaction was carried out under reflux conditions for 10 hours, whereby the desired product was not produced.
Comparative example 2
Preparation of Compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diethylamide)
Compound 1a (100.0g, 267.1mmol), acetic anhydride (55.4g, 544.3mmol) and 1000ml of dichloromethane were added into a reaction flask, tin tetrachloride (62ml, 537.8mmol) was slowly added under stirring, heating reflux reaction was carried out for 3 hours, the temperature was reduced to room temperature, the reaction solution was poured into 600ml of ice water and stirred for 20 minutes, liquid separation was carried out, the organic phase was washed twice with 50ml of water, the aqueous phase was combined, the aqueous phase was washed 4 times with 50ml of dichloromethane, the organic phase was combined, the organic phase was washed with a saturated sodium carbonate solution to pH of about 7, the organic phase was washed 1 time with 50ml of water, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and recrystallized with 200ml of ethylene glycol monomethyl ether to obtain 60.2g of compound 2, with a yield of 54.2%. mp.204-206 ℃; the purity of the product is 96.05 percent by HPLC detection; 1 H-NMR (400MHz,CDCl 3 ).δ(ppm):10.03(s,1H),9.20(s,1H),8.41(s,1H),7.26(s,1H),6.34(s,1H), 3.95(s,3H),3.84(s,3H),3.76(s,3H),3.68(s,2H),2.60(s,3H),2.48(s,3H),2.48(s,3H)；MS (ESI+):m/z,417([M+H] + )。
comparative example 3
Preparation of compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
A50 ml reaction flask was charged with 1 trimethoprim (2.000g, 6.889 mmol), acetic anhydride (3.516 g, 34.440 mmol) and 20ml chloroform, and aluminum trichloride (2.235g, 16.762mmol) was slowly added with stirring and heated under reflux for 10 hours, and no target product was formed.
Comparative example 4
Preparation of Compound 2 (N, N' - (5- (2-acetyl-3,4,5-trimethoxybenzyl) pyrimidine-2,4-diyl) diethylamide)
A50 ml reaction flask is charged with the compound 1 trimethoprim (2.000g, 6.889 mmol), acetic anhydride (3.502 g, 34.303 mmol) and 20ml chloroform, slowly added with stirring ferric trichloride (2.234g, 13.773 mmol), heated to reflux for 12h, cooled to room temperature and no target product is formed.
Comparative example 5
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
Compound 3 (3.000g, 9.036 mmol) and 60ml of methylene chloride were charged into a 100ml reaction flask, and aluminum trichloride (2.410g, 18.077 mmol) was slowly added with stirring, and the reaction was heated under reflux for 10 hours, whereby the desired compound was not produced.
Comparative example 6
Preparation of compound 4 (1- (6- ((2,4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3,4-dimethoxyphenyl) ethanone)
A100 ml reaction flask was charged with compound 3 (4.000g, 12.048 mmol), 20ml of acetic acid and 10ml of 48% hydrobromic acid, heated at reflux for 1h, and checked by TLC for substantial completion of the reaction but no target compound was formed.
Comparative example 7
Preparation of compound 8 (N, N' - (5- (2-acetyl-3-hydroxy-4,5-dimethoxybenzyl) pyrimidine-2,4-diyl) diethylamide)
Compound 2 (4.000g, 9.615mmol), 60ml of methylene chloride and aluminum trichloride (2.412g, 18.089mmol) were charged into a 100ml reaction flask, and the mixture was heated under reflux for 10 hours, whereby the desired compound was not produced.
Comparative example 8
Preparation of compound 8 (N, N' - (5- (2-acetyl-3-hydroxy-4,5-dimethoxybenzyl) pyrimidine-2,4-diyl) diacetamide)
A10 ml reaction flask was charged with compound 2 (4.000g, 9.615 mmol), 20ml of acetic acid and 10ml of 48% hydrobromic acid, and the mixture was heated under reflux for 2h, and TLC showed that the starting material had reacted substantially completely, but no target compound was formed.
Comparative example 9
Preparation of compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.000g, 12.579mmol), cyclopropanecarboxaldehyde (1.071g, 15.300 mmol) and 40ml acetonitrile were added to a 100ml reaction flask, pyrrolidine (1.38g, 19.437mmol) was slowly added dropwise, stirred at room temperature for 36h, concentrated in vacuo, and purified by thin layer column chromatography to give 0.156g of Compound 5 with 3.9% yield. mp.152-155 deg.C. 1 H-NMR(400 MHz,CDCl 3 )δ(ppm):7.13(s,1H),6.49(s,1H),6.31,(s,2H),5.92(s,2H),3.89-4.00(m,2H), 3.78-3.86(m,4H),3.71(s,3H),1.89(s,3H),1.19-1.25(m,1H),0.53-0.63(m,2H),0.45-0.51 (m,1H),0.37-0.43(m,1H)；MS(ESI + ):m/z,371([M+H] + ).
Comparative example 10
Preparation of compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.011g, 12.613mmol), cyclopropanecarboxaldehyde (1.072g, 15.314 mmol) and 40ml acetonitrile were added to a 100ml reaction flask, piperidine (1.607g, 18.875mol) was slowly added dropwise, stirred at room temperature for 48h, the dry solvent was concentrated under rotary vacuum, and the compound 5 was isolated and purified by thin layer column chromatography to give 0.105g, 2.25% yield. mp.152-155 deg.C. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):7.13(s,1H),6.49(s,1H),6.31,(s,2H),5.92(s,2H), 3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),1.89(s,3H),1.19-1.25(m,1H),0.53-0.63 (m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H)；MS(ESI + ):m/z,371([M+H] + ).
Comparative example 11
Preparation of Compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.000g, 12.579mmol), cyclopropanecarboxaldehyde (1.082g, 15.457 mmol) and 40ml acetonitrile are added into a 100ml reaction bottle, pyrrolidine (1.377g, 18.841mol) is slowly added dropwise, stirring is carried out for 50h at room temperature, vacuum concentration is carried out, and thin layer column chromatography separation and purification are carried out to obtain 0.175g of compound 5, wherein the yield is 3.76%. mp.152-155 deg.C. 1 H-NMR(400 MHz,CDCl 3 )δ(ppm):7.13(s,1H),6.49(s,1H),6.31,(s,2H),5.92(s,2H),3.89-4.00(m,2H), 3.78-3.86(m,4H),3.71(s,3H),1.89(s,3H),1.19-1.25(m,1H),0.53-0.63(m,2H),0.45-0.51 (m,1H),0.37-0.43(m,1H)；MS(ESI + ):m/z,371([M+H] + ).
Comparative example 12
Preparation of Compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.000g, 12.579mmol), cyclopropanecarbaldehyde (1.070g, 15.286 mmol), 40ml methanol and potassium hydroxide (1.060g, 18.687mol) were charged into a 100ml reaction flask, and the mixture was heated under reflux for 10 hours, whereby the objective compound 5 was not produced.
Comparative example 13
Preparation of Compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.001g, 12.582mmol), cyclopropanecarbaldehyde (1.072g, 15.314 mmol), 40ml of tetrahydrofuran and potassium tert-butoxide (2.090g, 18.629mol) were added to a 100ml reaction flask, and the mixture was heated under reflux for 8 hours, whereby the desired compound 5 was not formed.
Comparative example 14
Preparation of compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.018g, 12.635mmol), cyclopropanecarbaldehyde (1.082g, 15.457 mmol) and 40ml of isopropyl alcohol were charged into a 100ml reaction flask, pyrrolidine (1.347g, 18.972mol) was slowly added dropwise, stirred at room temperature for 36 hours, the dry solvent was concentrated in vacuo, and the compound 5 was isolated and purified by thin layer column chromatography to give 0.598g, 15.0% yield. mp.152-155 ℃. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):7.13(s,1H),6.49(s,1H),6.31,(s,2H),5.92(s,2H), 3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),1.89(s,3H),1.19-1.25(m,1H),0.53-0.63 (m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H)；MS(ESI + ):m/z,371([M+H] + ).
Comparative example 15
Preparation of Compound 5 (2-cyclopropyl-5- ((2,4-diaminopyrimidin-5-yl) methyl) -7,8-dimethoxychroman-4-one)
Compound 4 (4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00 mmol) and 40ml acetonitrile were added to a 100ml reaction flask, pyrrolidine (1.35g, 19.01mol) was slowly added dropwise with stirring, stirred at room temperature for 36h, filtered, dried and recrystallized from ethanol to give 2.15g of an off-white solid with a yield of 46.20%. mp.152-155 ℃; purity by HPLC 96.63%. 1 H-NMR(400MHz,CDCl 3 )δ(ppm):7.13(s,1H),6.49 (s,1H),6.31,(s,2H),5.92(s,2H),3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),1.89(s, 3H),1.19-1.25(m,1H),0.53-0.63(m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H)；MS(ESI + ): m/z,371([M+H] + ).
Comparative example 16
Preparation of Compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
After compound 6 (2.00g, 5.38mmol, hplc purity 99.23%), 20ml methanol and p-toluenesulfonic acid monohydrate (1.53g, 8.04mmol) were added to a reaction flask and stirred at room temperature for 0.5h, the starting material was substantially disappeared by TLC, but no target compound was produced. The methanol was concentrated off in vacuo, 20ml of saturated aqueous sodium carbonate solution was added to adjust the pH to 9, 10ml of dichloromethane was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, dichloromethane was concentrated off in vacuo, and the crude product was recrystallized from a solvent mixture of isopropanol and water (isopropanol: water = 2:1) to give 1.75g of compound 6, an alcohol hydroxymethyletherified compound (5- ((2-cyclopropyl-4,7,8-trimethoxychromen-5-yl) methyl) pyrimidine-2,4-diamine), in 84.3% yield.
mp.237-240℃； 1 H-NMR(600MHz,DMSO).δ(ppm):7.44(s,1H),6.30(s,1H),6.15(s, 2H),5.74(s,2H),4.41-4.42(t,1H),3.70(s,6H),3.57-3.59(d,1H),3.49-3.52(d,1H),3.39- 3.42(m,4H),2.39-2.42(d,2H),1.65-1.70(m,1H),1.20-1.24(m,1H),0.61-0.69(m,2H),0.52- 0.56(m,1H),0.38-0.42(m,1H)；MS(ESI+):m/z,387([M+H]+)。
Comparative example 17
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
After compound 6 (2.00g, 5.38mmol, HPLC purity 99.23%), 20ml of toluene and 3.07g of trifluoroacetic acid (26.9 mmol) were added to the reaction flask, and the reaction was stirred under reflux for 2 hours, the TLC detection starting material was substantially disappeared but no target compound was formed.
Comparative example 18
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
After compound 6 (2.00g, 5.38mmol, HPLC purity 99.23%) and 20ml of dilute sulfuric acid (2 mol/L) were added to the reaction flask and the reaction was stirred at room temperature for 2h, the starting material was substantially disappeared by TLC, but no target product was formed.
Comparative example 19
Preparation of Compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Compound No. 6 (2.00g, 5.38mmol, HPLC purity 99.23%), 20ml methanol and p-toluenesulfonic acid monohydrate (1.54g, 8.10 mmol) were added to a reaction flask, and after heating under reflux and stirring for 0.5h, the starting material was substantially disappeared by TLC, but no target compound was produced. The methanol was concentrated off in vacuo, the pH was adjusted to 9 with 20ml of saturated aqueous sodium carbonate solution, 10ml of dichloromethane were extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, the dichloromethane was concentrated off in vacuo, the crude product was recrystallized in a solvent mixture of isopropanol and water (isopropanol: water = 2:1) to give 1.80g of the alcoholic hydroxymethoylated compound of compound 6 (5- ((2-cyclopropyl-4,7,8-trimethoxybenzopyran-5-yl) methyl) pyrimidine-2,4-diamine) in 86.7% yield.
mp.237-240℃； 1 H-NMR(600MHz,DMSO).δ(ppm):7.44(s,1H),6.30(s,1H),6.15(s, 2H),5.74(s,2H),4.41-4.42(t,1H),3.70(s,6H),3.57-3.59(d,1H),3.49-3.52(d,1H),3.39- 3.42(m,4H),2.39-2.42(d,2H),1.65-1.70(m,1H),1.20-1.24(m,1H),0.61-0.69(m,2H),0.52- 0.56(m,1H),0.38-0.42(m,1H)；MS(ESI+):m/z,387([M+H]+)。
Comparative example 20
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
After compound 6 (2.01g, 5.40mmol, HPLC purity 99.23%) and 20ml of dilute sulfuric acid (2 mol/L) were added to the reaction flask, and the reaction was stirred under reflux for 1 hour, the starting material was substantially disappeared by TLC, but no target product was formed.
Comparative example 21
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (1.70g, 4.57mmol, HPLC purity 99.23%) and 7ml of dimethyl sulfoxide into a reaction bottle, adding trifluoroacetic acid (1.56g, 13.68mmol) under stirring, reacting at 80 ℃ for 5h, detecting by TLC that no raw material remains basically, cooling to room temperature, adding dichloromethane, adjusting pH to 9 with saturated sodium carbonate solution, separating, extracting the aqueous phase with dichloromethane for 3 times, combining the organic phases, washing the organic phase with water for 5 times, drying with anhydrous sodium sulfate, concentrating in vacuum, recrystallizing with ethanol, and drying to obtain 1.39g of compound 7, yield 85.92%. mp.215 ℃; purity by HPLC was 98.96%.
Comparative example 22
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (2.00g, 5.38mmol and HPLC purity of 99.23%) and 20ml of methyltetrahydrofuran into a reaction bottle, adding trifluoroacetic acid (1.84g and 16.14mmol) under stirring, reacting for 5h at 80 ℃, detecting by TLC that no raw material is remained basically, cooling to room temperature, adding dichloromethane, adjusting pH to 9 by using saturated sodium carbonate solution, separating, extracting an aqueous phase by using dichloromethane for 3 times, combining the organic phases, washing the organic phase for 5 times by using water, drying by using anhydrous sodium sulfate, concentrating in vacuum, recrystallizing by using ethanol, and drying to obtain 1.65g of compound 7, wherein the yield is 86.17%. mp.215 deg.C; purity by HPLC was 98.95%.
Comparative example 23
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (2.00g, 5.38mmol, HPLC purity of 99.23%) and 20ml of acetone into a reaction bottle, adding trifluoroacetic acid (1.83g, 16.05mmol) under stirring, reacting for 5h at 80 ℃, detecting by TLC that no raw material is remained basically, cooling to room temperature, adding dichloromethane, adjusting pH to 9 by using saturated sodium carbonate solution, separating, extracting an aqueous phase by dichloromethane for 3 times, combining organic phases, washing the organic phases for 5 times by water, drying by anhydrous sodium sulfate, concentrating in vacuum, recrystallizing by ethanol, and drying to obtain 1.67g of compound 7, wherein the yield is 87.5%. mp.215 deg.C; purity by HPLC was 98.97%.
Comparative example 24
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (2.01g, 5.40mmol, HPLC purity 99.23%) and 20ml of dimethylformamide into a reaction flask, adding trifluoroacetic acid (1.84g, 16.14mmol) under stirring, reacting at 80 ℃ for 5h, detecting by TLC that no raw material is remained, cooling to room temperature, adding dichloromethane, adjusting pH to 9 with saturated sodium carbonate solution, separating, extracting the aqueous phase with dichloromethane for 3 times, combining the organic phases, washing the organic phase with water for 5 times, drying with anhydrous sodium sulfate, concentrating in vacuum, recrystallizing with ethanol, and drying to obtain 1.69g of compound 7, wherein the yield is 88.8%. mp.215 deg.C; purity was 98.99% by HPLC.
Comparative example 25
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (1.69g, 4.54mmol, HPLC purity of 99.23%) and 20ml tetrahydrofuran into a reaction bottle, adding trifluoroacetic acid (1.56g, 13.68mmol) under stirring, heating reflux for reaction for 15h, detecting by TLC that no raw material is remained basically, adding dichloromethane after evaporating tetrahydrofuran, adjusting pH of an organic phase to 9 by using a saturated sodium carbonate solution, separating, extracting an aqueous phase by using dichloromethane for 3 times, combining the organic phases, drying by using anhydrous sodium sulfate, concentrating in vacuum, recrystallizing by using ethanol, and drying to obtain 1.43g of compound 7, wherein the yield is 88.44%. mp.215 ℃; purity by HPLC was 98.89%.
Comparative example 26
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding a mixed solution of compound 6 (2.21g, 5.94mmol, HPLC purity of 99.23%) and 12ml of tetrahydrofuran and 4ml of dimethyl sulfoxide into a reaction bottle, adding methanesulfonic acid (0.856g, 8.91mmol) under stirring, heating and refluxing for 3h, reducing the temperature to room temperature until no raw material is left, vacuum-concentrating to remove tetrahydrofuran, adding dichloromethane, adjusting the pH to 9 with a saturated sodium carbonate solution, demixing, washing a dichloromethane phase for 3 times, evaporating the solvent, recrystallizing with ethanol, performing suction filtration, and vacuum-concentrating to obtain 1.52g of white solid compound 7, wherein the yield is 72.28%. mp.215 ℃; purity was 98.93% by HPLC.
Comparative example 27
Preparation of compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (2.00g, 5.38mmol and HPLC purity of 99.23%) and 20ml of tetrahydrofuran into a reaction bottle, adding concentrated sulfuric acid (0.53g and 5.41mmol) under stirring, heating and refluxing for reaction for 3 hours, cooling to room temperature, performing suction filtration and drying to obtain sulfate of compound 7, stirring a filter cake in a saturated sodium carbonate solution for 1 hour, performing suction filtration and drying to obtain 1.72g of white solid compound 7, wherein the total yield is 90.37%. mp.215 deg.C; purity by HPLC was 98.90%.
Comparative example 28
Preparation of Compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding compound 6 (2.00g, 5.38mmol, HPLC purity of 99.23%) and 8ml of dimethyl sulfoxide into a reaction bottle, adding concentrated sulfuric acid (0.54g, 5.50mmol) under stirring, heating and refluxing for reaction for 3h, reducing the temperature to room temperature, adding dichloromethane, adjusting the pH of an organic phase to 9 with a saturated sodium carbonate solution, separating, extracting dichloromethane from an aqueous phase for 3 times, combining the organic phases, washing the organic phase for 5 times, drying with anhydrous sodium sulfate, filtering, vacuum concentrating, recrystallizing with ethanol, performing suction filtration, and drying to obtain 1.75g of compound 7, wherein the yield is 91.95%. mp.215 ℃; purity was 98.98% by HPLC.
Comparative example 29
Preparation of Compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding the compound 6 (2.00g, 5.38mmol and HPLC purity of 99.23%) and 20ml of methyltetrahydrofuran into a reaction bottle, adding concentrated sulfuric acid (0.54g and 5.51mmol) under stirring, heating and refluxing for reaction for 3 hours, cooling to room temperature, carrying out suction filtration and drying to obtain the sulfate of the compound 7, stirring a filter cake in a saturated sodium carbonate solution for 1 hour, carrying out suction filtration and drying to obtain 1.71g of a white solid compound 7, wherein the total yield is 89.85%. mp.215 deg.C; purity by HPLC was 98.92%.
Comparative example 30
Preparation of Compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding the compound 6 (2.00g, 5.38mmol and HPLC purity of 99.23%) and 20ml of acetone into a reaction bottle, adding concentrated sulfuric acid (0.55g and 5.61mmol) while stirring, heating and refluxing for reaction for 3 hours, cooling to room temperature, carrying out suction filtration and drying to obtain the sulfate of the compound 7, stirring a filter cake in a saturated sodium carbonate solution for 1 hour, carrying out suction filtration and drying to obtain 1.72g of a white solid compound 7, wherein the total yield is 90.37%. mp.215 ℃; purity by HPLC was 98.95%.
Comparative example 31
Preparation of Compound 7 (5- [ (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2,4-pyrimidine-diamine)
Adding the compound 6 (1.71g, 4.60mmol, HPLC purity 99.23%) and 20ml of dimethylformamide into a reaction bottle, adding concentrated sulfuric acid (0.48g, 4.90mmol) under stirring, heating and refluxing for reaction for 3h, cooling to room temperature, performing suction filtration and drying to obtain the sulfate of the compound 7, stirring the filter cake in a saturated sodium carbonate solution for 1h, performing suction filtration and drying to obtain 1.46g of white solid compound 7, wherein the total yield is 89.72%. mp.215 ℃; purity by HPLC was 98.97%.
Comparative example 32
Under nitrogen, compound 1b (2.000g, 4.646mmol), 10ml of DCM and acetic anhydride (1.513g, 14.818mmol) were added to a reaction flask, followed by slow dropwise addition (2.7ml, 23.072mmol) of tin chloride while cooling on ice. After stirring at room temperature for 18 hours, no compound 2a was formed.
On the basis of the failure to obtain the compound 2a, the target compound cannot be prepared by continuously referring to the reaction route of the invention.
Claims (25)
1. A preparation method of elaprine p-toluenesulfonate shown in a formula 7a is characterized by comprising the following steps of: in an aprotic solvent, under the action of p-toluenesulfonic acid, carrying out elimination reaction on a chroman compound shown as a formula 6 to obtain elaprine p-toluenesulfonic acid shown as a formula 7 a;
the aprotic solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide and dimethyl sulfoxide;
2. the method according to claim 1, wherein the aprotic solvent is a mixed solvent of tetrahydrofuran and dimethylsulfoxide, tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide or dimethylsulfoxide;
and/or in the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the dosage range of the volume-mass ratio of the aprotic solvent to the chroman compound shown in the formula 6 is 4-15ml/g;
and/or in the preparation method of the eplerenone p-toluenesulfonate shown in the formula 7a, the molar ratio of the p-toluenesulfonic acid to the chroman compounds shown in the formula 6 is (0.5-3): 1;
and/or in the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the temperature of the elimination reaction is 60-100 ℃;
and/or, in the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the elimination reaction time is 0.5 to 15 hours;
and/or in the preparation method of the esloprine p-toluenesulfonate shown in the formula 7a, the elimination reaction further comprises a post-treatment operation, and the post-treatment operation comprises any one of the following two operations: (i) cooling to separate out a solid, and then filtering and drying to obtain the product; (ii) Adding halogenated hydrocarbon solvent, washing the organic phase with water, separating out solid, filtering and drying.
3. The method for preparing the elaprine p-toluenesulfonate shown in the formula 7a according to claim 2, wherein the molar ratio of the p-toluenesulfonic acid to the chroman compound shown in the formula 6 is (1-3): 1.
4. The method for preparing the salt of elaprine p-toluene sulfonic acid represented by the formula 7a as claimed in any one of claims 1 to 3, wherein the method for preparing the salt of elaprine p-toluene sulfonic acid represented by the formula 7a further comprises the following steps: in an organic solvent, under the action of a reducing reagent, carrying out a reduction reaction on a chromanone compound shown in a formula 5 and/or a salt of the chromanone compound shown in the formula 5 to obtain a chromane compound shown in a formula 6;
the reducing reagent is sodium borohydride and/or potassium borohydride;
5. the method for preparing elaprine p-toluenesulfonate shown in the formula 7a according to claim 4, wherein in the method for preparing the chromane compound shown in the formula 6, the salt of the chromanone compound shown in the formula 5 is formed by the chromanone compound shown in the formula 5 and an acid in a molar ratio of 1:1;
and/or in the preparation method of the chroman compound shown in the formula 6, the organic solvent is methanol and/or ethanol;
and/or in the preparation method of the chromane compound shown in the formula 6, the volume-mass ratio dosage range of the organic solvent and the chromanone compound shown in the formula 5 and/or the salt of the chromanone compound shown in the formula 5 is 5-25ml/g;
and/or in the preparation method of the chromane compound shown in the formula 6, the molar ratio of the reducing reagent to the chromanone compound shown in the formula 5 is (0.5-2): 1, the molar ratio of the reducing reagent to the salt of the chromanone compound shown in the formula 5 is (1.5-2): 1;
and/or in the preparation method of the chroman compound shown in the formula 6, the temperature of the reduction reaction is-15-30 ℃;
and/or in the preparation method of the chroman compound shown in the formula 6, the reduction reaction time is 0.5-3 hours;
and/or in the preparation method of the chroman compound shown in the formula 6, the reduction reaction further comprises the following post-treatment steps: removing the solvent, washing, filtering and recrystallizing to obtain the product; wherein, the filtering step further comprises the following steps: adding an alcohol solvent into the filter cake for refluxing, and removing the solvent after refluxing.
6. The method for preparing elaprine p-toluenesulfonate shown in claim 5, as claimed in claim 7a, wherein in the preparation method of chroman compounds shown in formula 6, in the salt of chromanone compounds shown in formula 5, the acid is acetic acid and/or propionic acid;
and/or in the preparation method of the chroman compound shown in the formula 6, the organic solvent is methanol;
and/or in the preparation method of the chroman compound shown in the formula 6, the temperature of the reduction reaction is 20-30 ℃;
and/or in the preparation method of the chroman compound shown in the formula 6, in the post-treatment step, the recrystallization is carried out in a mixture of an alcohol solvent and water.
7. The method for preparing elaprine p-toluenesulfonate shown in claim 6, as claimed in claim 7a, wherein in the preparation method of chroman compounds shown in formula 6, the acid in the salt of chromanone compounds shown in formula 5 is acetic acid.
8. The method for preparing the salt of elaprine p-toluene sulfonic acid shown in the formula 7a according to claim 4, wherein the method for preparing the salt of elaprine p-toluene sulfonic acid shown in the formula 7a further comprises the following steps: step (1): in an organic solvent, in the presence of alkali and acid, carrying out aldol condensation-ring closure reaction on a phenol compound shown as a formula 4 and cyclopropanecarboxaldehyde as shown in the specification to obtain a tetrahydropyranone substance; the tetrahydropyranone substance comprises a chromanone compound shown in a formula 5 and the acid;
9. the method for preparing the salt of elaprine p-toluenesulfonic acid shown in formula 7a according to claim 8, wherein the method for preparing the salt of elaprine p-toluenesulfonic acid shown in formula 7a further comprises the following steps: step (1): in an organic solvent, in the presence of alkali and acid, carrying out aldol condensation-ring closure reaction on a phenol compound shown as a formula 4 and cyclopropanecarboxaldehyde as shown in the specification to obtain a tetrahydropyranone substance; the tetrahydropyranone substance comprises a chromanone compound shown as a formula 5 and the acid;
step (2): carrying out neutralization reaction on the tetrahydropyranone substance obtained in the step (1) and alkali as shown in the specification to obtain a chromanone compound shown in a formula 5;
10. the method for preparing elaprine p-toluenesulfonate shown in formula 7a according to claim 8 or 9, wherein in the method for preparing the chromanone compound shown in formula 5, in step (1), the organic solvent is a nitrile solvent;
and/or in the preparation method of the chromanone compound shown in the formula 5, the volume-mass ratio of the organic solvent to the phenol compound shown in the formula 4 can be 8-20ml/g;
and/or in the preparation method of the chromanone compound shown in the formula 5, the alkali is pyrrolidine and/or piperidine;
and/or in the preparation method of the chromanone compound shown in the formula 5, the molar ratio of the alkali to the phenol compound shown in the formula 4 is (1-2): 1;
and/or in the preparation method of the chromanone compound shown in the formula 5, the acid is acetic acid and/or propionic acid;
and/or in the preparation method of the chromanone compound shown as the formula 5, in the step (1), the molar ratio of the acid to the phenol compound shown as the formula 4 is (0.5-2): 1;
and/or in the preparation method of the chromanone compound shown in the formula 5, in the step (1), the molar ratio of the cyclopropane formaldehyde to the phenol compound shown in the formula 4 is (1-2): 1;
and/or in the preparation method of the chromanone compound shown as the formula 5, in the step (1), the temperature of the aldol condensation-ring closure reaction is 0-50 ℃;
and/or in the preparation method of the chromanone compound shown in the formula 5, in the step (1), the time of the aldol condensation-ring closure reaction is 20-40 hours;
and/or in the preparation method of the chromanone compound shown in the formula 5, the tetrahydropyranone substance consists of the chromanone compound shown in the formula 5 and the acid;
and/or in the preparation method of the chromanone compound shown in the formula 5, in the step (2), the alkali is alkali metal carbonate and/or alkali metal bicarbonate;
and/or in the preparation method of the chromanone compound shown in the formula 5, the aldol condensation-ring closure reaction further comprises post-treatment, and the post-treatment comprises the following steps: after the aldol condensation-ring closure reaction is finished, filtering and drying a reaction system to obtain the tetrahydropyranone substance;
and/or in the preparation method of the chromanone compound shown in the formula 5, the neutralization reaction further comprises post-treatment, and the post-treatment comprises the following steps: and after the neutralization reaction is finished, filtering and drying the reaction system to obtain the chromanone compound shown as the formula 5.
11. The method for preparing elaprine p-toluenesulfonate shown in claim 10, wherein in the method for preparing the chromanone compound shown in formula 5, the base is pyrrolidine;
and/or in the preparation method of the chromanone compound shown in the formula 5, the acid is acetic acid.
12. The method for preparing the salt of elaprine p-toluenesulfonic acid represented by the formula 7a according to claim 8 or 9, wherein the method for preparing the salt of elaprine p-toluenesulfonic acid represented by the formula 7a further comprises the following scheme 1 or scheme 2:
scheme 1 includes the following steps: in an organic solvent, in the presence of alkali, performing acetylamino hydrolysis reaction on a phenol compound shown as a formula 8 as shown in the specification to obtain a phenol compound shown as a formula 4;
scheme 2 comprises the following steps: in an organic solvent, in the presence of Lewis acid, performing selective demethylation reaction on the acetophenone compound shown in the formula 3 as shown in the specification to obtain a phenol compound shown in the formula 4;
13. the method for preparing eplerenone p-toluenesulfonate shown in claim 12, wherein in scheme 1, the organic solvent is an alcohol solvent;
and/or, in the scheme 1, the volume-mass ratio of the organic solvent to the phenol compound shown in the formula 8 is 5-20ml/g;
and/or, in the scheme 1, the base is alkali metal carbonate;
and/or, in the scheme 1, the molar ratio of the alkali to the phenol compound shown in the formula 8 is (0.1-1): 1;
and/or, in the scheme 1, the temperature of the acetamido hydrolysis reaction is 60-82 ℃;
and/or, in the scheme 1, the time of the hydrolysis reaction of the acetamido is 0.5 to 2 hours;
and/or, in the scheme 1, the preparation method further comprises post-treatment, and the post-treatment comprises the following steps: after the acetylamino hydrolysis reaction is finished, crystallizing a reaction system, filtering, washing and drying to obtain the phenol compound shown as the formula 4;
and/or, in the scheme 2, the organic solvent is a halogenated hydrocarbon solvent;
and/or in the scheme 2, the volume-mass ratio of the organic solvent to the acetophenone compound shown in the formula 3 is 8-25ml/g;
and/or, in the scheme 2, the lewis acid is boron tribromide and/or boron trichloride;
and/or, in the scheme 2, the molar ratio of the Lewis acid to the acetophenone compound shown in the formula 3 is (1-2): 1;
and/or, in said scheme 2, the temperature of said selective demethylation reaction is between-15 ℃ and 35 ℃;
and/or, in the scheme 2, the lewis acid is dropwise added into the acetophenone compound shown in the formula 3 and the organic solvent;
and/or, in the case of scheme 2, the time of the selective demethylation reaction is 2 to 5 hours;
and/or, in the scheme 2, the preparation method further comprises a post-treatment, and the post-treatment comprises the following steps: and after the selective demethylation reaction is finished, carrying out extraction and extinction, concentration and recrystallization on the reaction system to obtain the phenol compound shown in the formula 4.
14. The method for preparing elaprine p-toluenesulfonate according to claim 13, wherein in scheme 1, the organic solvent is one or more of methanol, ethanol and isopropanol;
and/or, in the scheme 1, the alkali is sodium carbonate and/or potassium carbonate;
and/or, in the scheme 2, the organic solvent is dichloromethane and/or chloroform;
and/or, in the scheme 2, the temperature of the selective demethylation reaction is-6 ℃ to 30 ℃.
15. The process for preparing elaprine p-toluenesulfonate according to claim 14, wherein in scheme 1, the organic solvent is methanol.
16. The method of claim 12, wherein when the method of preparing the salt of eplerenone p-toluene sulfonic acid of formula 7a further comprises scheme 1, the method of preparing the salt of eplerenone p-toluene sulfonic acid of formula 7a further comprises scheme a, wherein scheme a comprises the steps of: in an organic solvent, in the presence of Lewis acid, performing selective demethylation reaction on the acetyl compound shown as the formula 2 as shown in the specification to obtain the phenol compound shown as the formula 8;
when the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a further comprises the scheme 2, the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a further comprises a scheme B, and the scheme B comprises the following steps; in an organic solvent, in the presence of alkali, performing the following acetylamino hydrolysis reaction on an acetyl compound shown as a formula 2 to obtain an acetophenone compound shown as a formula 3;
17. the process for preparing elaprine p-toluenesulfonate according to claim 16, wherein in scheme a, the organic solvent is a halogenated hydrocarbon solvent;
and/or in the scheme A, the volume-mass ratio of the organic solvent to the acetyl compound shown in the formula 2 is 8-20ml/g;
and/or, in the scheme a, the lewis acid is boron tribromide and/or boron trichloride;
and/or in the scheme A, the molar ratio of the Lewis acid to the acetyl compound shown in the formula 2 is (1-2): 1;
and/or, in said scheme A, the temperature of said selective demethylation reaction is between-15 ℃ and 35 ℃;
and/or, in the scheme A, the Lewis acid is dropwise added into the acetyl compound shown in the formula 2 and the organic solvent;
and/or, in the scheme A, the time of the selective demethylation reaction is 10-20 hours;
and/or, the scheme A further comprises post-treatment, and the post-treatment comprises the following steps: after the selective demethylation reaction is finished, performing extraction and extinction on a reaction system, adjusting the pH value to 6, filtering and recrystallizing to obtain the phenol compound shown as the formula 8;
and/or, in the scheme B, the organic solvent is an alcohol solvent;
and/or in the scheme B, the volume-mass ratio of the organic solvent to the acetyl compound shown in the formula 2 is 5-15ml/g;
and/or, in the scheme B, the base is alkali metal carbonate;
and/or in the scheme B, the molar ratio of the alkali to the acetyl compound shown in the formula 2 is (0.1-1): 1;
and/or, in the scheme B, the temperature of the acetamido hydrolysis reaction is 60-82 ℃;
and/or, in the scheme B, the time of the hydrolysis reaction of the acetamido is 0.5-2 hours;
and/or, the scheme B further comprises post-treatment, and the post-treatment comprises the following steps: after the hydrolysis reaction of the acetamido, crystallizing, filtering, washing and drying a reaction system to obtain the acetophenone compound shown in the formula 3.
18. The method for preparing eplerenone p-toluenesulfonate shown in claim 17, wherein in scheme a, the organic solvent is dichloromethane and/or chloroform;
and/or, in said case of scheme a, the temperature of said selective demethylation reaction is between-8 ℃ and 30 ℃;
and/or, in the scheme B, the organic solvent is one or more of methanol, ethanol and isopropanol;
and/or, in the scheme B, the alkali is sodium carbonate and/or potassium carbonate;
and/or, in the scheme B, the temperature of the acetamido hydrolysis reaction is 65-70 ℃.
19. The process for preparing eplerenone p-toluenesulfonate shown in claim 18, wherein in scheme B, the organic solvent is methanol.
20. The method of claim 16, wherein the method for preparing the salt of eplerenone p-toluene sulfonic acid represented by formula 7a further comprises the following scheme a or scheme b:
the scheme a comprises the following steps: in an organic solvent, under the existence of Lewis acid, carrying out acetylation reaction on trimethoprim shown in a formula 1 and an acetylation reagent shown in the following formula to obtain an acetyl compound shown in a formula 2;
the scheme b comprises the following steps: in an organic solvent, in the presence of Lewis acid, performing acetylation reaction on an acetamide compound shown in a formula 1a and an acetylation reagent as shown in the specification to obtain an acetyl compound shown in a formula 2;
21. the process according to claim 20, wherein the organic solvent is a halogenated hydrocarbon solvent;
and/or in the scheme a, the volume-mass ratio of the organic solvent to the trimethoprim shown in the formula 1 is 5-15ml/g;
and/or, in the scheme a, the acetylation reagent is acetyl chloride and/or acetic anhydride;
and/or in the scheme a, the molar ratio of the acetylation reagent to the trimethoprim shown in the formula 1 is (3-6): 1;
and/or, in the scheme a, the Lewis acid is stannic chloride;
and/or in the scheme a, the molar ratio of the Lewis acid to the trimethoprim shown in the formula 1 is (1-3): 1;
and/or, in the scheme a, the temperature of the acetylation reaction is 25-85 ℃;
and/or, in the scheme a, the acetylation reaction time is 1-5 hours;
and/or, the scheme a further comprises post-treatment, and the post-treatment comprises the following steps: after the acetylation reaction is finished, carrying out extraction and sterilization on a reaction system, separating liquid to obtain an organic phase and a water phase, washing the organic phase with water, extracting the water phase with an organic solvent, adjusting the pH value of the combined organic phase to 7-8, separating liquid to obtain an organic phase, drying, filtering, concentrating and recrystallizing the washed organic phase and the organic phase to obtain the acetyl compound shown in the formula 2;
and/or, in the scheme b, the organic solvent is a halogenated hydrocarbon solvent;
and/or in the scheme b, the volume-mass ratio of the organic solvent to the acetamide compound shown in the formula 1a is 5-15ml/g;
and/or, in the scheme b, the acetylation reagent is acetyl chloride and/or acetic anhydride;
and/or in the scheme b, the molar ratio of the acetylation reagent to the acetamide compound shown in the formula 1a is (1.5-4): 1;
and/or, in the scheme b, the Lewis acid is stannic chloride;
and/or, in the scheme b, the molar ratio of the Lewis acid to the acetamide compound shown in the formula 1a is (1-3): 1;
and/or, in the scheme b, the temperature of the acetylation reaction is 25-85 ℃;
and/or, in the scheme b, the acetylation reaction time is 1-5 hours;
and/or, the scheme b further comprises post-treatment, and the post-treatment comprises the following steps: after the acetylation reaction is finished, carrying out extraction and sterilization on a reaction system, separating liquid to obtain an organic phase and a water phase, washing the organic phase with water, extracting the water phase with an organic solvent, adjusting the pH value of the combined organic phase to 7-8, separating liquid to obtain an organic phase, washing the organic phase with water, drying, filtering, concentrating, and recrystallizing to obtain the acetyl compound shown in the formula 2.
22. The method according to claim 21, wherein the organic solvent is one or more of chloroform, dichloromethane and dichloroethane;
and/or, in the scheme a, the acetylation reagent is acetic anhydride;
and/or, in the scheme a, the molar ratio of the acetylation reagent to the trimethoprim shown in the formula 1 is (4-5): 1;
and/or in the scheme a, the molar ratio of the lewis acid to the trimethoprim shown in the formula 1 is (2-3): 1;
and/or, in the scheme a, the temperature of the acetylation reaction is 60-65 ℃;
and/or, in the scheme b, the organic solvent is one or more of chloroform, dichloromethane and dichloroethane;
and/or, in the scheme b, the acetylation reagent is acetic anhydride;
and/or, in the scheme b, the molar ratio of the acetylation reagent to the acetamide compound shown in the formula 1a is 2:1;
and/or, in the scheme b, the molar ratio of the Lewis acid to the acetamide compound shown in the formula 1a is (2-3): 1;
and/or, in the scheme b, the temperature of the acetylation reaction is 60-65 ℃.
23. The method for preparing elaprine p-toluenesulfonate according to claim 22, wherein in scheme a, the organic solvent is chloroform;
and/or, in the scheme b, the organic solvent is chloroform.
24. The method of claim 20, wherein when the method of preparing the salt of eplerenone p-toluene sulfonic acid of formula 7a further comprises scheme b, the method of preparing the salt of eplerenone p-toluene sulfonic acid of formula 7a further comprises scheme c, and wherein scheme c comprises the steps of: in an organic solvent, under the action of an acetylation reagent, carrying out acetylation reaction on trimethoprim shown in a formula 1 to obtain an acetamide compound shown in a formula 1 a;
25. the process according to claim 24, wherein the organic solvent is toluene;
and/or in the scheme c, the dosage range of the volume mass ratio of the organic solvent to the trimethoprim shown in the formula 1 is 5-20ml/g;
and/or, in the scheme c, the acetylation reagent is acetic anhydride and/or acetyl chloride;
and/or, in the scheme c, the molar ratio of the acetylation reagent to the trimethoprim shown in the formula 1 is (2-5): 1;
and/or, in the scheme c, the temperature of the acetylation reaction is 100-110 ℃;
and/or, in the scheme c, the acetylation reaction time is 1-3 hours;
and/or, in the scheme c, the acetylation reaction further comprises the operation of post-treatment, and the post-treatment comprises the following post-treatment steps: crystallizing, filtering and drying.
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| CN102112108A (en) * | 2008-04-08 | 2011-06-29 | 阿西诺药品有限公司 | Aqueous pharmaceutical formulation |
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| CN102112108A (en) * | 2008-04-08 | 2011-06-29 | 阿西诺药品有限公司 | Aqueous pharmaceutical formulation |
| CN104394862A (en) * | 2012-05-30 | 2015-03-04 | 科门蒂斯公司 | Chromane compounds |
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