CN115521320B - Method for preparing pranoprofen - Google Patents
Method for preparing pranoprofen Download PDFInfo
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- CN115521320B CN115521320B CN202110710374.2A CN202110710374A CN115521320B CN 115521320 B CN115521320 B CN 115521320B CN 202110710374 A CN202110710374 A CN 202110710374A CN 115521320 B CN115521320 B CN 115521320B
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- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 title claims abstract description 132
- 229960003101 pranoprofen Drugs 0.000 title claims abstract description 128
- 238000000034 method Methods 0.000 title claims abstract description 126
- 230000008569 process Effects 0.000 claims abstract description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 435
- 150000001875 compounds Chemical class 0.000 claims description 397
- 238000006243 chemical reaction Methods 0.000 claims description 334
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 302
- 239000000203 mixture Substances 0.000 claims description 177
- 238000003756 stirring Methods 0.000 claims description 163
- 239000012065 filter cake Substances 0.000 claims description 133
- 239000008213 purified water Substances 0.000 claims description 127
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 120
- 238000001914 filtration Methods 0.000 claims description 117
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 102
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- 238000004519 manufacturing process Methods 0.000 claims description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 78
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 70
- 238000001816 cooling Methods 0.000 claims description 68
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 59
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 54
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 42
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 42
- 238000001291 vacuum drying Methods 0.000 claims description 39
- 239000007787 solid Substances 0.000 claims description 38
- 238000002360 preparation method Methods 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 28
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 27
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 27
- 230000035484 reaction time Effects 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 25
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 23
- 238000004321 preservation Methods 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 150000001263 acyl chlorides Chemical class 0.000 claims description 18
- 239000003638 chemical reducing agent Substances 0.000 claims description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 claims description 11
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000002841 Lewis acid Substances 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 238000006462 rearrangement reaction Methods 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 238000010751 Ullmann type reaction Methods 0.000 claims description 2
- XEFCWBLINXJUIV-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.CC(O)=O.IC1=CC=CC=C1 XEFCWBLINXJUIV-UHFFFAOYSA-N 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000007547 defect Effects 0.000 abstract description 3
- 238000011112 process operation Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 574
- 239000012535 impurity Substances 0.000 description 182
- 239000000243 solution Substances 0.000 description 173
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 101
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
- 239000000047 product Substances 0.000 description 81
- 239000012071 phase Substances 0.000 description 75
- 239000008346 aqueous phase Substances 0.000 description 70
- 239000000706 filtrate Substances 0.000 description 66
- 238000005406 washing Methods 0.000 description 62
- 229910052799 carbon Inorganic materials 0.000 description 57
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 49
- 235000017557 sodium bicarbonate Nutrition 0.000 description 49
- 230000001276 controlling effect Effects 0.000 description 43
- 229910052739 hydrogen Inorganic materials 0.000 description 40
- 239000001257 hydrogen Substances 0.000 description 40
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 35
- 239000007864 aqueous solution Substances 0.000 description 35
- RJYHHCRUWSEDEN-UHFFFAOYSA-N COC(C(C)C1=CC=C(OC2=NC=CC=C2C(=O)O)C=C1)=O Chemical compound COC(C(C)C1=CC=C(OC2=NC=CC=C2C(=O)O)C=C1)=O RJYHHCRUWSEDEN-UHFFFAOYSA-N 0.000 description 34
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 31
- 239000000523 sample Substances 0.000 description 30
- 238000007605 air drying Methods 0.000 description 27
- -1 2-hydroxy propyl Chemical group 0.000 description 26
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 26
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 25
- 238000001035 drying Methods 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 24
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 24
- 238000012546 transfer Methods 0.000 description 22
- VWMVAQHMFFZQGD-UHFFFAOYSA-N 4-hydroxyphenylacetone Chemical compound CC(=O)CC1=CC=C(O)C=C1 VWMVAQHMFFZQGD-UHFFFAOYSA-N 0.000 description 21
- 150000002148 esters Chemical class 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 21
- 238000010791 quenching Methods 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 20
- 238000007664 blowing Methods 0.000 description 20
- 230000007935 neutral effect Effects 0.000 description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 18
- 238000002156 mixing Methods 0.000 description 18
- 238000006386 neutralization reaction Methods 0.000 description 18
- 238000004537 pulping Methods 0.000 description 18
- 230000000171 quenching effect Effects 0.000 description 18
- 239000000126 substance Substances 0.000 description 17
- 150000001721 carbon Chemical group 0.000 description 16
- 238000000967 suction filtration Methods 0.000 description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- 238000002425 crystallisation Methods 0.000 description 15
- 230000008025 crystallization Effects 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 15
- 239000012279 sodium borohydride Substances 0.000 description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 description 15
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 13
- MMWNKXIFVYQOTK-UHFFFAOYSA-N 2-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Br MMWNKXIFVYQOTK-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
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- 238000010521 absorption reaction Methods 0.000 description 10
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 9
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 9
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- 238000001228 spectrum Methods 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- 238000002329 infrared spectrum Methods 0.000 description 7
- 238000003908 quality control method Methods 0.000 description 7
- 239000013558 reference substance Substances 0.000 description 7
- HXDOZKJGKXYMEW-UHFFFAOYSA-N 4-ethylphenol Chemical compound CCC1=CC=C(O)C=C1 HXDOZKJGKXYMEW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
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- 238000005259 measurement Methods 0.000 description 6
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
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- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 5
- HTQKYCKYLBQSJB-UHFFFAOYSA-N CCOC(C(C)C(C=C1)=CC=C1OC1=NC=CC=C1C(O)=O)=O Chemical compound CCOC(C(C)C(C=C1)=CC=C1OC1=NC=CC=C1C(O)=O)=O HTQKYCKYLBQSJB-UHFFFAOYSA-N 0.000 description 5
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- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- JBOYQZDFEWOILV-UHFFFAOYSA-N 5h-chromene Chemical compound O1C=CC=C2CC=CC=C21 JBOYQZDFEWOILV-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- AXDJCCTWPBKUKL-UHFFFAOYSA-N 4-[(4-aminophenyl)-(4-imino-3-methylcyclohexa-2,5-dien-1-ylidene)methyl]aniline;hydron;chloride Chemical compound Cl.C1=CC(=N)C(C)=CC1=C(C=1C=CC(N)=CC=1)C1=CC=C(N)C=C1 AXDJCCTWPBKUKL-UHFFFAOYSA-N 0.000 description 3
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
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- JEQDSBVHLKBEIZ-REOHCLBHSA-N (2s)-2-chloropropanoyl chloride Chemical compound C[C@H](Cl)C(Cl)=O JEQDSBVHLKBEIZ-REOHCLBHSA-N 0.000 description 2
- AYKYOOPFBCOXSL-UHFFFAOYSA-N (4-hydroxyphenyl)acetonitrile Chemical compound OC1=CC=C(CC#N)C=C1 AYKYOOPFBCOXSL-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KEYRTRGLKSAGJN-UHFFFAOYSA-N 2-iodopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1I KEYRTRGLKSAGJN-UHFFFAOYSA-N 0.000 description 2
- ADEKJVNFIQUGRR-UHFFFAOYSA-N 4h-pyridin-3-one Chemical compound O=C1CC=CN=C1 ADEKJVNFIQUGRR-UHFFFAOYSA-N 0.000 description 2
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- 206010061218 Inflammation Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
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- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
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- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical group C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 1
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- IQLUYYHUNSSHIY-HZUMYPAESA-N eicosatetraenoic acid Chemical class CCCCCCCCCCC\C=C\C=C\C=C\C=C\C(O)=O IQLUYYHUNSSHIY-HZUMYPAESA-N 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 description 1
- XGDZEDRBLVIUMX-UHFFFAOYSA-N methyl 2-(4-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(O)C=C1 XGDZEDRBLVIUMX-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
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- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical group CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicines, and relates to a method for preparing pranoprofen. The method overcomes the defects of the prior art, shortens the synthesis route, reduces the process conditions, simplifies the process operation, improves the labor safety, is more suitable for industrial production, is more environment-friendly and has higher yield.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a method for preparing pranoprofen.
Background
Pranoprofen is a propionic acid non-steroidal anti-inflammatory analgesic marketed by gefei pharmaceutical co.ltd in 1981, which was then developed as an eye drop by Qianshou pharmaceutical co.ltd in japan in 1988 under the trade name Pranopulin (Pranopulin) for symptomatic treatment of external and pre-ocular inflammations (blepharitis, conjunctivitis, keratitis, scleritis, superficial scleritis, iridocyclitis, postoperative inflammation). Pranoprofen belongs to the propionic acid non-steroidal anti-inflammatory drug, chemical name: (2 RS) -2- (10-hydro-9-oxa-1-azaanthracen-6-yl) propionic acid, CAS registry number 52549-17-4. The effect is stronger than aspirin, indomethacin and ibuprofen, and the action mechanism is to inhibit the activity of cyclooxygenase, block the synthesis of eicosatetraenoic acid derivatives and reduce the synthesis of prostaglandin, thereby blocking the action of inflammatory mediators and playing the role of medicine.
Pranoprofen has a structural formula shown in formula 0 below:
there are many reports on pranoprofen synthesis, and the main difference is that different methods are used to build side chains, specifically as follows:
route one: a rearrangement concept is used. A method for preparing 2-aryl propionic acid by reacting and rearranging 2-hydroxy propyl ketal and sulfonyl chloride is reported in literature (Bull. Chem. Soc. Jpn.1987, 60, 4015-4018), reference part Japanese patent (JP 4288080, JP 4288081) such as Jin Qingrong uses 2-chloronicotinic acid and phenol as raw materials in the synthesis research improvement of pranoprofen (fine chemical intermediate 2009, 39 (3), 37-39), and performs nucleophilic substitution and PPA cyclization reaction to obtain 5H- [1] -benzopyran [2,3-b ] pyridin-5-one, and then performs potassium borohydride reduction and acidic hydrolysis to obtain 5H- [1] -benzopyran [2,3-b ] pyridine, and then performs acylation reaction with 2-chloropropionyl chloride to obtain a key intermediate 6- (2-chloropropionyl) -10H-9-oxa-1-azaanthracene. And (3) reacting with sodium methoxide to obtain hydroxy ketal, and then carrying out sulfonylation, rearrangement and hydrolysis on the hydroxy ketal by utilizing sulfonyl chloride to obtain pranoprofen.
The first disadvantage of the route is that polyphosphoric acid (PPA) is used in the production process, and a large amount of phosphorus-containing wastewater is generated in the post-treatment process, so that the method is not beneficial to environmental protection; 2-chloropropionyl chloride and sulfonyl chloride are also used in the process, so that the odor is strong in irritation, and the labor protection of production personnel is not facilitated; the rearrangement reaction is put at the end, which makes the purification of related substances difficult and the quality control of the finished product inconvenient.
Route two: the side chain 2+1 is used, cyanide is used as a carbon source to introduce carboxyl, and cyanide is used for lengthening a carbon chain. The process uses 2-chloronicotinic acid and p-ethylphenol as raw materials, 7-ethyl-5H 1-benzopyran [2,3-b ] pyridine-5-ketone is obtained through nucleophilic substitution and Friedel-crafts reaction, alpha-halogeno-5H 1-benzopyran [2,3-b ] pyridine-7-ethane is obtained through halogenation reaction and reduction reaction, alpha-methyl-5H 1-benzopyran [2,3-b ] pyridine-7-acetonitrile is obtained through prolonging a carbon chain by cyanide, and finally pranoprofen is obtained through cyano hydrolysis.
The second route has the defects that the cyanide which is a highly toxic reagent is used in the production, so that the safety risk is increased, and the labor protection is not facilitated.
Route three: using the side chain "2+1", in CO 2 Introducing carboxyl into carbon source by CO 2 And (5) increasing the carbon chain. The process uses 2-chloronicotinic acid and p-ethylphenol as raw materials, and obtains 7-ethyl-5H 1 through nucleophilic substitution and Friedel-crafts reaction ring closure]Benzopyran [2,3-b ]]The pyridine-5-ketone is subjected to halogenation reaction and reduction reaction to obtain alpha-halogenated-5H 1]Benzopyran [2,3-b ]]Pyridine-7-ethane, halogenated hydrocarbon and magnesium are prepared into a Grignard reagent, and then carbon dioxide is introduced to obtain pranoprofen under the acidic hydrolysis condition.
The third route has the disadvantages of high reaction condition, need of Grignard reaction, and need of cryogenic condition at-80 ℃, and severe condition, thus being unfavorable for industrial production.
Route four: the methyl thought is introduced by using a side chain of '2+1' and taking methyl iodide as a carbon source. 2-chloronicotinic acid and p-hydroxyphenylacetonitrile or 4-hydroxyphenylacetic acid methyl ester are used as starting materials, and 7-R-5H- [1] -benzopyran [2,3-b ] pyridine-5-ketone (R=COOMe, CN) is obtained through substitution reaction and friedel-crafts reaction ring closure. Then reducing by sodium borohydride and hydrolyzing by isopropanol hydrochloride to obtain 7-R-5H- [1] -benzopyran [2,3-b ] pyridine (R=COOMe, CN). Methyl is introduced into alpha position by methyl iodide, and cyano or ester group is hydrolyzed to obtain pranoprofen.
The fourth disadvantage is that when methyl is introduced by methyl iodide, the reaction selectivity is poor, and the bi-methylated impurities are difficult to purify, which is unfavorable for the quality of the product. And methyl iodide is a highly toxic reagent, which is unfavorable for production and health of researchers.
Route five: the three carbon side chain was constructed using the side chain "1+1+1" concept. The process uses 2-chloronicotinic acid and phenol as raw materials, and uses nucleophilic substitution and phosphorus oxychloride to catalyze Friedel-crafts reaction to close ring to obtain 5H 1-benzopyran [2,3-b ] pyridine-5-one, then uses Na-Hg/ethanol reduction and isopropanol hydrochloride hydrolysis to make tricyclic parent 5H 1-benzopyran [2,3-b ] pyridine. Introducing the first carbon through chloromethylation, introducing the second carbon through cyanidation, introducing the third carbon into methyl iodide to obtain alpha-methyl-5H 1-benzopyran [2,3-b ] pyridine-7-methyl acetate, and hydrolyzing to obtain pranoprofen.
The fifth disadvantage is the lengthy reaction steps, which have an impact on labor, energy consumption and yield. In addition, the production uses the extremely toxic reagents such as phosphorus oxychloride, cyanide, methyl iodide and the like, thereby increasing the safety risk and being not beneficial to the health of production and researchers; methyl is introduced into methyl iodide, so that double methylation impurities which are difficult to separate and remove are easily generated, and the product quality is influenced.
In addition, regarding stability and impurities, japanese pharmacopoeia prescribes that total impurities are not more than 1.0%, single impurities are not more than 0.5%, wherein impurity structures are not specifically prescribed. The Chinese pharmacopoeia does not contain pranoprofen at present, so there is no relevant regulation.
In general, the prior art for synthesizing pranoprofen has a lot of defects, mainly focuses on lengthy synthetic routes and has low total yield; for example, a total yield of route 23.7%, a total yield of route three 29.2%, a total yield of route five 3.7% (route two and route four integrate a plurality of prior art techniques, no clear total yield report); the use of highly toxic chemical reagents is not beneficial to personnel safety protection; the reaction conditions are harsh, which is not beneficial to industrial production and other aspects; there is also room for improvement in terms of impurities and impurity content, for example: in addition, if the impurity content of the bulk drug is higher, the quality level of the eye drop product can be affected, so that the purity of the bulk drug is improved, and the variety and the quantity of the impurities are reduced.
At present, an innovation is needed to be carried out on the synthesis process of pranoprofen, and a process technology more suitable for commercial production is developed.
Disclosure of Invention
The inventor of the present invention has conducted intensive studies and creative efforts to obtain a novel process for preparing pranoprofen. The inventors have surprisingly found that the method overcomes the deficiencies of the prior art, shortens the synthesis route, reduces the process conditions, simplifies the process operation, improves the labor safety, is more suitable for industrial production, is more environment-friendly and has higher yield.
The following invention is thus provided:
(one)
One aspect of the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt or ester thereof,
wherein R is C 2 -C 10 Straight or branched alkyl, preferably R is C 2 -C 6 A linear or branched alkyl group, more preferably R is C 2 -C 4 Straight or branched alkyl groups are, for example, ethyl, propyl, isopropyl or n-butyl.
Another aspect of the invention relates to a process for preparing a compound of formula I comprising the step of reacting a compound of formula a with a compound of formula B to form a compound of formula I:
wherein,,
x is halogen, such as fluorine, chlorine, bromine or iodine, preferably chlorine or bromine;
r is C 2 -C 10 Straight or branched alkyl, preferably R is C 2 -C 6 A linear or branched alkyl group, more preferably R is C 2 -C 4 Straight or branched alkyl groups are, for example, ethyl, propyl, isopropyl or n-butyl.
The structural formulas of the compound of the formula A and the compound of the formula B are respectively as follows:
wherein,,
x is halogen, for example fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
Wherein R is C 2 -C 10 Straight or branched alkyl, preferably R is C 2 -C 6 A linear or branched alkyl group, more preferably R is C 2 -C 4 Straight or branched alkyl groups are, for example, ethyl, propyl, isopropyl or n-butyl.
In some embodiments of the invention, the method of preparing a compound of formula I, wherein the compound of formula a (2-halonicotinic acid) is selected from the group consisting of 2-chloronicotinic acid, 2-bromonicotinic acid, and 2-iodonicotinic acid; preferably 2-chloronicotinic acid or 2-bromonicotinic acid.
In some embodiments of the invention, the method for preparing a compound of formula I, wherein the compound of formula B (4-hydroxy-benzophenone compound) is selected from the group consisting of 4-hydroxy-propiophenone, 4-hydroxy-phenylbutanone, and 4-hydroxy-phenylpentanone.
In some embodiments of the invention, the process for preparing a compound of formula I, wherein the temperature of the reaction system is from 60 ℃ to 150 ℃, preferably from 80 ℃ to 120 ℃, more preferably from 95 ℃ to 120 ℃, 95 ℃ to 110 ℃, 105 ℃ to 120 ℃, 105 ℃ to 115 ℃, 110 ℃ to 120 ℃, 95 ℃ to 105 ℃, 105 ℃ to 110 ℃, 95 ℃, 100 ℃, 105 ℃, 115 ℃, or 120 ℃.
In some embodiments of the invention, the method of preparing a compound of formula I, wherein the reaction time is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, 1-10 hours, 2-8 hours, 3-7 hours, 4-6 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.
In some embodiments of the present invention, the process for preparing a compound of formula I, wherein a compound of formula a is reacted with a compound of formula B in an organic solvent as reaction solvent, preferably, the organic solvent is N, N-dimethylformamide or dimethylsulfoxide; more preferably, the organic solvent is N, N-dimethylformamide.
In some embodiments of the invention, the process for preparing a compound of formula I, wherein the compound of formula a is reacted with a compound of formula B in the presence of a catalyst, preferably, the catalyst is cuprous iodide.
In some embodiments of the invention, the process for preparing a compound of formula I, wherein the reaction system further comprises an acid binding agent, such as potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
In some embodiments of the invention, the process for preparing a compound of formula I, wherein the compound of formula a is calculated as the molar ratio: a compound of formula B: catalyst: the acid binding agent is 1: (1-5): (0.05-1): (1-4), preferably 1: (1-3): (0.05-0.1): (1-2).
In some embodiments of the present invention, the method for preparing a compound of formula I further comprises a step of separating the compound of formula I from the reaction system, preferably comprising the steps of:
cooling (e.g. to 50 ℃ or lower) the reaction system, adding water, acidifying to pH 3-4, collecting precipitated solids, dispersing with water, adjusting pH to 7-7.5, filtering off solids, acidifying filtrate to pH 3-4, collecting precipitated solids, washing with water, and drying to obtain the compound of formula I.
Without being bound by theory, it is also possible to prepare the following compound of formula II by direct continuous reaction without isolation of the compound of formula I, but this is not the preferred option, since if there is no isolation and purification process, the unreacted complete starting material for preparing the compound of formula I will also participate in the second reaction step (the reaction for preparing the compound of formula II), which will consume additional IBD in the second step, and will also generate new impurities, reducing product purity, increasing the difficulties in post-treatment and purification.
In some embodiments of the invention, the process for preparing a compound of formula I comprises the steps of:
2-halogenated nicotinic acid (compound of formula A), cuprous iodide and a reaction solvent are put into a reaction vessel, the temperature is controlled to be 60-150 ℃, an acid binding agent and 4-hydroxy-phenyl ketone compound (compound of formula B) are added in batches, the temperature is controlled to be 60-150 ℃, and the reaction is carried out for 2-8 hours;
Cooling, adding water, acidifying to pH 3-4, collecting precipitated solid, adding water, dispersing, regulating pH 7-7.5 with sodium bicarbonate, filtering to remove solid, acidifying filtrate to pH 3-4, collecting precipitated solid, washing with water, and drying to obtain intermediate 2- [4- (1-oxo-alkyl) phenoxy ] -3-picolinic acid (compound of formula I).
In some embodiments of the invention, the methods of making the compounds of formula I are described, wherein the yield of the compounds of formula I is greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 75%, 50% -80%, 50% -75%, 50% -70%, 50% -60%, 60% -80%, 60% -75%, 60% -70%, 70% -80%, 70% -75%, 75% -80%, or 75% -85%.
Still another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt or ester thereof for the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound of formula I is prepared according to the process for preparing a compound of formula I according to any one of the present invention.
The compounds of formula I have other uses, for example, they can be synthesized as intermediates in other compounds, e.gEtc., wherein R is independently C 1 -C 10 Straight or branched alkyl, preferably R is C 1 -C 6 A linear or branched alkyl group, more preferably R is C 1 -C 4 Straight or branched alkyl groups are, for example, ethyl, propyl, isopropyl or n-butyl.
(II)
One aspect of the present invention relates to a compound of formula II, or a pharmaceutically acceptable salt or ester thereof,
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Linear or branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups are, for example, methyl, ethyl, propyl or isopropyl.
Another aspect of the invention relates to a process for preparing a compound of formula II comprising the step of reacting a compound of formula I with a compound of formula C and a compound of formula D to form a compound of formula II:
wherein,,
r is C 2 -C 10 Straight or branched alkyl, preferably R is C 2 -C 6 A linear or branched alkyl group, more preferably R is C 2 -C 4 Straight or branched alkyl groups such as ethyl, propyl, isopropyl or n-butyl;
R 1 is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Linear or branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups such as methyl, ethyl, propyl or isopropyl;
preferably, R is greater than R 1 One more carbon atom.
In some embodiments of the present invention, the process for preparing a compound of formula II is described, wherein the compound of formula I is preferably 2- [4- (1-oxopropyl) phenoxy ] -3-picolinic acid, 2- [4- (1-oxobutyl) phenoxy ] -3-picolinic acid or 2- [4- (1-oxopentyl) phenoxy ] -3-picolinic acid, more preferably 2- [4- (1-oxopropyl) phenoxy ] -3-picolinic acid. Preferably, the compound of formula I is prepared according to the process for preparing a compound of formula I according to any one of the present invention.
In some embodiments of the invention, the method for preparing a compound of formula II, further comprises the steps of:
the compounds of formula I are prepared according to the process of the invention for preparing compounds of formula I.
In some embodiments of the invention, the process for preparing a compound of formula II, wherein the temperature of the reaction system is-5 ℃ to 30 ℃, preferably-5 ℃ to 20 ℃, more preferably-5 ℃ to 15 ℃, -5 ℃ to 10 ℃, 5 ℃ to 5 ℃, 5 ℃ to 20 ℃, 5 ℃ to 15 ℃, 5 ℃ to 10 ℃, 10 ℃ to 15 ℃, 15 ℃ to 20 ℃, -5 ℃, 10 ℃, 15 ℃, or 20 ℃.
In some embodiments of the invention, the method of preparing a compound of formula II, wherein the reaction time is at least 0.2 hours, at least 0.4 hours, at least 0.6 hours, at least 0.8 hours, at least 0.9 hours, at least 1 hour, 0.2-2 hours, 0.4-1.6 hours, 0.6-1.4 hours, 0.8-1.2 hours, 0.2 hours, 0.4 hours, 0.6 hours, 0.8 hours, 1 hour, 1.2 hours, 1.4 hours, 1.6 hours, 1.8 hours, or 2 hours.
In some embodiments of the present invention, the process for preparing a compound of formula II, wherein a compound of formula I is reacted with a compound of formula C in an organic solvent as the reaction solvent, preferably the organic solvent is trimethyl orthoformate. Without being bound by theory, trimethyl orthoformate is not only the reaction solvent, but also a substrate, which participates in the reaction.
In some embodiments of the present invention, the method for preparing a compound of formula II, wherein the compound of formula I is reacted with a compound of formula C under the influence of a catalyst, preferably the catalyst is an acid, preferably the acid is one or more selected from concentrated sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid, preferably concentrated sulfuric acid.
In some embodiments of the invention, the process for preparing a compound of formula II, wherein the compound of formula I is calculated as the molar ratio: iodobenzene diacetate: the acid is 1: (1-3): (1-4), preferably 1: (1-2): (1-3).
In some embodiments of the present invention, the method for preparing a compound of formula II further comprises a step of separating the compound of formula II from the reaction system, preferably comprising the steps of:
adding alkaline solution (such as sodium bicarbonate aqueous solution) for neutralization, extracting with organic solvent (preferably dichloromethane) to obtain water phase, acidifying to pH 3-4, collecting precipitated solid, washing with water, and drying to obtain compound of formula II.
Without being bound by theory, if the compound of formula II is not isolated, the subsequent compound of formula III is prepared by direct continuous reaction, and the excess trimethyl orthoformate may participate in the next reaction, reducing the yield and producing impurities.
In some embodiments of the invention, the process for preparing a compound of formula II comprises the steps of:
adding a compound of the formula I and triethyl orthoformate into a reaction vessel, slowly adding acid liquor, and controlling the reaction temperature to be between-5 ℃ and 30 ℃;
slowly adding iodobenzene diacetate, and controlling the reaction temperature at-5 ℃ to 30 ℃;
slowly adding acid liquor, and controlling the reaction temperature at-5 ℃ to 30 ℃;
and (3) carrying out heat preservation reaction for 0.5-2 hours, adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining a water phase, acidifying to pH 3-4, collecting precipitated solid, washing with water, and drying to obtain an intermediate 2- [4- (2-alkoxy-1-methyl-2-oxo-ethyl) phenoxy ] -3-picolinic acid (a compound shown in a formula II).
Still another aspect of the present invention relates to the use of a compound of formula II or a pharmaceutically acceptable salt or ester thereof for the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound of formula II is prepared according to the process of preparing a compound of formula I according to any one of the present invention.
The compounds of formula II have other uses, for example, they can be synthesized as intermediates in other compounds, e.gEtc., wherein R is independently C 1 -C 10 Straight or branched alkyl, preferably R is C 1 -C 6 A linear or branched alkyl group, more preferably R is C 1 -C 4 Straight or branched alkyl groups are, for example, ethyl, propyl, isopropyl or n-butyl.
(III)
One aspect of the present invention relates to a compound represented by formula III, or a pharmaceutically acceptable salt or ester thereof,
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Linear or branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups are, for example, methyl, ethyl, propyl or isopropyl.
Another aspect of the invention relates to a process for preparing a compound of formula III comprising the step of preparing a compound of formula III from a compound of formula II:
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Linear or branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups are, for example, methyl, ethyl, propyl or isopropyl.
The above equation contains two reactions, as shown below; the products in brackets in the middle are not separated; preferably, the subsequent reaction is carried out by direct feeding.
In some embodiments of the present invention, the process for preparing a compound of formula III, wherein the compound of formula II is preferably 2- [4- (2-methoxy-1-methyl-2-oxoethyl) phenoxy ] -3-picolinic acid, 2- [4- (2-ethoxy-1-methyl-2-oxoethyl) phenoxy ] -3-picolinic acid or 2- [4- (2-propoxy-1-methyl-2-oxoethyl) phenoxy ] -3-picolinic acid; more preferably 2- [4- (2-methoxy-1-methyl-2-oxoethyl) phenoxy ] -3-picolinic acid. Preferably, the compound of formula II is prepared according to the method of preparing a compound of formula II according to any one of the present invention.
In some embodiments of the invention, the method for preparing a compound of formula III, further comprises the steps of:
the compounds of formula II are prepared according to the process of any one of the present invention for preparing compounds of formula II.
In some embodiments of the invention, the method for preparing a compound of formula III, comprises the steps of:
(1) Reacting a compound of formula II with an acylating agent to obtain a reaction product,
(2) Reacting the reaction product in step (1) with a lewis acid to form a compound of formula III;
preferably, the method further comprises the following steps:
(3) Isolating the compound of formula III; preferably, the reaction product obtained in step (2) is cooled to below 20 ℃ and is quenched (e.g. by adding cold water), the pH is adjusted and the solvent is removed under reduced pressure to obtain the compound of formula III.
In some embodiments of the invention, the process for preparing a compound of formula III, wherein in step (1), the reaction temperature is from 10 ℃ to 30 ℃, preferably from 15 ℃ to 25 ℃, from 15 ℃ to 20 ℃ or from 20 ℃ to 25 ℃.
In some embodiments of the invention, the method of preparing a compound of formula III, wherein in step (1), the reaction time is at least 0.2 hours, at least 0.4 hours, at least 0.6 hours, at least 0.8 hours, at least 0.9 hours, at least 1 hour, 0.2-2 hours, 0.4-1.6 hours, 0.6-1.4 hours, 0.8-1.2 hours, 0.2 hours, 0.4 hours, 0.6 hours, 0.8 hours, 1 hour, 1.2 hours, 1.4 hours, 1.6 hours, 1.8 hours, or 2 hours.
In some embodiments of the invention, the method for preparing a compound of formula III, wherein in step (1), further comprises the steps of:
the reaction product obtained is cooled to-10 ℃ to 0 ℃.
In some embodiments of the invention, the process for preparing a compound of formula III, wherein in step (2), the reaction temperature is from 10 ℃ to 30 ℃, preferably from 15 ℃ to 25 ℃, from 15 ℃ to 20 ℃ or from 20 ℃ to 25 ℃.
In some embodiments of the invention, the method of preparing a compound of formula III, wherein in step (2), the reaction time is at least 0.2 hours, at least 0.4 hours, at least 0.6 hours, at least 0.8 hours, at least 0.9 hours, at least 1 hour, 0.2-2 hours, 0.4-1.6 hours, 0.6-1.4 hours, 0.8-1.2 hours, 1-1.5 hours, 0.2 hours, 0.4 hours, 0.6 hours, 0.8 hours, 1 hour, 1.2 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.8 hours, or 2 hours.
In some embodiments of the invention, the method for preparing a compound of formula III, wherein the acylating agent is one or more selected from oxalyl chloride and thionyl chloride.
In some embodiments of the invention, the method of preparing a compound of formula III, wherein the lewis acid is a catalyst; preferably, the lewis acid is selected from one or more of anhydrous aluminum trichloride and titanium tetrachloride, preferably anhydrous aluminum trichloride.
In some embodiments of the invention, the process for preparing a compound of formula III, wherein the reaction is carried out in an organic solvent as reaction solvent, preferably dichloromethane and/or N, N-dimethylformamide. Without being bound by theory, dichloromethane is the reaction solvent, and the amount of N, N-dimethylformamide is only 0.1 equivalent, which is more suitable as a catalyst.
In some embodiments of the invention, the method for preparing a compound of formula III, wherein the molar ratio of compound of formula II to acylating agent is from (1:1) to (1:5), preferably 1: (1.5-3), particularly preferably 1:2.5.
in some embodiments of the invention, the method for preparing a compound of formula III, wherein the molar ratio of compound of formula II to oxalyl chloride is from (1:1) to (1:5), preferably 1: (1.5-3), particularly preferably 1:2.5.
in some embodiments of the invention, the method of preparing a compound of formula III, wherein step (3) comprises the following operations:
adding cold water into the reaction product obtained in the step (2) to quench the reaction, separating out an organic phase, adjusting the pH to 7-8 (for example, using sodium carbonate solution), and separating out the organic phase; concentrating the organic phase under reduced pressure, adding methanol or mixed solvent of methanol and dichloromethane, pulping for 3-8 hr (preferably 5-6 hr) when the fraction is not distilled, filtering, eluting the residue with methanol, and drying to obtain compound of formula III. In some embodiments of the invention, the volume ratio of methanol to dichloromethane is 1: (0-0.4), preferably 1: (0.1-0.2).
Without being bound by theory, the inventors have found that if the compound of formula III is not isolated, it is not possible to prepare the following compound of formula IV by direct continuous reaction, because there is a large amount of aluminum trichloride in the system when preparing the compound of formula III, which reacts with methanol to affect the yield when the fourth reaction is carried out, and the aluminum trichloride is mixed with potassium/sodium borohydride, and it is also possible to reduce the methyl ester of the compound of formula III to an alcohol without producing the compound of formula IV.
In some embodiments of the invention, the method of preparing a compound of formula III comprises the steps of:
adding a compound of the formula II, methylene dichloride and N, N-dimethylformamide into a first reaction vessel, mixing and stirring, controlling the temperature to 15-25 ℃, adding an acylating reagent, reacting for 0.5-2 hours at a temperature of between 10 ℃ below zero and 0 ℃ for standby;
adding Lewis acid and methylene dichloride into a second reaction container, uniformly stirring, adding the solution into the first reaction container at the temperature of 15-25 ℃, reacting for 1-1.5h at the temperature of 20 ℃ and slowly adding cold water for quenching;
maintaining an organic phase, regulating pH to 7-8 with sodium carbonate solution, separating liquid, and concentrating the organic phase under reduced pressure;
and adding a mixed solvent of methanol and dichloromethane when the fraction is not distilled out, pulping for 5-6 hours, filtering, eluting with methanol, and drying to obtain an intermediate 2- (10-oxo-9-oxa-1-aza-6-yl) propionate compound (a compound of formula III).
The inventors have also surprisingly found that specific impurities contained in the resulting product, including compounds of formula II and impurities formed by the transfer of by-products of compounds of formula II, are designated as formula III compound-IMP-A, formula III compound-IMP-B, formula III compound-IMP-C, etc., respectively, having the following structure:
compound of formula III-IMP-A Compound of formula III-IMP-B Compound of formula III-IMP-C
Wherein R is 1 Is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Linear or branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups are, for example, methyl, ethyl, propyl or isopropyl.
The inventors speculate that these three impurities, if delivered posteriorly, may be derivatized to impurities similar in structure to pranoprofen in subsequent reactions as follows:
without being bound by theory, since the structure of these derivatized impurities is very similar to that of pranoprofen, it is presumed that it is difficult to separate and remove these impurities from the finished product, and the limits of these three impurities are controlled in advance, for example, it is required that each impurity is not more than 0.1% of the total mass of the intermediate product (the maximum of the impurities resulting from the conversion of these three impurities is not more than 0.1%), and the quality of the finished product can be controlled upstream; the finished product does not need to additionally detect the derivatization impurity.
In some embodiments of the invention, these impurities are refined to remove using the following steps:
after the solvent dichloromethane is distilled off, the slurry is washed (i.e., beaten) with methanol or a methanol/dichloromethane mixed solvent. The impurities can be controlled to the desired level by the preferred solvent ratio.
The inventors conducted excessive batch experimental data to verify that when the three impurities were controlled below 0.1%, the derivatized impurities of the three impurities were not detected in the finished pranoprofen.
Still another aspect of the present invention relates to the use of a compound of formula III or a pharmaceutically acceptable salt or ester thereof for the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound of formula III is prepared according to the method of preparing a compound of formula III according to any one of the present invention.
The compounds of formula III have other uses, for example, the synthesis of several other compounds as intermediates, e.gEtc., wherein R is independently C 1 -C 10 Straight or branched alkyl, preferably R is C 1 -C 6 A linear or branched alkyl group, more preferably R is C 1 -C 4 Straight or branched alkyl groups are, for example, ethyl, propyl, isopropyl or n-butyl.
(IV)
One aspect of the present invention relates to a compound of formula IV, or a pharmaceutically acceptable salt or ester thereof,
Wherein R is 1 Is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Straight chainOr branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups are, for example, methyl, ethyl, propyl or isopropyl.
Another aspect of the invention relates to a process for preparing a compound of formula IV comprising the step of preparing a compound of formula IV from a compound of formula III:
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Linear or branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups are, for example, methyl, ethyl, propyl or isopropyl.
In some embodiments of the invention, the process for preparing a compound of formula IV, wherein the compound of formula III is preferably methyl 2- (10-oxo-9-oxa-1-azaanthracen-6-yl) propionate, ethyl 2- (10-oxo-9-oxa-1-azaanthracen-6-yl) propionate, or propyl 2- (10-oxo-9-oxa-1-azaanthracen-6-yl) propionate; more preferably methyl 2- (10-oxo-9-oxa-1-azaanthracen-6-yl) propionate. Preferably, the compound of formula III is prepared according to the method of preparing a compound of formula III according to any one of the present invention.
In some embodiments of the invention, the method for preparing a compound of formula IV, further comprises the steps of:
The compounds of formula III are prepared according to the process of any one of the present invention for preparing compounds of formula III.
In some embodiments of the invention, the methods of preparing a compound of formula IV, wherein a compound of formula III is reacted with a reducing agent to produce a compound of formula IV. Preferably, the reducing agent is a borohydride, more preferably sodium borohydride.
In some embodiments of the invention, the process for preparing a compound of formula IV is described wherein the reaction temperature is from 20 ℃ to 40 ℃, preferably from 30 ℃ to 40 ℃, from 30 ℃ to 35 ℃ or from 35 ℃ to 40 ℃.
In some embodiments of the invention, the method of preparing a compound of formula IV, wherein the reaction time is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, 1-100 hours, 2-50 hours, 3-40 hours, 4-30 hours, 5-25 hours, 6-20 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, or 20 hours.
In some embodiments of the present invention, the process for preparing a compound of formula IV, wherein the reaction is carried out in an organic solvent as the reaction solvent, preferably, dichloromethane and methanol (mixed solvent). Without being bound by theory, dichloromethane is the solvent and methanol is both the solvent and the substrate, providing a source of hydrogen. The molar ratio of dichloromethane to methanol is 1 (2.11-3.16), preferably 1:2.11. In some embodiments of the invention, the compound of formula III is of the formula (i): the volume (mL) of the mixed solvent is 1: (5-15), preferably 1 (8-10).
In some embodiments of the invention, the method of preparing a compound of formula IV, wherein the molar ratio of compound of formula III to reducing agent is from (1:0.8) to (1:1.2), preferably 1:0.9-1.1.
In some embodiments of the invention, the method of preparing a compound of formula IV further comprises the step of separating the compound of formula IV from the reaction system; preferably, the method comprises the following steps:
cooling the reaction product to-10 ℃ to 10 ℃ and adjusting the pH value to 5.5-6.5; preferably, a dilute acid solution (e.g., 30% aqueous acetic acid) is slowly added dropwise to a pH of 5.5-6.5 (without being limited by theory, the acid may act to quench excess reducing agent, dilute mineral or organic acids, in the reaction); the dilute acid may be an inorganic or organic acid at a concentration of less than or equal to 30%;
stirring at-10deg.C to 10deg.C for 5-30 min (preferably 15 min), adding purified water, collecting organic phase, and washing with saturated sodium bicarbonate and purified water sequentially;
concentrating the washed organic phase at 40 ℃ under reduced pressure to dryness to obtain yellow-green oily matter;
adding crystallization solvent and stirring at 20-40 deg.c for 5-30 min (preferably 15 min); and
slowly adding purified water dropwise, collecting solid, washing with water, and vacuum drying to obtain compound of formula IV.
In some embodiments of the present invention, the method for preparing a compound of formula IV, wherein, preferably, the crystallization solvent may be selected from aqueous methanol (preferably methanol: water 1:2), aqueous acetone (preferably acetone: water 1:2), a mixture of methanol and acetone and water (preferably methanol: acetone: water 1:1.5:5), preferably a mixture of methanol and acetone and water (preferably methanol: acetone: water 1:1.5:5). Preferably, the mass (g) of the compound of formula III: crystallization solvent volume (mL) was 1:5.
in some embodiments of the invention, the process for preparing a compound of formula IV comprises the steps of:
adding a compound of formula III, methylene dichloride and methanol into a reaction vessel, and stirring and dissolving at a temperature of 15-30 ℃;
slowly adding borohydride, keeping the temperature at 20-40 ℃ for reaction for 6-20h, cooling to-10 ℃ to 10 ℃, slowly dripping 30% acetic acid aqueous solution until the pH is 5.5-6.5, stirring for 5-30min (preferably 15 min) at-10 ℃ to 10 ℃, adding purified water, collecting an organic phase, washing with saturated sodium bicarbonate, and washing with the purified water once again;
concentrating the organic phase at 40deg.C under reduced pressure to obtain yellow green oily substance;
adding the methanol/acetone mixed solution, stirring and dispersing for 15min at 20-40 ℃. Slowly dropwise adding purified water for crystallization for 1-5h (preferably 2 h), collecting solid, washing with water, and vacuum drying to obtain intermediate 2- (10-hydroxy-9-oxa-1-aza-anthracene-6-yl) propionate compound (compound of formula IV).
Without being bound by theory, acetic acid acts to quench excess sodium borohydride, and the pH range is controlled to ensure complete quenching.
Still another aspect of the present invention relates to the use of a compound of formula IV or a pharmaceutically acceptable salt or ester thereof for the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound of formula IV is prepared according to the method of preparing a compound of formula IV according to any one of the present invention.
The compounds of formula IV have other uses, for example, the synthesis of several other compounds as intermediates, e.g Etc., wherein R and R' are independently C 1 -C 10 Straight or branched alkyl, preferably R is C 1 -C 6 A linear or branched alkyl group, more preferably R is C 1 -C 4 Straight or branched alkyl groups such as ethyl, propyl, isopropyl or n-butyl; x is halogen, such as fluorine, chlorine, bromine or iodine.
(V)
Yet another aspect of the invention relates to a process for preparing pranoprofen (compound of formula 0) or a pharmaceutically acceptable salt or ester of pranoprofen comprising preparing the present invention:
a compound of formula I or a pharmaceutically acceptable salt or ester thereof,
A compound of formula II or a pharmaceutically acceptable salt or ester thereof,
A compound of formula III or a pharmaceutically acceptable salt or ester thereof, and/or
A compound of formula IV or a pharmaceutically acceptable salt or ester thereof
Is carried out by the steps of (a);
preferably, the compound of formula I is prepared according to the process for preparing a compound of formula I according to any one of the present invention;
preferably, the compound of formula II is prepared according to the process of preparing a compound of formula III according to any one of the present invention;
preferably, the compound of formula III is prepared according to the method of preparing a compound of formula III according to any one of the present invention;
preferably, the compound of formula IV is prepared according to the method of preparing a compound of formula IV according to any one of the present invention.
In some embodiments of the invention, the method for preparing pranoprofen (compound of formula 0) is described wherein the synthetic route is illustrated as follows:
in some embodiments of the invention, the method of preparing pranoprofen (compound of formula 0) comprises the steps of:
(1) Taking 2-halogenated nicotinic acid (compound shown in a formula A) and 4-hydroxy benzophenone compound (compound shown in a formula B) as starting materials, and carrying out an ullmann condensation reaction in the presence of cuprous iodide to prepare an intermediate 2- [4- (1-oxo alkyl) phenoxy ] -3-picolinic acid (compound shown in a formula I);
(2) Under the action of acid and iodobenzene diacetic acid, carrying out rearrangement reaction in trimethyl orthoformate to prepare an intermediate 2- [4- (2-methoxy-1-methyl-2-oxo alkyl) phenoxy ] -3-picolinic acid (a compound of formula II);
(3) Through halogenating into acyl chloride and intramolecular ring closure under the action of Lewis acid, an intermediate 2- (10-oxo-9-oxa-1-aza-anthracene-6-yl) propionate compound (compound of formula III) is obtained;
(4) Reducing by borohydride to obtain an intermediate 2- (10-hydroxy-9-oxa-1-aza-6-yl) propionate compound (compound of formula IV);
(5) Finally, the pranoprofen (the compound of the formula 0) is obtained by reduction and alkaline hydrolysis of hydrogen chloride isopropanol and post-treatment acidification by a one-pot method.
The structural formulas of the compound of formula A and the compound of formula B are as follows:
wherein,,
x is halogen, for example fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
Wherein R is C 2 -C 10 Straight or branched alkyl, preferably R is C 2 -C 6 A linear or branched alkyl group, more preferably R is C 2 -C 4 Straight or branched alkyl groups are, for example, ethyl, propyl, isopropyl or n-butyl.
Yet another aspect of the present invention relates to a process for preparing pranoprofen (compound of formula 0) or a pharmaceutically acceptable salt or ester of pranoprofen comprising the step of preparing pranoprofen from a compound of formula IV:
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Linear or branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups are, for example, methyl, ethyl, propyl or isopropyl.
In some embodiments of the invention, the method for preparing pranoprofen (compound of formula 0) comprises the steps of:
(1) Firstly, preparing a compound of a formula V from the compound of the formula IV (reduction reaction);
(2) Preparing pranoprofen (compound of formula 0) from the compound of formula V (hydrolysis reaction);
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Linear or branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups are, for example, methyl, ethyl, propyl or isopropyl.
In some embodiments of the invention, the process for preparing pranoprofen (compound of formula 0) wherein the compound of formula IV is preferably methyl 2- (10-hydroxy-9-oxa-1-aza-6-yl) propionate, ethyl 2- (10-hydroxy-9-oxa-1-aza-6-yl) propionate or propyl 2- (10-hydroxy-9-oxa-1-aza-6-yl) propionate; more preferably methyl 2- (10-hydroxy-9-oxa-1-aza-6-yl) propionate.
In some embodiments of the invention, the process for preparing pranoprofen (compound of formula 0) wherein, in step (1), the compound of formula IV is reacted with a reducing agent to produce the compound of formula V.
In some embodiments of the invention, the method for preparing pranoprofen (compound of formula 0) wherein, in step (1), the reducing agent is selected from one or more of hydrogen chloride isopropanol and hydrochloric acid isopropanol.
In some embodiments of the invention, the method for preparing pranoprofen (compound of formula 0) wherein in step (1), the molar ratio of the compound of formula IV to the reducing agent is 1: (1.5-3.5), preferably 1 (2.5-3.5), for example 1:2.5, 1:3 or 1:3.5.
in some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0) wherein, in step (1), the reaction is performed in an organic solvent as a reaction solvent, preferably, the organic solvent is isopropanol.
In some embodiments of the invention, the process for preparing pranoprofen (compound of formula 0) wherein, in step (1), the reaction temperature is 50 ℃ to 90 ℃, preferably 60 ℃ to 80 ℃, 60 ℃ to 70 ℃, 70 ℃ to 80 ℃ or 65 ℃ to 75 ℃.
In some embodiments of the invention, the method of preparing pranoprofen (compound of formula 0) wherein, in step (1), the reaction time is at least 0.5 hours, at least 1 hour, at least 1.5 hours, at least 2 hours, 1-10 hours, 2-8 hours, 2-6 hours, 2-4 hours, 2-3 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours.
In some embodiments of the invention, the process for preparing pranoprofen (compound of formula 0) wherein, in step (2), the compound of formula V is reacted with a base (hydrolysis reaction) to produce pranoprofen (compound of formula 0).
In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0) wherein in step (2), the base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, preferably sodium hydroxide and/or potassium hydroxide.
In some embodiments of the invention, the process for preparing pranoprofen (compound of formula 0) wherein, in step (2), the reaction temperature is 40 ℃ to 75 ℃, preferably 40 ℃ to 55 ℃, 40 ℃ to 50 ℃, 45 ℃ to 55 ℃, 40 ℃ to 45 ℃, 45 ℃ to 50 ℃ or 50 ℃ to 55 ℃.
In some embodiments of the invention, the method of preparing pranoprofen (compound of formula 0) wherein, in step (2), the reaction time is at least 0.5 hours, at least 1 hour, at least 1.5 hours, 0.5-10 hours, 1-8 hours, 1.5-6 hours, 1.5-4 hours, 1.5-3 hours, 1.5-2.5 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours.
In some embodiments of the invention, the method for preparing pranoprofen (compound of formula 0) further comprises a step of separating pranoprofen (compound of formula 0) from the reaction system; preferably, the method comprises the following step (3):
adding purified water into the reaction system, and then extracting the water phase with ethyl acetate;
collecting water phase, adjusting pH to 2-7 with acid (preferably 20% diluted acid solution), and gradually precipitating solid;
filtering, sequentially eluting the filter cake with purified water and methanol, and vacuum drying to obtain crude pranoprofen (compound of formula 0); and
recrystallizing with methanol (preferably with 8-12 times volume such as 10 times volume methanol reflux) to obtain refined pranoprofen (compound of formula 0); .
In some embodiments of the invention, the process for preparing pranoprofen (compound of formula 0) wherein in step (3), the pH is preferably 5 to 7, more preferably 5.5 to 6.5, particularly preferably 5.8 to 6.2.
In some embodiments of the present invention, the method for preparing pranoprofen (the compound of formula 0) described above, wherein in step (3), the acid is one or more selected from acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid, preferably acetic acid and/or hydrochloric acid.
In some embodiments of the invention, the process for preparing pranoprofen (compound of formula 0) does not comprise a step of isolating the compound of formula V.
In some embodiments of the invention, the process for preparing pranoprofen (compound of formula 0) wherein the compound of formula IV is preferably methyl 2- (10-hydroxy-9-oxa-1-azaanthracen-6-yl) propionate, ethyl 2- (10-hydroxy-9-oxa-1-azaanthracen-6-yl) propionate or propyl 2- (10-hydroxy-9-oxa-1-azaanthracen-6-yl) propionate; more preferably methyl 2- (10-hydroxy-9-oxa-1-aza-6-yl) propionate.
In some embodiments of the invention, the method of preparing pranoprofen (compound of formula 0) wherein the compound of formula IV is prepared according to the method of preparing a compound of formula IV of any one of the present inventions.
In some embodiments of the invention, the method for preparing pranoprofen (compound of formula 0) further comprises the following steps:
the compounds of formula IV are prepared according to the process of any one of the present invention for preparing compounds of formula IV.
In some embodiments of the invention, the method of preparing pranoprofen (compound of formula 0) wherein the molar ratio of compound of formula IV to reducing agent is from (1:1) to (1:5), preferably from (1:1) to (1:3) or from (1:1.5) to (1:3.5), more preferably from (1:2) to (1:3) or from (1:2) to (1:3.5), for example 1:2. 1:2.5 or 1:3.
In some embodiments of the invention, the method of preparing pranoprofen (compound of formula 0) comprises the steps of:
adding a compound shown in a formula IV, a reducing agent and isopropanol into a reaction vessel, stirring and heating to 50-90 ℃, carrying out heat preservation reaction for 2-4h, concentrating under reduced pressure at 55 ℃ until the mixture is dried, cooling to room temperature, adding methanol (methanol is used as a solvent), then adding alkaline water (or adding alkaline water, cooling to room temperature, then adding methanol), and carrying out heat preservation reaction for 2h at 40-75 ℃;
adding purified water into the reaction solution, extracting the water phase with ethyl acetate, collecting the water phase, adjusting the pH value of the water phase to 2-7 with 20% dilute acid solution, and gradually precipitating solids;
filtering, and sequentially eluting a filter cake by using purified water and methanol;
vacuum drying to obtain crude product, recrystallizing with methanol, and refining to obtain pranoprofen (formula 0 compound) product.
In some embodiments of the invention, the process for preparing pranoprofen (compound of formula 0) comprises the process steps of preparation examples 1a, 2c, 3c, 4b, 5 a.
Yet another aspect of the invention relates to a process for preparing a compound of formula V or a pharmaceutically acceptable salt or ester of a compound of formula V comprising the step of preparing a compound of formula V from a compound of formula IV:
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl, preferably R 1 Is C 1 -C 5 Linear or branched alkyl, more preferably R 1 Is C 1 -C 3 Straight or branched alkyl groups are, for example, methyl, ethyl, propyl or isopropyl.
In some embodiments of the invention, the methods of preparing a compound of formula V, wherein a compound of formula IV is reacted with a reducing agent to produce a compound of formula V.
In some embodiments of the invention, the method of preparing the compound of formula V, wherein the reducing agent is selected from one or more of hydrogen chloride isopropanol and hydrochloric acid isopropanol.
In some embodiments of the invention, the method for preparing a compound of formula V, wherein the molar ratio of the compound of formula IV to the reducing agent is 1: (1.5-3.5), preferably 1 (2.5-3.5), for example 1:2.5, 1:3 or 1:3.5.
in some embodiments of the invention, the process for preparing a compound of formula V, wherein the reaction is carried out in an organic solvent as reaction solvent, preferably, the organic solvent is isopropanol.
In some embodiments of the invention, the process for preparing a compound of formula V is described wherein the reaction temperature is from 50 ℃ to 90 ℃, preferably from 60 ℃ to 80 ℃, from 60 ℃ to 70 ℃, from 70 ℃ to 80 ℃ or from 65 ℃ to 75 ℃.
In some embodiments of the invention, the method of preparing a compound of formula V, wherein the reaction time is at least 0.5 hours, at least 1 hour, at least 1.5 hours, at least 2 hours, 1-10 hours, 2-8 hours, 2-6 hours, 2-4 hours, 2-3 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.
Still another aspect of the present invention relates to the use of a compound of formula V or a pharmaceutically acceptable salt or ester thereof for the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound of formula V is prepared according to the process for preparing a compound of formula V according to any one of the present invention.
Some of the intermediate compounds to which the present invention relates are shown in table a below.
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(six)
A composition comprising pranoprofen and an impurity, wherein the impurity is present in the composition in an amount of 0.5% or less, 0.4% or less, 0.3% or less, 0.25% or less, 0.24% or less, 0.23% or less, 0.22% or less, 0.21% or less, 0.20% or less, 0.19% or less, 0.18% or less, 0.17% or less, 0.16% or less, 0.15% or less, 0.14% or less, 0.13% or less, 0.12% or less, 0.11% or less, 0.10% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or 0.02% or less, 0.01% or less, or 0.005% by mass.
In one or more embodiments of the present invention, the composition wherein the amount (purity) of pranoprofen in the composition is greater than or equal to 99%, greater than or equal to 99.1%, greater than or equal to 99.2%, greater than or equal to 99.3%, greater than or equal to 99.4%, greater than or equal to 99.5%, greater than or equal to 99.6%, greater than or equal to 99.7%, greater than or equal to 99.8%, greater than or equal to 99.9%, greater than or equal to 99.91%, greater than or equal to 99.92%, greater than or equal to 99.93%, greater than or equal to 99.94%, greater than or equal to 99.95%, greater than or equal to 99.96%, greater than or equal to 99.98%, or greater than or equal to 99.99% by mass percent.
In one or more embodiments of the invention, the composition wherein the level of impurities is greater than zero.
In one or more embodiments of the invention, the composition consists of pranoprofen and impurities.
In one or more embodiments of the invention, the composition wherein the impurities are total impurities.
In one or more embodiments of the invention, the composition wherein the impurity is the largest single impurity.
In one or more embodiments of the present invention, the composition, wherein the impurity is any one, any two, any three, or any four selected from the group consisting of impurity a, impurity C, impurity D, impurity L.
In one or more embodiments of the present invention, the composition wherein the impurity is any one, any two, any three or any four selected from the group consisting of impurity a, impurity C, impurity D and impurity L.
In one or more embodiments of the invention, the composition wherein the impurity is impurity a, impurity C, impurity D, or impurity L.
In one or more embodiments of the invention, the composition, wherein the impurity is impurity a.
In one or more embodiments of the invention, the composition, wherein the impurity is impurity C.
In one or more embodiments of the invention, the composition, wherein the impurity is impurity D.
In one or more embodiments of the invention, the composition, wherein the impurity is impurity L.
In one or more embodiments of the invention, the composition wherein the impurities are impurity a and impurity C.
In one or more embodiments of the invention, the composition wherein the impurities are impurity a and impurity D.
In one or more embodiments of the invention, the composition wherein the impurities are impurity a and impurity L.
In one or more embodiments of the invention, the composition wherein the impurities are impurity C and impurity D.
In one or more embodiments of the invention, the composition wherein the impurities are impurity C and impurity L.
In one or more embodiments of the invention, the composition wherein the impurities are impurity D and impurity L.
In one or more embodiments of the invention, the composition wherein the impurities are impurity a, impurity C, and impurity D.
In one or more embodiments of the invention, the composition wherein the impurities are impurity a, impurity C, and impurity L.
In one or more embodiments of the invention, the composition wherein the impurities are impurity a, impurity D, and impurity L.
In one or more embodiments of the invention, the composition wherein the impurities are impurity C, impurity D, and impurity L.
In one or more embodiments of the invention, the composition wherein the impurities are impurity a, impurity C, impurity D, and impurity L.
In one or more embodiments of the invention, the composition wherein the impurities are impurities comprising impurity a, impurity C, impurity D, and impurity L.
In one or more embodiments of the invention, the composition wherein the total impurities are present in an amount of less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, or less than or equal to 0.01%.
In one or more embodiments of the present invention, the composition wherein the content of impurity a is less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, or less than or equal to 0.01%.
In one or more embodiments of the present invention, the composition wherein the content of impurity C is less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, less than or equal to 0.01%, or less than or equal to 0.005%.
In one or more embodiments of the present invention, the composition wherein the content of impurity D is less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, less than or equal to 0.01%, or less than or equal to 0.005%.
In one or more embodiments of the present invention, the composition wherein the content of impurity L is less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, less than or equal to 0.01%, or less than or equal to 0.005%.
In one or more embodiments of the invention, the composition wherein the total impurity, maximum single impurity, impurity a, impurity C, impurity D and/or impurity L content varies (increases or decreases) by no more than 50%, 40%, 30%, 20%, 10% or 5% compared to 0 months after 1 month, 2 months or 3 months of accelerated experiments.
In one or more embodiments of the invention, the composition wherein the total impurity, maximum single impurity, impurity a, impurity C, impurity D, and/or impurity L content varies (increases or decreases) by no more than 300%, 250%, 200%, 150%, 130%, 120%, 110%, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5% compared to 0 months after 6 months of the accelerated experiment.
In one or more embodiments of the invention, the composition wherein the total impurity, maximum single impurity, impurity a, impurity C, impurity D, and/or impurity L content is less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, or less than or equal to 0.01% after 1 month, 2 months, or 3 months of the accelerated experiment.
In one or more embodiments of the invention, the composition wherein the total impurity, maximum single impurity, impurity a, impurity C, impurity D, and/or impurity L content is less than or equal to 0.5%, less than or equal to 0.45%, less than or equal to 0.4%, less than or equal to 0.35%, less than or equal to 0.3%, less than or equal to 0.25%, less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, or less than or equal to 0.01% after 6 months of the accelerated experiment.
The structures of the impurity a, the impurity C, the impurity D, and the impurity L are shown in table B below.
A further aspect of the invention relates to a pharmaceutical formulation comprising a composition according to any of the preceding inventions, together with one or more pharmaceutically acceptable excipients.
In the present invention, the composition is a pranoprofen product comprising a pranoprofen compound in an absolute amount, and one or more impurities, if not specified. Those skilled in the art will appreciate that the presence or production of impurities is unavoidable during the synthesis, purification and/or storage of the compounds, etc.
In the present invention, the pranoprofen refers to pure pranoprofen unless otherwise specified.
In the present invention, unless otherwise specified, the acceleration test is performed under the conditions of 40 ℃ ± 2 ℃ and 75% ± 5% RH according to the rules of guidelines for chemical drug stability research; preferably, 3 samples are averaged in parallel.
In the present invention, the content of each impurity or total impurity is measured by high performance liquid chromatography unless otherwise specified. Preferably, chromatographic conditions: octadecylsilane chemically bonded silica was used as a filler (5 μm,250 mm. Times.4.6 mm); aqueous solution of sodium perchlorate 0.05 mol/L-methanol= (90:10, pH was adjusted to 3.2) as mobile phase A and methanol as mobile phase B, eluting according to the gradient in Table 10, flow rate 1.0ml/min, column temperature 40℃and detection wavelength 275nm. The elution procedure is also shown in table 10.
In the present invention, the content of pranoprofen, impurities, total impurities, maximum single impurities, impurity a, impurity C, impurity D or impurity L refers to the content in mass percent in the composition, unless otherwise specified.
In yet another aspect, the present invention relates to a method for quality control or quality control of a pranoprofen product, comprising the step of detecting the content of (pure) pranoprofen or the content of impurities therein; preferably, the pranoprofen product is a composition or pharmaceutical formulation according to any of the preceding inventions. Preferably, the method is high performance liquid chromatography. Preferably, chromatographic conditions: octadecylsilane chemically bonded silica was used as a filler (5 μm,250 mm. Times.4.6 mm); aqueous solution of sodium perchlorate 0.05 mol/L-methanol= (90:10, pH was adjusted to 3.2) as mobile phase A and methanol as mobile phase B, eluting according to the gradient in Table 10, flow rate 1.0ml/min, column temperature 40℃and detection wavelength 275nm. The elution procedure is also shown in table 10.
In a further aspect the invention relates to the use of any one, any two, any three or any four selected from impurity a, impurity C, impurity D and impurity L for quality control or quality control of a pranoprofen product; preferably, the pranoprofen product is a composition or pharmaceutical formulation according to any of the preceding inventions.
A further aspect of the invention relates to the use of the following impurities or impurity combinations for quality control or quality control of a pranoprofen product; preferably, the pranoprofen product is a composition or pharmaceutical formulation according to any one of the preceding inventions:
the impurity L is present in the mixture,
an impurity L and an impurity A,
an impurity L and an impurity C,
an impurity L and an impurity D,
impurity L, impurity A and impurity C,
impurity L, impurity A and impurity D,
impurity L, impurity C and impurity D,
or alternatively
Impurity L, impurity a, impurity C, and impurity D.
In one or more embodiments of the invention, the process for preparing a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV, or pranoprofen, wherein the preparation process does not use highly toxic chemical reagents such as potassium cyanide, methyl iodide. Thus, the preparation method of the invention reduces production hazards and risks of worker operation.
In one or more embodiments of the invention, the process for preparing a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV, or pranoprofen, wherein the preparation process does not use a phosphorus-containing chemical reagent such as polyphosphoric acid. Therefore, the preparation method reduces environmental pollution and is more environment-friendly.
In the present invention,
the term "C 1-10 Alkyl "means a straight-chain or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neo-pentylPentyl, hexyl, 2-hexyl, 3-hexyl, and the like; c (C) 2-10 Alkyl, C 1-6 Alkyl, C 2-6 Alkyl, C 1-3 Alkyl or C 2-4 Alkyl groups are similarly understood. Preferably C 1-6 Alkyl, C 2-6 Alkyl, C 1-3 Alkyl or C 2-4 An alkyl group.
Advantageous effects of the invention
The invention achieves any one or more of the following technical effects (1) - (11):
(1) The raw materials used in the invention are more easily obtained;
(2) The method is favorable for purifying impurities continuously in the process and improving the product quality;
(3) The use of highly toxic chemicals such as potassium cyanide and methyl iodide is avoided, and the production hazard and the operation risk of workers are reduced;
(4) The use of phosphorus-containing chemicals such as polyphosphoric acid is avoided, the environmental pollution is reduced, and the environment is more friendly;
(5) The reaction steps are short, and the process route is simplified;
(6) The reaction condition is mild;
(7) The operation is simple and convenient;
(8) Is more suitable for industrial production;
(9) The invention has higher yield of the compounds of the formula 0, the formula I, the formula II, the formula III and/or the formula IV;
(10) The purity of the compounds of the formula 0, the formula I, the formula II, the formula III and/or the formula IV is higher;
(11) The preparation of the compounds of formula 0, formula I, formula II, formula III and/or formula IV according to the invention achieves a good balance of yield and purity.
Drawings
Fig. 1: high resolution mass spectrum of the sample.
Fig. 2A: standard fuchsin outer graph spectrogram.
Fig. 2B: sample fuchsin outer graph spectrogram.
Fig. 3A: ultraviolet spectrogram of neutral standard.
Fig. 3B: ultraviolet spectrogram of the acid standard.
Fig. 3C: ultraviolet spectrogram of alkaline standard.
Fig. 3D: ultraviolet spectrogram of neutral sample.
Fig. 3E: ultraviolet spectrogram of the acid sample.
Fig. 3F: ultraviolet spectrogram of alkaline sample.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Preparation examples 1a-1i: preparation of 2- [4- (1-oxopropyl) phenoxy ]]3-Pyridinecarboxylic acid (Compound I-A) or 2- [4- ]
(1-oxobutyl) phenoxy]3-Pyridinecarboxylic acid (Compound I-B)
1a：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (2.4 g,0.1 equiv.) were put, stirred and mixed, heated to 75℃to 80℃and sodium carbonate (26.9 g,2 equiv.) and 4-hydroxyphenylacetone (38.1 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 110℃to 115℃and the reaction was continued for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake by blowing at 60 ℃ to obtain 29.5g of compound I-A with the yield of 85.6% and the purity of 97.53%.
1b：
Into a 250ml reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 ml) and cuprous iodide (1.2 g,0.05 equiv.) were put, stirred and mixed, heated to 75℃to 80℃and sodium carbonate (26.9 g,2 equiv.) and 4-hydroxyphenylacetone (38.1 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 110℃to 115℃and the reaction was continued for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake by blowing at 60 ℃ to obtain 29.4g of compound I-A with the yield of 85.5% and the purity of 97.36%.
1c：
Into a 250mL reaction flask, 2-bromonicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (1.9 g,0.1 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (21.0 g,2 equiv.) and 4-hydroxyphenylacetone (29.7 g,2 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture is filtered, and the obtained filter cake is dried by blowing at 60 ℃ to obtain 23.1g of compound I-A with 86.0 percent of yield and 97.68 percent of purity.
1d：
2-bromonicotinic acid (50.0 g,1 equiv.) N, N-dimethyl methyl (50 ml) and cuprous iodide (4.7 g,0.1 equiv.) are put into a 500ml reaction flask, stirred and mixed, heated to 75-80 ℃, sodium carbonate (52.5 g,2 equiv.) and 4-hydroxybenzene butanone (81.3 g,2 equiv.) are added in portions, and after the addition, heated to 110-115 ℃ and reacted for 5 hours. The reaction solution was cooled to 50℃and 250g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 2L beaker, adding 500g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 2L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake at 60 ℃ by blowing to obtain 58.4g of compound I-B, wherein the yield is 83.0% and the purity is 97.11%.
1e：
Into a 250ml reaction flask, 2-bromonicotinic acid (20.0 g,1 equiv.), N-dimethyl methyl (20.0 g) and cuprous iodide (1.9 g,0.1 equiv.) were put, stirred and mixed, the temperature was raised to 75℃to 80℃and potassium carbonate (27.4 g,2 equiv.) and 4-hydroxyphenylacetone (29.7 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 110℃to 115℃and the reaction was continued for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake at 60 ℃ by blowing to obtain 22.9g of compound I-A with the yield of 85.0% and the purity of 97.44%.
1f：
Into a 250ml reaction flask, 2-bromonicotinic acid (20.0 g,1 equiv.), N-dimethyl methyl (20.0 g) and cuprous iodide (1.9 g,0.1 equiv.) were put, stirred and mixed, heated to 75℃to 80℃and sodium hydrogencarbonate (16.6 g,2 equiv.) and 4-hydroxyphenylacetone (29.7 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 110℃to 115℃and the reaction was continued for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture is filtered, and the obtained filter cake is dried by blowing at 60 ℃ to obtain 21.6g of compound I-A with the yield of 80.6% and the purity of 96.87%.
1g：
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Into a 250ml reaction flask, 2-bromonicotinic acid (20.0 g,1 equiv.), N-dimethyl methyl (20.0 g) and cuprous iodide (1.9 g,0.1 equiv.) were put, stirred and mixed, the temperature was raised to 75℃to 80℃and potassium bicarbonate (19.8 g,2 equiv.) and 4-hydroxyphenylacetone (29.7 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 110℃to 115℃and the reaction was continued for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake by blowing at 60 ℃ to obtain 21.5g of compound I-A with the yield of 80.2% and the purity of 96.56%.
1h：
Into a 250mL reaction flask, 2-bromonicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (1.9 g,0.1 equiv.) were put, stirred and mixed, heated to 60℃to 65℃and sodium carbonate (21.0 g,2 equiv.) and 4-hydroxyphenylacetone (29.7 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 75℃to 80℃and the reaction was continued for 10 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 22.4g of Compound I-A in 83.4% yield and 96.48% purity.
1i：
Into a 250mL reaction flask, 2-bromonicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (1.9 g,0.1 equiv.) were put, stirred and mixed, heated to 75℃to 80℃and sodium carbonate (21.0 g,2 equiv.) and 4-hydroxyphenylacetone (29.7 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 120℃to 125℃and the reaction was continued for 4 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture is filtered, and the obtained filter cake is dried by blowing at 60 ℃ to obtain 23.4g of compound I-A with the yield of 87.0% and the purity of 96.11%.
Comparative examples 1j to 1w
1j：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (4.8 g,0.2 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (13.5 g,1 equiv.) and 4-hydroxyphenylacetone (19.1 g,1 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake by blowing at 60 ℃ to obtain 25.6g of compound I-A with the yield of 74.2% and the purity of 93.88%.
1k：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (4.8 g,0.2 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (13.5 g,1 equiv.) and 4-hydroxyphenylacetone (38.1 g,2 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 27.2g of Compound I-A in 79.1% yield and 96.43% purity.
1l：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (4.8 g,0.2 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (13.5 g,1 equiv.) and 4-hydroxyphenylacetone (57.2 g,3 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 27.1g of Compound I-A in a yield of 78.8% and a purity of 96.57%.
1m：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (4.8 g,0.2 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (13.5 g,1 equiv.) and 4-hydroxyphenylacetone (76.3 g,4 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 27.4g of Compound I-A in a yield of 79.7% and a purity of 95.29%.
1n：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (4.8 g,0.2 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (13.5 g,1 equiv.) and 4-hydroxyphenylacetone (95.3 g,5 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and transferred to a 500ml beaker, 100g of water was added and stirred for 15min. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake at 60 ℃ by blowing to obtain 27.2g of compound I-A, wherein the yield is 78.9%, and the purity is 95.11%.
1o：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (4.8 g,0.2 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (26.9 g,2 equiv.) and 4-hydroxyphenylacetone (38.1 g,2 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake at 60 ℃ by blowing to obtain 29.6g of compound I-A with the yield of 85.9% and the purity of 95.73%.
1p：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (4.8 g,0.2 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (40.4 g,3 equiv.) and 4-hydroxyphenylacetone (38.1 g,2 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 24.5g of Compound I-A in 71.1% yield and 94.53% purity.
1q：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (4.8 g,0.2 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (53.8 g,4 equiv.) and 4-hydroxyphenylacetone (38.1 g,2 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake at 60 ℃ by blowing to obtain 24.2g of compound I-A with the yield of 70.2% and the purity of 94.17%.
1r：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (12.1 g,0.5 equiv.) were put, stirred and mixed, heated to 75℃to 80℃and sodium carbonate (26.9 g,2 equiv.) and 4-hydroxyphenylacetone (38.1 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 110℃to 115℃and the reaction was continued for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 29.7g of Compound I-A in 86.1% yield and 94.77% purity.
1s：
Into a 250mL reaction flask, 2-chloronicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (24.2, 1.0 equiv.) were charged, and stirred and mixed, and then heated to 75℃to 80℃and sodium carbonate (26.9 g,2 equiv.) and 4-hydroxyphenylacetone (38.1 g,2 equiv.) were added in portions, and then heated to 110℃to 115℃and reacted at a constant temperature for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. Filtering, and drying the obtained filter cake by blowing at 60 ℃ to obtain 30.1g of compound I-A with the yield of 87.3% and the purity of 93.85%.
1t：
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Into a 250ml reaction flask, 2-iodonicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 ml) and cuprous iodide (1.5 g,0.1 equiv.) were put, stirred and mixed, heated to 75℃to 80℃and sodium carbonate (17.0 g,2 equiv.) and 4-hydroxyphenylacetone (24.1 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 110℃to 115℃and the reaction was continued for 4 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 19.5g of Compound I-A in 89.4% yield and 91.98% purity.
1u：
Into a 250ml reaction flask, 2-bromonicotinic acid (20.0 g,1 equiv.), dimethyl sulfoxide (20.0 g), and cuprous iodide (1.9 g,0.1 equiv.) were put, stirred and mixed, heated to 75-80 ℃, sodium carbonate (21.0 g,2 equiv.) and 4-hydroxy propiophenone (29.7 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 110-115 ℃, and the reaction was continued for 5 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 21.2g of Compound I-A in a yield of 78.9% and a purity of 96.38%.
1v：
Into a 250mL reaction flask, 2-bromonicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (1.9 g,0.1 equiv.) were put, stirred and mixed, heated to 75℃to 80℃and sodium carbonate (21.0 g,2 equiv.) and 4-hydroxyphenylacetone (29.7 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 130℃to 135℃and the reaction was continued for 4 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 22.4g of Compound I-A in a yield of 87.3% and a purity of 93.14%.
1w：
Into a 250mL reaction flask, 2-bromonicotinic acid (20.0 g,1 equiv.), N-dimethylformamide (20 mL) and cuprous iodide (1.9 g,0.1 equiv.) were put, stirred and mixed, heated to 75℃to 80℃and sodium carbonate (21.0 g,2 equiv.) and 4-hydroxyphenylacetone (29.7 g,2 equiv.) were added in portions, and after the addition, the temperature was raised to 140℃to 150℃and the reaction was continued at a constant temperature for 3 hours. The reaction solution was cooled to 50℃and 100g of water was added thereto and stirred for 15 minutes. Acidifying to pH 3-4, transferring the filter cake obtained by filtering into a 1L beaker, adding 200g of water, stirring uniformly, adjusting pH to 7-7.5 by sodium bicarbonate, filtering, washing the filter cake with a proper amount of water, retaining the filtrate, and transferring to a clean 1L beaker. The obtained filtrate is acidified to adjust the pH value to 3-4 to separate out a product. The mixture was filtered, and the obtained cake was air-dried at 60℃to give 23.3g of Compound I-A in 86.8% yield and 91.32% purity.
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Preparation examples 2a-2d: preparation of 2- [4- (2-methoxy-1-methyl-2-oxoethyl) phenoxy]-3-Pyridinecarboxylic acid
(Compound II-A) and 2- [4- (2-ethoxy-1-methyl-2-oxoethyl) phenoxy]3-Pyridinecarboxylic acid (Compound II-B)
2a：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (60 g) were charged, and after stirring and mixing, the reaction mixture was cooled to 0 ℃. Concentrated sulfuric acid (11.1 g,1.5 equiv.) is slowly added dropwise, the temperature is controlled below 10deg.C, iodobenzene diacetate (47.5 g,2 equiv.) is slowly added after stirring for 15min, the temperature is controlled at 15-20deg.C for about 10-15min, and stirring is carried out for 15min at 15-20deg.C after adding. Cooling to 0deg.C, slowly adding concentrated sulfuric acid (11.1 g,1.5 equiv.) dropwise, and controlling temperature below 10deg.C. After the concentrated sulfuric acid is dropped, slowly returning the temperature to 10-20 ℃, and preserving the heat for reaction for 1h. Adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight 16.9g, yield 76.0% and purity 97.34%.
2b：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (60 g) were charged, and after stirring and mixing, the reaction mixture was cooled to 0 ℃. Concentrated sulfuric acid (11.1 g,1.5 equiv.) is slowly added dropwise at a temperature below 5deg.C, and iodobenzene diacetate (47.5 g,2 equiv.) is slowly added after stirring for 15min, at a temperature of 5 deg.C to 10deg.C for about 10-15min, and stirring for 15min at a temperature of 5 deg.C to 10deg.C. Cooling to 0 ℃, slowly dripping concentrated sulfuric acid (11.1 g,1.5 equiv.), controlling the temperature below 10 ℃, controlling the temperature between 5 ℃ and 10 ℃ after dripping the concentrated sulfuric acid, and reacting for 1h at a constant temperature. Adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight 16.1g, yield 72.4% and purity 96.28%.
2c：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (60 g) were charged, and after stirring and mixing, the reaction mixture was cooled to-5 ℃. Concentrated sulfuric acid (11.1 g,1.5 equiv.) is slowly added dropwise, the temperature is controlled below-5 ℃, iodobenzene diacetate (47.5 g,2 equiv.) is slowly added after stirring for 15min, the temperature is controlled between-5 ℃ and 0 ℃, the temperature is controlled between about 10 and 15min, and stirring is carried out for 15min at-5 ℃ to 0 ℃. Cooling to-5 ℃, slowly dripping concentrated sulfuric acid (11.1 g,1.5 equiv.), controlling the temperature below-5 ℃, controlling the temperature to-5 ℃ to-0 ℃ after dripping the concentrated sulfuric acid, and reacting for 1h at a constant temperature. Adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with 15.9g weight, 71.6% yield and 95.61% purity.
2d：
Into a 500ml reaction flask, compound I-B (50.0 g,1 equiv.) and trimethyl orthoformate (150 g) were charged, and the mixture was stirred and cooled to 0 ℃. Concentrated sulfuric acid (26.4 g,1.5 equiv.) is slowly added dropwise, the temperature is controlled below 10deg.C, iodobenzene diacetate (113.3 g,2 equiv.) is slowly added after stirring for 15min, the temperature is controlled at 10-20deg.C for about 10-15min, and stirring is carried out for 15min at 10-20deg.C after adding. Cooling to 0deg.C, slowly adding concentrated sulfuric acid (26.4 g,1.5 equiv.) dropwise, and controlling temperature below 10deg.C. After the concentrated sulfuric acid is dropped, slowly returning the temperature to 10-20 ℃, and preserving the heat for reaction for 1h. Adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-B with weight of 41.5g, yield of 75.4%, and purity of 96.98%.
Comparative examples 2e to 2p
2e：
Into a 500ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (200 g) were put, and after stirring and mixing uniformly, concentrated sulfuric acid (3.7 g,0.5 equiv.) was slowly added dropwise, and after stirring for 5min, iodobenzene diacetate (23.7 g,1 equiv.) was slowly added, followed by Bi Jiaoban min. Concentrated sulfuric acid (3.7 g,0.5 equiv.) is slowly added dropwise, and after the addition of the concentrated sulfuric acid, the mixture is heated to 105 ℃ for reflux and reaction is carried out for 1h at a constant temperature. Cooling to room temperature, adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight 16.5g, yield 74.5% and purity 89.73%.
2f：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (100 g) were put, and after stirring and mixing uniformly, concentrated sulfuric acid (3.7 g,0.5 equiv.) was slowly added dropwise, and after stirring for 5min, iodobenzene diacetate (23.7 g,1 equiv.) was slowly added, followed by Bi Jiaoban min. Slowly adding concentrated sulfuric acid (3.7 g,0.5 equiv.) dropwise, heating to 70-75deg.C, and reacting for 1 hr. Cooling to room temperature, adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight 16.1g, yield 72.4%, and purity 92.86%.
2g：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (100 g) were put, and after stirring and mixing uniformly, concentrated sulfuric acid (3.7 g,0.5 equiv.) was slowly added dropwise, and after stirring for 5min, iodobenzene diacetate (23.7 g,1 equiv.) was slowly added, followed by Bi Jiaoban min. Slowly adding concentrated sulfuric acid (3.7 g,0.5 equiv.) dropwise, heating to 45-50deg.C, and reacting at constant temperature for 1 hr. Cooling to room temperature, adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight of 15.7g, yield of 70.8% and purity of 93.16%.
2h：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (100 g) were put, and after stirring and mixing uniformly, concentrated sulfuric acid (3.7 g,0.5 equiv.) was slowly added dropwise, and after stirring for 5min, iodobenzene diacetate (47.5 g,2 equiv.) was slowly added, followed by Bi Jiaoban min. Slowly adding concentrated sulfuric acid (3.7 g,0.5 equiv.) dropwise, heating to 45-50deg.C, and reacting at constant temperature for 1 hr. Cooling to room temperature, adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight 16.0g, yield 71.9% and purity 93.68%.
2i：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (100 g) were put, and after stirring and mixing uniformly, concentrated sulfuric acid (3.7 g,0.5 equiv.) was slowly added dropwise, and after stirring for 5min, iodobenzene diacetate (71.2 g,2 equiv.) was slowly added, followed by Bi Jiaoban min. Slowly adding concentrated sulfuric acid (3.7 g,0.5 equiv.) dropwise, heating to 45-50deg.C, and reacting at constant temperature for 1 hr. Cooling to room temperature, adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with 15.9g weight, 71.7% yield and 93.01% purity.
2j：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (100 g) were put, and after stirring and mixing uniformly, concentrated sulfuric acid (7.4 g,1 equiv.) was slowly added dropwise, and after stirring for 5min, iodobenzene diacetate (47.5 g,2 equiv.) was slowly added, followed by adding Bi Jiaoban min. Slowly adding concentrated sulfuric acid (7.4 g,1 equiv.) dropwise, heating to 45-50deg.C, and reacting at constant temperature for 1 hr. Cooling to room temperature, adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight 16.1g, yield 72.3% and purity 94.28%.
2k：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (100 g) were put, and after stirring and mixing uniformly, concentrated sulfuric acid (11.1 g,1.5 equiv.) was slowly added dropwise, and after stirring for 5min, iodobenzene diacetate (47.5 g,2 equiv.) was slowly added, followed by Bi Jiaoban min. Concentrated sulfuric acid (11.1 g,1.5 equiv.) is slowly added dropwise, and the mixture is heated to 45-50deg.C and reacted for 1h at a constant temperature. Cooling to room temperature, adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight 16.2g, yield 72.9%, and purity 94.64%.
2l：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (100 g) were put, and after stirring and mixing uniformly, concentrated sulfuric acid (14.8 g,2 equiv.) was slowly added dropwise, and after stirring for 5min, iodobenzene diacetate (47.5 g,2 equiv.) was slowly added, and then Bi Jiaoban min was added. Slowly adding concentrated sulfuric acid (14.8 g,2 equiv.) dropwise, heating to 45-50deg.C, and reacting at constant temperature for 1 hr. Cooling to room temperature, adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight 16.1g, yield 72.3% and purity 93.45%.
2m：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (60.0 g) were put, and after stirring and mixing uniformly, hydrochloric acid (30.1 g,1.5 equiv.) was slowly added dropwise, and after stirring for 15min, iodobenzene diacetate (47.5 g,2 equiv.) was slowly added, and Bi Jiaoban min was added. Slowly dropwise adding hydrochloric acid (30.1 g,1.5 equiv.) and heating to 45-50deg.C, and reacting at constant temperature for 1 hr. Adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight of 14.9g, yield 67.1% and purity 93.33%.
2n：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (60.0 g) were put, and after stirring and mixing uniformly, 85% phosphoric acid (12.8 g,1.5 equiv.) was slowly added dropwise, and after stirring for 15min, iodobenzene diacetate (47.5 g,2 equiv.) was slowly added, and Bi Jiaoban min was added. 85% phosphoric acid (12.8 g,1.5 equiv.) is slowly added dropwise, and after that, the mixture is heated to 45-50 ℃ and reacted for 1h at a constant temperature. Adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight of 14.3g, yield of 64.5% and purity of 91.79%.
2o：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (60.0 g) were put, and acetic acid (10.8 g,1.5 equiv.) was slowly added dropwise after stirring and mixing them uniformly, and iodobenzene diacetate (47.5 g,2 equiv.) was slowly added after stirring for 15min after stirring for Bi Jiaoban min. Acetic acid (10.8 g,1.5 equiv.) is slowly added dropwise, and the mixture is heated to 45-50 ℃ and reacted for 1h at a constant temperature. Adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight of 12.4g, yield of 55.7%, and purity of 88.67%.
2p：
Into a 250ml reaction flask, compound I-A (20.0 g,1 equiv.) and trimethyl orthoformate (60 g) were charged, and after stirring and mixing, the reaction mixture was cooled to 0℃to 10 ℃. Concentrated sulfuric acid (11.1 g,1.5 equiv.) is slowly added dropwise at a temperature below 10deg.C, and iodobenzene diacetate (47.5 g,2 equiv.) is slowly added after stirring for 15min, at a temperature below 20deg.C for about 10-15min, and Bi Jiaoban min. Cooling to 0-10 ℃, slowly dripping concentrated sulfuric acid (11.1 g,1.5 equiv.), controlling the temperature below 10 ℃, heating to 25-30 ℃ after dripping the concentrated sulfuric acid, and reacting for 1h at a constant temperature. Adding sodium bicarbonate aqueous solution for neutralization, extracting with dichloromethane, retaining water phase, acidifying to pH 3-4, filtering, washing filter cake with water until the filtrate is nearly neutral, and air drying at 60deg.C until constant weight to obtain off-white compound II-A with weight 16.2g, yield 73.1% and purity 94.96%.
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Preparation examples 3a-3g: preparation of methyl 2- (10-oxo-9-oxa-1-azaanthracen-6-yl) propionate (Compound III-A)
And ethyl 2- (10-oxo-9-oxa-1-azaanthracen-6-yl) propionate (Compound III-B)
3a：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, oxalyl chloride (12.6 g,1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (17.7 g,2 equiv.) and methylene chloride (100 ml) were put into each other and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching the filter cake with methanol, and air drying at 45 ℃ to obtain the compound III-A with 16.3g weight, 86.8% yield and 99.55% purity.
3b：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, oxalyl chloride (12.6 g,1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (26.6 g,2 equiv.) and methylene chloride (100 ml) were charged and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching the filter cake with methanol, and drying by blowing at 45 ℃ to obtain the compound III-A with 15.8g weight, yield of 84.1% and purity of 99.59%.
3c：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, oxalyl chloride (12.6 g,1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (35.4 g,4 equiv.) and methylene chloride (100 ml) were put into each other and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching the filter cake with methanol, and drying by blowing at 45 ℃ to obtain the compound III-A with 15.9g weight, yield of 84.3% and purity of 99.54%.
3d：
Into a 500ml reaction flask A, compound II-B (40.0 g,1 equiv.), dichloromethane (200 ml) and N, N-dimethylformamide (0.9 g) were put, stirred and mixed, oxalyl chloride (24.2 g,1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. Further, in a 1000ml reaction flask B, anhydrous aluminum trichloride (33.9 g,2 equiv.) and methylene chloride (200 ml) were charged and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (80 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The solution was separated and the dichloromethane layer was washed once with purified water (200 ml). Recovering dichloromethane by vacuum concentration, adding methanol (200 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, eluting the filter cake with methanol, and air drying at 45 ℃ to obtain compound III-B with weight of 32.2g, yield of 85.7% and purity of 99.26%.
3e：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, thionyl chloride (11.8, 1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (17.7 g,2 equiv.) and methylene chloride (100 ml) were put into each other and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching the filter cake with methanol, and air drying at 45 ℃ to obtain the compound III-A with 16.4g weight, 87.1% yield and 99.67% purity.
3f：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, thionyl chloride (11.8, 1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (17.7 g,2 equiv.) and methylene chloride (100 ml) were put into each other and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol/dichloromethane mixed solvent (100 ml, solvent ratio 1:0.1) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching filter cake with methanol, and air drying at 45 ℃ to obtain compound III-A with weight of 16.1g, yield of 85.6% and purity of 99.71%.
3g：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, thionyl chloride (11.8, 1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (17.7 g,2 equiv.) and methylene chloride (100 ml) were put into each other and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol/dichloromethane mixed solvent (100 ml, solvent ratio 1:0.2) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching filter cake with methanol, and air drying at 45 ℃ to obtain compound III-A with 15.7g, yield of 83.5% and purity of 99.73%.
Comparative examples 3h-3p
3h：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, oxalyl chloride (9.3 g,1.1 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (9.7 g,1.1 equiv.) and methylene chloride (100 ml) were charged and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, eluting the filter cake with methanol, and air drying at 45 ℃ to obtain compound III-A with 14.4g weight, yield of 76.8% and purity of 91.26%.
3i：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, oxalyl chloride (12.6 g,1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (9.7 g,1.1 equiv.) and methylene chloride (100 ml) were charged and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, eluting the filter cake with methanol, and drying by blowing at 45 ℃ to obtain the compound III-A with 14.9g weight, 79.2% yield and 94.07% purity.
3j：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, oxalyl chloride (16.9 g,2 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (9.7 g,1.1 equiv.) and methylene chloride (100 ml) were charged and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching the filter cake with methanol, and air drying at 45 ℃ to obtain compound III-A with 14.8g weight, yield of 78.7% and purity of 94.11%.
3k：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, oxalyl chloride (25.3 g,3 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (9.7 g,1.1 equiv.) and methylene chloride (100 ml) were charged and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, eluting the filter cake with methanol, and drying by blowing at 45 ℃ to obtain the compound III-A with 14.7g weight, yield of 78.2% and purity of 93.84%.
3l：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, oxalyl chloride (12.6 g,1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (13.3 g,1.5 equiv.) and methylene chloride (100 ml) were charged and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching the filter cake with methanol, and drying by blowing at 45 ℃ to obtain the compound III-A with 15.4g weight, yield of 81.8% and purity of 98.57%.
3m：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, oxalyl chloride (12.6 g,1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (44.3 g,5 equiv.) and methylene chloride (100 ml) were put into each other and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching the filter cake with methanol, and drying by blowing at 45 ℃ to obtain the compound III-A with 16.0g weight, yield of 85.1% and purity of 98.71%.
3n：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, and the mixture was stirred and mixed, and thionyl chloride (11.8 g,1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated for 1 hour at 15℃to 25 ℃. Titanium tetrachloride (25.2 g,2 equiv.) and methylene chloride (100 ml) were put into a 500ml reaction flask B and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol (100 ml) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, eluting the filter cake with methanol, and drying by blowing at 45 ℃ to obtain the compound III-A with 13.6g weight, yield of 72.4% and purity of 95.43%.
3o：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, thionyl chloride (11.8, 1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (17.7 g,2 equiv.) and methylene chloride (100 ml) were put into each other and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol/dichloromethane mixed solvent (100 ml, solvent ratio 1:0.3) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching filter cake with methanol, and air drying at 45 ℃ to obtain compound III-A with 15.0g, yield of 79.9% and purity of 99.78%.
3p：
Into a 250ml reaction flask A, compound II-A (20.0 g,1 equiv.), dichloromethane (100 ml) and N, N-dimethylformamide (0.5 g) were put, stirred and mixed, thionyl chloride (11.8, 1.5 equiv.) was added dropwise at 15℃to 25℃and the mixture was incubated at 15℃to 25℃for 1 hour. In a 500ml reaction flask B, anhydrous aluminum trichloride (17.7 g,2 equiv.) and methylene chloride (100 ml) were put into each other and mixed with stirring. And (3) dropwise transferring the acyl chloride solution in the reaction bottle A into the reaction bottle B, controlling the temperature to be 15-25 ℃, carrying out heat preservation reaction for 1-1.5h after the dropwise addition, and cooling the reaction solution to-10 ℃ after the reaction is finished. Slowly transferring the reaction solution into cold water for quenching, and controlling the temperature below 20 ℃. Bi Jiaoban 15 and 30min are added, the mixture is separated, the dichloromethane phase is reserved, the aqueous phase is extracted with dichloromethane (40 ml), the dichloromethane phases are combined, and the pH is adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, and the dichloromethane layer was washed once with purified water (100 ml). Recovering dichloromethane by vacuum concentration, adding methanol/dichloromethane mixed solvent (100 ml, solvent ratio 1:0.4) when the fraction is not distilled out, pulping for 5-6h at 20-25 ℃, filtering, leaching filter cake with methanol, and air drying at 45 ℃ to obtain compound III-A with weight of 14.5g, yield of 77.0% and purity of 99.81%.
Preparation examples 4a-4b: preparation of methyl 2- (10-hydroxy-9-oxSup>A-1-azaanthracen-6-yl) propionate (Compound IV-A)
And ethyl 2- (10-hydroxy-9-oxa-1-azaanthracen-6-yl) propionate (Compound IV-B)
4a：
Adding a compound III-A (20.0 g,1 equiv.) to a 500ml reaction bottle, methylene chloride (80 ml) and methanol (80 ml), stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (2.7 g,1 equiv.) for about 30min, preserving heat for 8h at 25-30 ℃, cooling to-5 ℃ to 5 ℃, slowly dropwise adding 30% acetic acid aqueous solution to pH5.5-6.5, preserving heat and stirring at-5 ℃ to 15min, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. Concentrating the obtained dichloromethane solution at 35deg.C under reduced pressure to dryness (-0.09 Mpa) to obtain yellowish green oily substance (20.0 g), adding methanol/acetone (50 ml/50 ml) mixed solution, dissolving, dispersing and stirring at 25deg.C-30deg.C for 15min to obtain yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 16.4g, the yield is 81.5%, and the purity is 96.72%.
4b：
Adding a compound III-A (20.0 g,1 equiv.) to a 500ml reaction bottle, methylene chloride (80 ml) and methanol (80 ml), stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (2.7 g,1 equiv.) for about 30min, keeping the temperature at 35-40 ℃ for 6h, cooling to-5 ℃ to 5 ℃, slowly dropwise adding a 30% acetic acid aqueous solution to pH5.5-6.5, keeping the temperature at-5 ℃ to 5 ℃ and stirring for 15min, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. Concentrating the obtained dichloromethane solution at 35deg.C under reduced pressure to dryness (-0.09 Mpa) to obtain yellowish green oily substance (20.0 g), adding methanol/acetone (50 ml/50 ml) mixed solution, dissolving, dispersing and stirring at 25deg.C-30deg.C for 15min to obtain yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 16.6g, the yield is 82.5%, and the purity is 98.46%.
4c：
Adding 30.0g of compound III-B, 1 equiv.), methylene chloride (120 ml) and methanol (120 ml) into a 500ml reaction bottle, stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (3.8 g,1 equiv.) into the clear solution, keeping the temperature at 35-40 ℃ for 6h after about 30min, cooling to-5 ℃ to 5 ℃, transferring the clear solution into a 1L beaker, slowly dropwise adding 30% acetic acid aqueous solution to pH5.5-6.5, keeping the temperature at-5 ℃ to 5 ℃ after the completion of the dropwise adding, stirring and separating the clear solution, adding purified water (180 ml), stirring and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (60 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (30 ml); purified water (60 ml) was washed once more. Concentrating the obtained dichloromethane solution at 35deg.C under reduced pressure to dryness (-0.09 Mpa) to obtain yellowish green oily substance (30.0 g), adding methanol/acetone (75 ml/75 ml) mixed solution, dissolving, dispersing and stirring at 20-30deg.C for 15min to obtain yellowish green clear solution. Slowly adding purified water (300 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying a water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-B with the weight of 24.1g, the yield of 79.8% and the purity of 98.77%.
Comparative examples 4d to 4l
4d：
Adding a compound III-A (20.0 g,1 equiv.), methylene dichloride (80 ml) and methanol (80 ml) into a 500ml reaction bottle, stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (1.3 g,0.5 equiv.) into the clear solution, keeping the temperature at 15-20 ℃ for 12h after about 30min, cooling to-5 ℃ to 5 ℃, slowly dropwise adding a 30% acetic acid aqueous solution until the pH is 5.5-6.5, keeping the temperature at-5 ℃ to 5 ℃ after the dropwise adding, stirring for 15min, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. The obtained dichloromethane solution was concentrated to dryness (-0.09 Mpa) under reduced pressure at 35 ℃ to obtain a yellowish green oily substance (20.0 g), and acetone (100 ml) was added thereto, and the resulting solution was dissolved, dispersed and stirred at 25 ℃ to 30 ℃ for 15 minutes to obtain a yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 15.0g, the yield is 74.7%, and the purity is 89.86%.
4e：
Adding a compound III-A (20.0 g,1 equiv.), methylene dichloride (80 ml) and methanol (80 ml) into a 500ml reaction bottle, stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (1.6 g,0.6 equiv.) for about 30min, preserving heat for 12h at 15-20 ℃, cooling to-5 ℃ to 5 ℃, slowly dropwise adding a 30% acetic acid aqueous solution to pH5.5-6.5, preserving heat and stirring for 15min at-5 ℃ to 5 ℃, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. The obtained dichloromethane solution was concentrated to dryness (-0.09 Mpa) under reduced pressure at 35 ℃ to obtain a yellowish green oily substance (20.0 g), and acetone (100 ml) was added thereto, and the resulting solution was dissolved, dispersed and stirred at 25 ℃ to 30 ℃ for 15 minutes to obtain a yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 15.4g, the yield is 76.4%, and the purity is 92.58%.
4f：
Adding a compound III-A (20.0 g,1 equiv.) to a 500ml reaction bottle, methylene chloride (80 ml) and methanol (80 ml), stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (2.7 g,1 equiv.) for about 30min, keeping the temperature at 15-20 ℃ for 10h, cooling to-5 ℃ to 5 ℃, slowly dropwise adding 30% acetic acid aqueous solution to pH5.5-6.5, keeping the temperature at-5 ℃ to 5 ℃ and stirring for 15min, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. The obtained dichloromethane solution was concentrated to dryness (-0.09 Mpa) under reduced pressure at 35 ℃ to obtain a yellowish green oily substance (20.0 g), and acetone (100 ml) was added thereto, and the resulting solution was dissolved, dispersed and stirred at 25 ℃ to 30 ℃ for 15 minutes to obtain a yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 16.4g, the yield is 81.4%, and the purity is 94.86%.
4g：
Adding a compound III-A (20.0 g,1 equiv.) to a 500ml reaction bottle, methylene chloride (80 ml) and methanol (80 ml), stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (2.7 g,1 equiv.) for about 30min, keeping the temperature at 15-20 ℃ for 10h, cooling to-5 ℃ to 5 ℃, slowly dropwise adding 30% acetic acid aqueous solution to pH5.5-6.5, keeping the temperature at-5 ℃ to 5 ℃ and stirring for 15min, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. The obtained dichloromethane solution was concentrated to dryness (-0.09 Mpa) under reduced pressure at 35 ℃ to obtain a yellowish green oily substance (20.0 g), and methanol (100 ml) was added thereto, and the resulting solution was dissolved, dispersed and stirred at 25 ℃ to 30 ℃ for 15 minutes to obtain a yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 17.8g, the yield is 83.5%, and the purity is 93.97%.
4h：
Adding a compound III-A (20.0 g,1 equiv.) to a 500ml reaction bottle, methylene chloride (80 ml) and methanol (80 ml), stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (2.7 g,1 equiv.) for about 30min, keeping the temperature at 15-20 ℃ for 10h, cooling to-5 ℃ to 5 ℃, slowly dropwise adding 30% acetic acid aqueous solution to pH5.5-6.5, keeping the temperature at-5 ℃ to 5 ℃ and stirring for 15min, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. Concentrating the obtained dichloromethane solution at 35deg.C under reduced pressure to dryness (-0.09 Mpa) to obtain yellowish green oily substance (20.0 g), adding methanol/acetone (50 ml/50 ml) mixed solution, dissolving, dispersing and stirring at 25deg.C-30deg.C for 15min to obtain yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2h, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 16.3g, the yield is 81.0%, and the purity is 95.23%.
4i：
Adding a compound III-A (20.0 g,1 equiv.) to a 500ml reaction bottle, methylene chloride (80 ml) and methanol (80 ml), stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (3.8 g,1 equiv.) for about 30min, keeping the temperature at 15-20 ℃ for 10h, cooling to-5 ℃ to 5 ℃, slowly dropwise adding 30% acetic acid aqueous solution to pH5.5-6.5, keeping the temperature at-5 ℃ to 5 ℃ and stirring for 15min, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. Concentrating the obtained dichloromethane solution at 35deg.C under reduced pressure to dryness (-0.09 Mpa) to obtain yellowish green oily substance (20.0 g), adding methanol/acetone (50 ml/50 ml) mixed solution, dissolving, dispersing and stirring at 25deg.C-30deg.C for 15min to obtain yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 16.1g, the yield is 80.0%, and the purity is 95.28%.
4j：
Adding a compound III-A (20.0 g,1 equiv.) to a 500ml reaction bottle, methylene chloride (80 ml) and methanol (80 ml), stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (3.8 g,1 equiv.) for about 30min, keeping the temperature at 15-20 ℃ for 10h, cooling to-5 ℃ to 5 ℃, slowly dropwise adding 30% acetic acid aqueous solution to pH5.5-6.5, keeping the temperature at-5 ℃ to 5 ℃ and stirring for 15min, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. Concentrating the obtained dichloromethane solution at 35deg.C under reduced pressure to dryness (-0.09 Mpa) to obtain yellowish green oily substance (20.0 g), adding methanol/acetone (50 ml/50 ml) mixed solution, dissolving, dispersing and stirring at 25deg.C-30deg.C for 15min to obtain yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 15.9g, the yield is 78.7%, and the purity is 94.03%.
4k：
Adding a compound III-A (20.0 g,1 equiv.) to a 500ml reaction bottle, methylene chloride (80 ml) and methanol (80 ml), stirring and dissolving at 15-30 ℃ for 5-10min to obtain a clear solution, slowly adding sodium borohydride (3.8 g,1 equiv.) for about 30min, keeping the temperature at 20-25 ℃ for 8h, cooling to-5 ℃ to 5 ℃, slowly dropwise adding a 30% acetic acid aqueous solution to pH5.5-6.5, keeping the temperature at-5 ℃ to 5 ℃ and stirring for 15min, adding purified water (120 ml), stirring and separating liquid, and separating an organic phase; the aqueous phase was extracted once more with dichloromethane (40 ml), the dichloromethane phases were combined and washed once with saturated aqueous sodium bicarbonate (20 ml); purified water (40 ml) was washed once more. Concentrating the obtained dichloromethane solution at 35deg.C under reduced pressure to dryness (-0.09 Mpa) to obtain yellowish green oily substance (20.0 g), adding methanol/acetone (50 ml/50 ml) mixed solution, dissolving, dispersing and stirring at 25deg.C-30deg.C for 15min to obtain yellowish green clear solution. Slowly adding purified water (200 ml) dropwise for crystallization for 2 hours, carrying out suction filtration, purifying Sup>A water washing filter cake, and carrying out light-proof vacuum drying at 40 ℃ to obtain the compound IV-A, wherein the weight of the compound IV-A is 16.4g, the yield is 81.5%, and the purity is 95.86%.
Preparation examples 5a-5g: preparation of pranoprofen
5a：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 14.3g and yield of 79.9% and purity 99.62%. And recrystallizing with methanol to obtain pranoprofen product with purity of 99.9% and single impurity less than 0.05%.
5b：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 60℃to 65℃to conduct Sup>A reaction under heat-preserving for 2.5 hours, and concentrated under reduced pressure at 55℃to no fraction, to give Sup>A foamy oil (24 g). After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 14.4g and yield of about 80.5% and purity of 99.27%. And recrystallizing with methanol to obtain pranoprofen product with purity of 99.9% and single impurity less than 0.05%.
5c：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved with stirring, heated to 70℃to 75℃and reacted at Sup>A constant temperature for 2.5 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, to give Sup>A foamy oil (24 g). After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 14.3g and yield of 79.9% and purity of 99.48%. And recrystallizing with methanol to obtain pranoprofen product with purity of 99.9% and single impurity less than 0.05%.
5d：
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Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added thereto, and the mixture was dissolved by stirring, and a potassium hydroxide solution prepared from potassium hydroxide (15.7 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 14.2g and yield of 79.4% and purity of 99.63%. And recrystallizing with methanol to obtain pranoprofen product with purity of 99.9% and single impurity less than 0.05%.
5e：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 40℃to 45℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 14.6g and yield of 81.6% and purity of 99.68%. And recrystallizing with methanol to obtain pranoprofen product with purity of 99.9% and single impurity less than 0.05%.
5f：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 40℃to 45℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 10% dilute hydrochloric acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 14.6g and yield of 81.6% and purity of 99.67%. And recrystallizing with methanol to obtain pranoprofen product with purity of 99.9% and single impurity less than 0.05%.
5g：
Into a 250ml reaction flask were added compound IV-B (20.0 g,1 euqiv.), hydrochloric acid (23.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved with stirring, heated to 80℃to 85℃and refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, to give a foamy oil (24 g). After cooling to room temperature, methanol (10 ml) was added thereto, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (10.7 g,4 equiv.) and purified water (40 ml) were added thereto, followed by reaction at 40℃to 45℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml) separately, separate out the aqueous phase, adjust the pH to 5-6 with 10% dilute hydrochloric acid, gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 13.6g and yield of 79.5% and purity 99.62%. And recrystallizing with methanol to obtain pranoprofen product with purity of 99.9% and single impurity less than 0.05%.
Comparative examples 5h to 5t
5h：
Into Sup>A 250ml reaction flask, compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (10.6 g,1.5 euqiv.) and isopropyl alcohol (240 ml) were added, and the mixture was dissolved and heated to 50℃to 55℃with stirring, and reacted for 4 hours at 55℃under reduced pressure and concentrated to no fraction, to give Sup>A foamy oil (24 g). After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product 13.1g with yield of 73.2% and purity of 97.76%.
5i：
To Sup>A 250ml reaction flask were added compound IV-Sup>A (20.0 g,1 euqiv.), hydrogen chloride isopropyl alcohol (29.0 g,13.2wt.%,1.5 euqiv.), isopropyl alcohol (208 ml), and the mixture was stirred, dissolved and heated to 50-55 ℃ for 4h, and concentrated under reduced pressure at 55 ℃ until no fraction was obtained, to give Sup>A foamy oil (24 g). After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 13.1g, yield of 73.2% and purity of 97.78%.
5j：
Into Sup>A 250ml reaction flask, compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (14.2 g,2 euqiv.), and isopropyl alcohol (240 ml) were added, and the mixture was dissolved and heated to 50℃to 55℃to react for 4 hours under heat preservation, and concentrated under reduced pressure at 55℃until no fraction was obtained, to give Sup>A foamy oil (24 g). After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product with 13.3g and yield of 74.3% and purity 98.12%.
5k：
Into Sup>A 250ml reaction flask, compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (17.7 g,2.5 euqiv.) and isopropyl alcohol (240 ml) were added, and the mixture was dissolved and heated to 50℃to 55℃with stirring, and reacted for 4 hours at 55℃under reduced pressure and concentrated to no fraction, to give Sup>A foamy oil (24 g). After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 13.6g and yield of 76.0% and purity 98.63%.
5l：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 50℃to 55℃to react for 4 hours under heat preservation, and concentrated under reduced pressure at 55℃until no fraction was obtained, to give Sup>A foamy oil (24 g). After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 13.7g and yield of 76.6% and purity of 98.77%.
5m：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added thereto, and the mixture was dissolved by stirring, and a sodium carbonate solution prepared from sodium carbonate (29.7 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 13.9g and yield of 77.7% and purity 98.79%.
5n：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added thereto, and the mixture was dissolved by stirring, and a potassium carbonate solution prepared from potassium carbonate (38.8 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 50℃to 55℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 13.8g and yield of 77.1% and purity 98.92%.
5o：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 60℃to 65℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 5-6 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 14.0g and yield of 78.2% and purity of 98.86%.
5p：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 40℃to 45℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), adjust the pH to 5-6 with 10% dilute sulfuric acid after separating out the aqueous phase, gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 13.7g and yield of 76.6% and purity of 98.81%.
5q：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 40℃to 45℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), adjust the pH to 5-6 with 10% dilute sulfuric acid after separating out the aqueous phase, gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 13.9g and yield of 77.7% and purity 98.64%.
5r：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 40℃to 45℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 4-5 with 10% dilute hydrochloric acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product in 14.7g and yield of 82.1% and purity of 98.74%.
5s：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 40℃to 45℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 6-7 with 10% dilute hydrochloric acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product 13.3g with yield 74.3% and purity 99.77%.
5t：
Into Sup>A 250ml reaction flask were added compound IV-A (20.0 g,1 euqiv.), hydrochloric acid (24.8 g,3.5 euqiv.), isopropyl alcohol (240 ml), and the mixture was dissolved and heated to 80℃to 85℃under stirring, and then the mixture was refluxed for 2 hours, and concentrated under reduced pressure at 55℃until no fraction was obtained, whereby Sup>A foamy oil (24 g) was obtained. After cooling to room temperature, methanol (10 ml) was added, and the mixture was dissolved by stirring, and a sodium hydroxide solution prepared from sodium hydroxide (11.2 g,4 quiv.) and purified water (40 ml) was added thereto, followed by reaction at 40℃to 45℃for 2 hours. Transfer to a 500ml beaker, add purified water (300 ml), then extract the aqueous phase 4 times with ethyl acetate (100 ml), separate the aqueous phase, adjust the pH to 3-4 with 10% dilute hydrochloric acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 deg.c to obtain pranoprofen product 15.0g with yield of 83.8% and purity of 98.53%.
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Experimental example 1: structural characterization
Pranoprofen samples were synthesized according to the process described in the foregoing of the present invention, and the synthesis process of this batch of samples was performed according to the preparation conditions of 1a, 2c, 3c, 4b, 5 a. Pranoprofen standard can be purchased directly at the middle school of care.
Structural confirmation was performed.
Compound element composition:
(1) High Resolution Mass Spectrum (HRMS)
Instrument model: bruker SolariX 7.0T (FT-ICR MS).
Test conditions: ESI ionization mode.
Test results: as shown in fig. 1. The result shows that the excimer ion peak M/z 254.081876 in the high-resolution mass spectrogram is [ M-H ]] - Peak, corresponding element composition is C 15 H 12 NO 3 The elemental composition of the sample is C 15 H 13 NO 3 Consistent with the elemental composition of the free base portion of the molecule.
(2) Infrared ray spectrum (IR)
Instrument model: bruker IFS-55 type infrared photometer (corrected according to China pharmacopoeia 2015 edition general rule 0402).
The experimental method comprises the following steps: KBr tabletting method.
Experimental results: the measurement data are shown in Table 6 below. The standard infrared spectrum is shown in figure 2A. The sample fuchsin external map is shown in figure 2B.
Table 6: infrared spectrum measurement data of sample
Analysis:
a.3427.6cm -1 the stretching vibration peak of the stretching vibration of-O-H is used for indicating that carboxyl groups possibly exist in the molecule.
b.2968.2,2943.1,2881.9 and 1465-1376 cm -1 The absorption peaks are C-H stretching and bending vibration peaks, which indicate that methyl and methylene can exist in the molecule.
c.1706.7cm -1 For c=o stretching vibrational peak, a carbonyl group may be present in the molecule.
d.1608.6、1584.3、1499.5cm -1 Is C=C telescopic vibration of benzene ring, 767.8cm -1 Is C-H bending vibration peak of benzene ring, 804.0cm -1 The c=c bending vibration peak of the benzene ring indicates the presence of the benzene ring in the molecule.
Conclusion: the absorption peak position, peak type and intensity of each functional group in the infrared spectrum of the sample are consistent with the molecular structure of pranoprofen; the infrared spectrum of the sample is consistent with that of the reference substance, and the infrared spectrum of the sample is consistent with that of the reference substance of Japanese pharmacopoeia JP17 version.
(3) Ultraviolet spectrum (UV)
Instrument model: agilent cary-60 type ultraviolet spectrometer
Preparing a solution: taking 0.02g of the product, adding 1mol/L hydrochloric acid solution to dissolve and dilute to 100ml, and taking the product as mother solution; 10ml of the mother solution was diluted with water to 100ml to prepare a neutral sample.
Taking 10ml of the mother solution, adding 1mol/L hydrochloric acid solution to dilute to 100ml, and taking the mother solution as an acidic test sample; 10ml of the mother solution was taken and diluted to 100ml with 1mol/L sodium hydroxide solution to prepare an alkaline sample. The results of the measurements are shown in Table 7 below and in FIGS. 3A-3F.
Table 7: sample and standard UV assay results
Analysis: the peak shapes of the ultraviolet scanning of the sample and the reference substance are consistent, and the maximum absorption wavelength is consistent.
Conclusion: the ultraviolet absorption of the sample is consistent with the molecular structure of pranoprofen; the ultraviolet spectrum of the sample is consistent with that of the reference substance.
(4) Nuclear magnetic resonance spectrum (NMR)
1 H-nuclear magnetic resonance
Instrument model: bruker AV-600 type NMR apparatus.
Test conditions: solvent DMSO-d6, TMS internal standard.
The measurement data are shown in Table 8 below.
Table 8: analysis of sample nuclear magnetic resonance H-spectrum data
Analysis:
the single peak at δ12.34ppm is carboxyhydrogen.
Delta 7.09ppm 1H is hydrogen at position 8 of the benzene ring.
Delta 7.16ppm 1H is hydrogen at position 7 of the benzene ring.
Delta 7.18 is hydrogen at position 5 of the 1H benzene ring.
1H at δ7.15ppm is hydrogen at position 3 of the pyridine ring.
1H at δ7.72ppm is hydrogen at position 4 of the pyridine ring.
1H at δ8.13ppm is hydrogen at position 2 on the pyridine ring.
The 2H single peak at δ4.11ppm is hydrogen on the methylene at position 10.
The 1H quartet at delta 3.66ppm was isopropylhydrogen at position 15 coupled with methylhydrogen at position 17 split into quartets.
The 3H doublet at delta 1.36ppm was methyl hydrogen at position 17 coupled with isopropyl hydrogen at position 15 split into doublets.
Conclusion: of samples 1 The H-NMR spectrum data is consistent with the pranoprofen structure, and the sample and the reference substance are identicalThe patterns are consistent.
13 C-Nuclear magnetic resonance
Instrument model: bruker AV-600 type NMR apparatus.
Test conditions: solvent DMSO-d6, TMS internal standard.
The measurement data are shown in Table 9 below.
Table 9: analysis of sample nuclear magnetic resonance C-spectrum data
Analysis:
pranoprofen contains 15 carbon atoms in the molecule, wherein 1 primary carbon, 1 secondary carbon, 7 tertiary carbon and 6 quaternary carbon; containing 13 hydrogen atoms, resolved as follows:
1. the carbon at δ 175.39ppm is a quaternary carbon atom, which is related to the hydrogen on carbons 15 and 17 in the HMBC spectrum, and can be determined to be the carboxyl carbon at 16.
2. Delta 157.83ppm carbon is a quaternary carbon atom, which is related to hydrogen on the pyridine ring at the 2-position, 4-position and hydrogen on the methylene at the 10-position in the HMBC spectra, and can be identified as the 11-position picoline ring carbon.
3. Delta 150.03ppm carbon is a quaternary carbon atom, which is related to hydrogen on benzene rings at the 5-, 7-, 8-and 10-positions methylene carbons in HMBC spectra, which is a 14-position oxygen-linked benzene ring carbon.
4. The carbon at δ136.71ppm is a quaternary carbon atom, and is related to hydrogen on the 7-position benzene ring carbon, hydrogen on the 15-position isopropyl carbon, and hydrogen on the 17-position methyl group in the HMBC spectrum, which is the 6-position benzene ring carbon.
5. The delta 120.00ppm position is a quaternary carbon atom, and the HMBC spectrum is related to hydrogen on 8-position benzene ring carbon and hydrogen on 10-position methylene carbon, which is 14-position benzene ring carbon.
6. Delta 115.62ppm is a quaternary carbon atom, which is related to hydrogen on the 4-position pyridine ring carbon and hydrogen on the 10-position methylene carbon in the HMBC spectra, which is the 12-position pyridine ring carbon.
7. Delta 146.26ppm is a tertiary carbon atom, which is related to hydrogen on the 2-position pyridine ring carbon in the HSQC spectrum, and to hydrogen on the 3-and 4-position pyridine ring carbons, which is the 2-position pyridine ring carbon, in the HMBC spectrum.
8. Delta 138.89ppm is a tertiary carbon atom, which is related to hydrogen on the 4-position pyridine ring carbon in the HSQC spectrum, and to hydrogen on the 2-position pyridine ring carbon and hydrogen on the 10-position methylene carbon, which are 4-position pyridine ring carbons, in the HMBC spectrum.
Delta 127.79ppm is a tertiary carbon atom, and is related to hydrogen on the benzene ring carbon at the 5-position in the HSQC spectrum, and is related to methylene hydrogen at the 10-position and isopropyl hydrogen at the 15-position in the HMBC spectrum, and is the benzene ring carbon at the 5-position.
10. Delta 127.01ppm is a tertiary carbon atom, which is related to hydrogen on the 7-position benzene ring carbon in HSQC spectrum, and is related to hydrogen on the 5-position benzene ring carbon and 15-position isopropyl hydrogen, which are 7-position benzene ring carbon in HMBC spectrum.
11. Delta 120.27ppm is a tertiary carbon atom, which is related to the 3-position pyridine ring carbon in the HSQC spectrum, and to the 10-position methylene hydrogen, which is the 3-position pyridine ring carbon in the HMBC spectrum.
12. Delta 116.41ppm is a tertiary carbon atom, which is related to hydrogen on the 8-position benzene ring carbon in the HSQC spectrum, and is not related to hydrogen in the HMBC spectrum, which is the 8-position benzene ring carbon.
13. 27.19ppm is a tertiary carbon atom, which is related to hydrogen on the 15-isopropyl carbon in the HSQC spectrum, and to hydrogen on the 5-and 7-benzene ring carbons, which is the 15-isopropyl carbon in the HMBC spectrum.
14. Delta 43.94ppm is a secondary carbon atom, which is related to the hydrogen of the methylene group at position 10 in the HSQC spectrum, which is the methylene carbon at position 10.
15. Delta 18.54ppm is a primary carbon atom, which is related to hydrogen on methyl carbon at position 17 in the HSQC spectrum, and to isopropyl hydrogen at position 15 in the HMBC spectrum, which is methyl carbon at position 17.
Conclusion: of samples 13 The C-NMR spectrum data were consistent with the structure of pranoprofen, and the sample was consistent with the spectrum of the control.
The small knot:
(1) The measurement results of the sample and the IR, UV, NMR, MS of the reference substance are consistent, and the sample and the reference substance are the same in structure and the same in crystal form, namely the sample is pranoprofen.
(2) High resolution mass spectrum of sample M/z 295.201619 is [ M-H ]] - Peak, corresponding element composition is C 15 H 12 NO 3 The elemental composition of the sample is C 15 H 13 NO 3 Is consistent with the partial structure of organic alkali in the molecule.
(3) UV spectrum shows strong absorption peak at 260-270nm, IR spectrum 1591.9,1521.1cm -1 、804.0cm -1 And 767.8cm -1 The absorption peak at the point of the reaction, 1 absorption peaks at delta 7.30ppm, delta 7.25ppm and delta 6.87ppm of H-NMR spectrum, 13 the absorption peaks at C-NMR spectrum delta 118.14ppm, delta 113.35ppm and delta 109.91ppm indicate the presence of trisubstituted benzene ring structural fragments.
(4) IR spectrum 1706.7cm -1 The absorption peak at the point of the reaction, 13 the absorption peak at delta 175.39ppm of the C-NMR spectrum indicated the presence of carbonyl structural fragments.
In conclusion, the molecular structure of the sample is consistent with that of pranoprofen.
Experimental example 2: stability study
1. Experimental sample
According to the process, three kilogram-scale amplified batches, named 20190101, 20190201 and 20190202 respectively, were prepared under preferred experimental conditions. The three batches of products are prepared in independent batches, the synthesis process is carried out according to the preparation conditions of 1a, 2c, 3c, 4b and 5a, and the three batches of products are prepared by refining and purifying methanol (namely, methanol recrystallization). The purity of the three batches was 99.91%,99.90% and 99.95%, respectively.
2. Experimental method
According to the relevant regulations in the technical guidelines of chemical drug stability study, the three batches of samples are taken and tested for 6 months under the conditions of 40+/-2 ℃ and 75+/-5% RH. And samples were taken at the end of the 0, 1, 2, 3, 6 months during the test to examine the index.
Chromatographic conditions:
the test was performed according to high performance liquid chromatography (China pharmacopoeia 2015 edition general rule 0512). Octadecylsilane chemically bonded silica was used as a filler (5 μm,250 mm. Times.4.6 mm); aqueous solution of sodium perchlorate 0.05 mol/L-methanol= (90:10, pH was adjusted to 3.2) as mobile phase A and methanol as mobile phase B, and the column temperature was 40℃and the detection wavelength was 275nm, according to the following table, the gradient elution was carried out at a flow rate of 1.0 ml/min. The elution procedure is shown in table 10 below.
Table 10: elution procedure
| Time | Mobile phase a | Mobile phase B |
| 0 | 80 | 20 |
| 40 | 55 | 45 |
| 60 | 45 | 55 |
10 μl of the sample solution is precisely measured and injected into the liquid chromatograph. The chromatogram of the sample solution has impurity peaks, the single impurity content is less than 0.1%, and the total impurity content is less than 0.5%.
The detected impurity objects are total impurities, impurity A, impurity C, impurity D, impurity L and the maximum single impurity; the detection conditions are the same as above.
The preparation method of the impurity A comprises the following steps: purified water (140 ml), sodium hydroxide (14.8 g) and dissolved by stirring are added into a 1000ml three-necked flask, then compound III-A (35 g) and absolute methanol (20 ml) are added, the temperature is raised to 45 ℃ for reaction for 2 hours, the temperature is reduced to 20-30 ℃, 70ml of purified water is added for dilution, 105ml of ethyl acetate is used for extracting the reaction liquid, and the water phase is collected. The aqueous phase was adjusted to pH 5-6 with 20% aqueous phosphoric acid to precipitate a white solid, which was stirred for 30 minutes, suction filtered and the filter cake washed with 105ml water. And (5) carrying out forced air drying at 50 ℃ to obtain a target product.
The preparation method of the impurity C comprises the following steps: to a 500ml three-necked flask was added 2-chloronicotinic acid (30 g,0.19 mol), 4-ethylphenol (69.6 g,0.57 mol), anhydrous potassium carbonate (52.5 g,0.38 mol), cuprous iodide (1.8 g,0.01 mol), N, N-dimethylformamide (30 ml), and after reacting for 6 hours at 100℃to 110℃the temperature was cooled to 30℃to 35℃and 120ml of water was added for dilution, and the mixture was transferred to a 2L plastic beaker, pH3 to 4 was adjusted with 30% phosphoric acid, suction filtration, and petroleum ether for washing the cake. Adding the filter cake into 100ml of water, regulating the pH value to 7-8 by saturated sodium bicarbonate aqueous solution, carrying out suction filtration, collecting filtrate, regulating the pH value of the filtrate to 3-4 by 30% phosphoric acid, carrying out suction filtration, and drying the filter cake.
Adding 37g of solid into a 1000ml three-mouth bottle, adding 125g of polyphosphoric acid, heating to 120-130 ℃ for reaction for 4 hours, cooling to 20-30 ℃, adding 600ml of water, carrying out suction filtration, washing a filter cake with 200ml of water, and carrying out forced air drying on the obtained filter cake at 60 ℃ to obtain the target product.
The preparation method of the impurity D comprises the following steps: pranoprofen (15 g), N, N-dimethylformamide (4.5 ml), anhydrous methanol (90 ml) and the system were suspended in a 250ml three-necked flask. A solution of thionyl chloride (8.4 g) in methylene chloride (20 ml) was added dropwise thereto, and the mixture was reacted at 20℃to 30℃for 4 hours. After the reaction, the system was transferred to a 500ml single-necked flask, concentrated under reduced pressure at 55℃in a water bath until no significant fraction was obtained, the concentrate was diluted with 150ml of methylene chloride, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and the mixture was stirred for 10 minutes and allowed to stand for separation. The organic phase was washed with 100ml of a saturated aqueous sodium hydrogencarbonate solution and 100ml of a saturated brine, respectively. Concentrating the organic phase under reduced pressure in a water bath at 45 ℃ until no obvious fraction exists to obtain a white solid, adding 100ml of n-hexane, stirring for 30 minutes, carrying out suction filtration, and carrying out vacuum drying on a filter cake at 40 ℃ to obtain a target product.
The preparation method of the impurity L comprises the following steps: THF (150 ml), compound IV-A (25 g), and acetone (30.7 g) were added to Sup>A 500ml single-port flask and the mixture was stirred to obtain Sup>A colorless solution. Aluminum trichloride (23.5 g) was added in portions to give a pale yellow solution, which was reacted at a constant temperature for 4 hours. Concentrating under pressure at 45deg.C until there is no significant fraction, pouring into 100ml water, and adjusting pH to 2-3 with saturated sodium bicarbonate aqueous solution. DCM100ml x 2 extraction, combining the organic phases, washing with 50ml water, taking the organic phase, concentrating under reduced pressure at 45 ℃ until no significant fraction is present. Column chromatography to obtain the product. The resultant product (25 g), methanol (125 ml), water (12.5 ml) and sodium hydroxide (9.2 g) were reacted with stirring for 1 hour. Transfer to a 500ml beaker, add purified water (300 g), then extract the aqueous phase 4 times with ethyl acetate (90 g) separately, separate the aqueous phase, adjust the pH to about 5.8 with 20% aqueous acetic acid, and gradually precipitate a white powdery solid. Filtering, and sequentially eluting the filter cake by purified water and cold methanol. Vacuum drying at 40 ℃ to obtain the target product.
Preparation of test solution: 50mg of the sample was dissolved in a solvent (acetonitrile-water=1:1) and diluted to 50ml to prepare a sample solution.
Mixing an impurity control stock: weighing 10.0mg of each impurity A, C, D, L, respectively, placing into 10.0ml volumetric flasks, adding methanol for dissolution and dilution to scale, taking 1.0ml to 100.0ml volumetric flasks of each solution, adding solvent for dilution to scale, and taking the solution as an impurity control stock solution.
Mixing an impurity control solution: precisely measuring 1.0ml of the sample solution, and adding a solvent to dilute to 100.0ml; 1.0ml of the above solution was precisely measured, and 1.0ml of the mixed impurity control stock solution was added, and the solvent was added to 10.0ml as the mixed impurity control solution.
Preparation of a System applicability solution: 1.0ml of mixed impurity control stock solution is precisely measured, and the sample solution is added to dilute to 10ml to obtain a system applicability solution.
Preparation of control solution: taking 1.0ml of a sample solution, and adding a solvent to dilute to 10.0ml; 1.0ml of the above solution was diluted to 100.0ml with a solvent to prepare a control solution.
3. Experimental results
The experimental results are shown in table 11 below.
TABLE 11
Remarks: the maximum single impurity generally refers to the maximum unknown single impurity, and known impurities are directly indicated by impurity numbers.
The results show that the three batches of products prepared by the method have stable and reliable quality.
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Numerous modifications and substitutions of details are possible in light of all the teachings disclosed, and such modifications are contemplated as falling within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (56)
1. A process for preparing pranoprofen or a pharmaceutically acceptable salt of pranoprofen comprising the steps of:
(1) taking a compound of a formula A and a compound of a formula B as starting materials, and carrying out an Ullmann condensation reaction in the presence of cuprous iodide to prepare a compound of a formula I;
(2) under the action of acid and iodobenzene diacetic acid, carrying out rearrangement reaction in trimethyl orthoformate to obtain a compound of a formula II;
(3) after halogenating into acyl chloride, intramolecular ring closure is carried out under the action of Lewis acid to obtain a compound of a formula III;
(4) reducing by borohydride to obtain a compound of formula IV;
(5) finally, the pranoprofen is obtained by reduction and alkaline hydrolysis of hydrogen chloride isopropanol and post-treatment acidification;
wherein the structural formulas of the compound of the formula A, the compound of the formula B and the compounds of the formulas I to IV are as follows:
wherein,,
x is halogen;
wherein R is C 2 -C 10 Linear or branched alkyl;
wherein R is C 2 -C 10 Linear or branched alkyl;
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl;
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl;
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl.
2. The method according to claim 1, wherein the halogen is fluorine, chlorine, bromine or iodine.
3. The process of claim 1, wherein in formula B or formula I, R is C 2 -C 6 Linear or branched alkyl.
4. The process of claim 1, wherein in formula B or formula I, R is C 2 -C 4 Linear or branched alkyl.
5. The process of claim 1, wherein in formula B or formula I, R is ethyl, propyl, isopropyl or n-butyl.
6. The process of claim 1, wherein in formula II, formula III or formula IV, the R 1 Is C 1 -C 5 Linear or branched alkyl.
7. The process of claim 1, wherein in formula II, formula III or formula IV, the R 1 Is C 1 -C 3 Linear or branched alkyl.
8. The process of claim 1, wherein in formula II, formula III or formula IV, the R 1 Methyl, ethyl, propyl or isopropyl.
9. A process for preparing pranoprofen comprising the steps of:
(1) Preparing a compound of formula V from a compound of formula IV;
(2) Preparing pranoprofen from a compound of formula V;
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl;
wherein R is 1 Is C 1 -C 10 Linear or branched alkyl;
wherein:
in step (1), reacting a compound of formula IV with a reducing agent selected from one or more of hydrogen chloride isopropanol and hydrochloric acid isopropanol to produce a compound of formula V; the reaction is carried out in an organic solvent which is isopropanol as a reaction solvent;
In step (2), the compound of formula V is reacted with a base selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate to produce pranoprofen.
10. The process of claim 9, wherein in formula IV or formula V, the R 1 Is C 1 -C 5 Linear or branched alkyl.
11. The process of claim 9, wherein in formula IV or formula V, the R 1 Is C 1 -C 3 Linear or branched alkyl.
12. The process of claim 9, wherein in formula IV or formula V, the R 1 Methyl, ethyl, propyl or isopropyl.
13. The process according to any one of claims 1 to 12, wherein the compound of formula IV is methyl 2- (10-hydroxy-9-oxa-1-aza-6-yl) propionate, ethyl 2- (10-hydroxy-9-oxa-1-aza-6-yl) propionate, or propyl 2- (10-hydroxy-9-oxa-1-aza-6-yl) propionate.
14. The process according to claim 9, wherein the molar ratio of the compound of formula IV to the reducing agent is 1: (1.5-3.5).
15. The process according to claim 9, wherein the molar ratio of the compound of formula IV to the reducing agent is 1 (2.5-3.5).
16. The process according to claim 9, wherein the molar ratio of the compound of formula IV to the reducing agent is 1:2.5, 1:3 or 1:3.5.
17. The production process according to claim 9, wherein in the step (1), the reaction temperature is 50 to 90 ℃.
18. The production process according to claim 9, wherein in the step (1), the reaction temperature is 60℃to 80 ℃.
19. The production process according to claim 9, wherein in the step (1), the reaction temperature is 60℃to 70 ℃.
20. The production process according to claim 9, wherein in the step (1), the reaction temperature is 70℃to 80 ℃.
21. The production process according to claim 9, wherein in the step (1), the reaction temperature is 65℃to 75 ℃.
22. The process according to claim 9, wherein in step (1), the reaction time is at least 0.5 hours.
23. The process according to claim 9, wherein in step (1), the reaction time is at least 1 hour.
24. The process according to claim 9, wherein in step (1), the reaction time is at least 1.5 hours.
25. The process according to claim 9, wherein in step (1), the reaction time is at least 2 hours.
26. The production process according to claim 9, wherein in the step (1), the reaction time is 1 to 10 hours.
27. The production process according to claim 9, wherein in the step (1), the reaction time is 2 to 8 hours.
28. The production process according to claim 9, wherein in the step (1), the reaction time is 2 to 6 hours.
29. The production process according to claim 9, wherein in the step (1), the reaction time is 2 to 4 hours.
30. The production process according to claim 9, wherein in the step (1), the reaction time is 2 to 3 hours.
31. The production process according to claim 9, wherein in the step (2), the reaction temperature is 40 to 75 ℃.
32. The production process according to claim 9, wherein in the step (2), the reaction temperature is 40 to 55 ℃.
33. The production process according to claim 9, wherein in the step (2), the reaction temperature is 40 to 50 ℃.
34. The production process according to claim 9, wherein in the step (2), the reaction temperature is 45 to 55 ℃.
35. The production process according to claim 9, wherein in the step (2), the reaction temperature is 40 to 45 ℃ or 50 to 55 ℃.
36. The production process according to claim 9, wherein in the step (2), the reaction temperature is 45 to 50 ℃.
37. The process according to claim 9, wherein in step (2), the reaction time is at least 0.5 hours.
38. The process according to claim 9, wherein in step (2), the reaction time is at least 1 hour.
39. The process according to claim 9, wherein in step (2), the reaction time is at least 1.5 hours.
40. The production process according to claim 9, wherein in the step (2), the reaction time is 0.5 to 10 hours.
41. The production process according to claim 9, wherein in the step (2), the reaction time is 1 to 8 hours.
42. The production process according to claim 9, wherein in the step (2), the reaction time is 1.5 to 6 hours.
43. The production process according to claim 9, wherein in the step (2), the reaction time is 1.5 to 4 hours.
44. The production process according to claim 9, wherein in the step (2), the reaction time is 1.5 to 3 hours.
45. The production process according to claim 9, wherein in the step (2), the reaction time is 1.5 to 2.5 hours.
46. The preparation method according to claim 9, further comprising the steps of:
(3) Pranoprofen is separated from the reaction system.
47. The method of manufacturing of claim 46, wherein step (3) comprises:
adding purified water into the reaction system, and then extracting the water phase with ethyl acetate;
collecting water phase, adjusting pH to 2-7 with acid, and gradually precipitating solid;
Filtering, sequentially eluting a filter cake by using purified water and methanol, and vacuum drying to obtain crude pranoprofen; and
recrystallizing with methanol to obtain refined pranoprofen.
48. The method of claim 47, wherein the acid is a 20% dilute acid solution.
49. The process according to claim 47, wherein the mixture is recrystallized from 8 to 12 times by volume of methanol under reflux.
50. The process according to claim 47, wherein the mixture is recrystallized from 10 times by volume of methanol under reflux.
51. The process according to claim 47, wherein in step (3), the pH is 5 to 7.
52. The process according to claim 47, wherein in step (3), the pH is 5.5 to 6.5.
53. The process according to claim 47, wherein in step (3), the pH is 5.8 to 6.2.
54. The process according to any one of claims 46 to 53, wherein in step (3), the acid is one or more selected from acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid.
55. The process of any one of claims 46 to 53, wherein the step of isolating the compound of formula V is not included.
56. A method of manufacture according to any one of claims 46 to 48, comprising the steps of:
Adding a compound of the formula IV, a reducing agent and isopropanol into a reaction vessel, stirring and heating to 50-90 ℃, carrying out heat preservation reaction for 2-4h, concentrating under reduced pressure at 55 ℃ until the mixture is dried, cooling to room temperature, adding methanol, and then adding alkaline water; or adding alkaline water, cooling to room temperature, and adding methanol; reacting for 2h at 40-75 ℃ with heat preservation;
adding purified water into the reaction solution, extracting the water phase with ethyl acetate, collecting the water phase, adjusting the pH value of the water phase to 2-7 with 20% dilute acid solution, and gradually precipitating solids;
filtering, and sequentially eluting a filter cake by using purified water and methanol;
vacuum drying to obtain crude product, recrystallizing with methanol, and refining to obtain pranoprofen.
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| CN202110710374.2A CN115521320B (en) | 2021-06-25 | 2021-06-25 | Method for preparing pranoprofen |
| KR1020247002884A KR20240025659A (en) | 2021-06-25 | 2022-06-15 | Method for producing planopropene and composition containing planopropene and impurities |
| EP22827441.1A EP4361155A1 (en) | 2021-06-25 | 2022-06-15 | Method for preparing pranoprofen and composition containing pranoprofen and impurity |
| PCT/CN2022/098881 WO2022267945A1 (en) | 2021-06-25 | 2022-06-15 | Method for preparing pranoprofen and composition containing pranoprofen and impurity |
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