CN117263870A - Preparation method of Resmetirom key intermediate III - Google Patents
Preparation method of Resmetirom key intermediate III Download PDFInfo
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- CN117263870A CN117263870A CN202311220522.8A CN202311220522A CN117263870A CN 117263870 A CN117263870 A CN 117263870A CN 202311220522 A CN202311220522 A CN 202311220522A CN 117263870 A CN117263870 A CN 117263870A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 72
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229940121486 resmetirom Drugs 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 320
- 238000000034 method Methods 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims description 135
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 114
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 83
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 75
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 52
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 48
- 238000006460 hydrolysis reaction Methods 0.000 claims description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 239000003960 organic solvent Substances 0.000 claims description 42
- 238000010511 deprotection reaction Methods 0.000 claims description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 32
- 238000002156 mixing Methods 0.000 claims description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 17
- 150000007514 bases Chemical class 0.000 claims description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 16
- 238000006467 substitution reaction Methods 0.000 claims description 16
- 230000002378 acidificating effect Effects 0.000 claims description 15
- 150000001408 amides Chemical class 0.000 claims description 15
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 14
- 239000001632 sodium acetate Substances 0.000 claims description 14
- 235000017281 sodium acetate Nutrition 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 claims description 8
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- SMPAPEKFGLKOIC-UHFFFAOYSA-N oxolane;hydrochloride Chemical compound Cl.C1CCOC1 SMPAPEKFGLKOIC-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims 1
- 239000007787 solid Substances 0.000 abstract description 60
- 239000000543 intermediate Substances 0.000 abstract description 43
- 239000007788 liquid Substances 0.000 abstract description 17
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 abstract description 10
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 abstract description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 abstract description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 abstract description 6
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 229910001961 silver nitrate Inorganic materials 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000002910 solid waste Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- UZNGRHDUJIVHQT-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].C[C-]=C UZNGRHDUJIVHQT-UHFFFAOYSA-M 0.000 abstract description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 66
- 238000005406 washing Methods 0.000 description 43
- 239000000203 mixture Substances 0.000 description 41
- 238000001914 filtration Methods 0.000 description 33
- 239000000047 product Substances 0.000 description 32
- 239000000243 solution Substances 0.000 description 29
- 238000001035 drying Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
- 229960000583 acetic acid Drugs 0.000 description 20
- 239000005457 ice water Substances 0.000 description 20
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 17
- 238000001816 cooling Methods 0.000 description 17
- 239000012043 crude product Substances 0.000 description 16
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000001291 vacuum drying Methods 0.000 description 15
- 239000012295 chemical reaction liquid Substances 0.000 description 14
- 239000012362 glacial acetic acid Substances 0.000 description 14
- 230000001105 regulatory effect Effects 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- 230000005311 nuclear magnetism Effects 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000000643 oven drying Methods 0.000 description 8
- 230000001376 precipitating effect Effects 0.000 description 8
- 239000012265 solid product Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- KGEXISHTCZHGFT-UHFFFAOYSA-N 4-azaniumyl-2,6-dichlorophenolate Chemical compound NC1=CC(Cl)=C(O)C(Cl)=C1 KGEXISHTCZHGFT-UHFFFAOYSA-N 0.000 description 3
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 3
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 229940123876 Thyroid hormone receptor beta agonist Drugs 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
- C07D237/16—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of pharmaceutical intermediates, and provides a preparation method of a Resmetirom key intermediate III. The method utilizes the compound with the structure shown in the formula V and the compound with the structure shown in the formula E to prepare the Resmetiram key intermediate III, has simple preparation steps, is easy to operate, does not need expensive silver nitrate, cesium carbonate, isopropenyl magnesium bromide and lithium chloride, has high product yield, is solid and convenient to purify, has small solid waste and waste liquid amount, has good environmental protection, and finally has stable property and is not easy to oxidize. In conclusion, the method provided by the invention can obviously reduce the production difficulty and the production cost of the Resmetirom key intermediate III, and is more beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical intermediates, in particular to a preparation method of a Resmetirom key intermediate III.
Background
Resmetiram (Chinese name Resimitinol, CAS: 920509-32-6) is a selective thyroid hormone receptor-beta agonist developed by Madrigal Pharmaceuticals and can be used to treat nonalcoholic steatohepatitis, month 2022, the key phase III clinical trial of the original research company Madrigal announced that Resmetiram reaches positive top line results. In 2022, 7 months, resmetirom was applied to the FDA in united states, and after being marketed in batches, resmetirom became the first-marketed non-alcoholic steatohepatitis treatment drug worldwide.
The molecular structure of Resmetirom is shown in formula I:
patent WO2007009913 and CN112707892a disclose a process for preparing resepirom, the first synthetic route being as follows:
according to the synthetic route, the compound D and isobutyric acid are reacted under the action of silver nitrate and ammonium persulfate to generate a compound C, and the yield is 67%; the compound C and 2, 6-dichloro-4-aminophenol undergo substitution reaction to prepare a compound B with a yield of 53%; the compound III is obtained after the hydrolysis of the compound B, and the yield is 50%; the compound III is added with the compound A after diazo reaction and then double bond shift is carried out, and the compound II is generated with 56 percent of yield; and finally, closing the ring of the compound II to obtain the compound I, wherein the yield is 50%.
Patent WO2014043706, CN105008335 discloses another preparation method of Resmetirom, the second synthesis route is as follows:
the synthetic route is that a compound D and 2, 6-dichloro-4-aminophenol are subjected to substitution reaction in the presence of cesium carbonate to prepare a compound VII; reacting the compound VII with benzoic anhydride to obtain an amino-protected compound VI-1c; hydrolyzing the compound VI-1C to obtain a compound V-1C; the total yield of the three steps of reaction is 74%; the compound V-1C and isopropenylmagnesium bromide (3.5 equivalents) are subjected to addition reaction in the presence of lithium chloride (3 equivalents) to give a compound F; the compound F is subjected to alkali hydrolysis and double bond displacement reaction to obtain a compound III with the purity of 87.6%; the compound III is subjected to diazonium reaction, double bond displacement reaction and ring closure reaction to obtain a compound I.
From the above routes, it can be found that the compound III is a key intermediate for synthesizing Resmetirom, however, in the first synthetic route, the yield of each step is lower, silver nitrate is used in the first step, the cost is high, and the compound C is oily and is not easy to purify; cesium carbonate, isopropyl magnesium bromide and lithium chloride used in the second route are high in price, and the use amount of the isopropyl magnesium bromide and the lithium chloride is large, so that a large amount of solid waste and waste liquid are caused, and the environmental protection is not facilitated; finally, both the first and second routes use 2, 6-dichloro-4-aminophenol, which is unstable in chemical nature and easily oxidized, and thus makes purification difficult. Therefore, there is a need to develop a method for preparing Resmetirom key intermediate III with high yield, low cost, easy purification and better environmental protection.
Disclosure of Invention
In view of this, the present invention provides a method for preparing Resmetiraom key intermediate III. The invention utilizes the structural compound shown in the formula V and the structural compound shown in the formula E to prepare the key intermediate III, and has the advantages of simple preparation method, low cost, high yield, easy purification of the intermediate and good environmental protection.
In order to achieve the above object, the present invention provides the following technical solutions:
A preparation method of a Resmetiram key intermediate III comprises the following steps:
providing a compound of the structure shown in formula V:
in formula V: r is R 1 Is H or an amino protecting group, wherein the carbon number of the amino protecting group is 1-10; r is R 2 Is H or
When R in V 1 And R is 2 And when H is the same time, the preparation method of the Resmetiraom key intermediate III comprises the following steps of:
(i) Mixing a compound with a structure shown in a formula V, a compound with a structure shown in a formula E, an alkaline compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a Resmetiram key intermediate III; the structural formula of the Resmetiram key intermediate III is shown in a formula III;
in formula E: r is R 3 is-NO 2 、-SO 2 Ph、-SO 2 Me、-CN、-CF 3 or-CCl 3 ；
When R in V 1 And R is 2 When the two are not H, the preparation method of the Resmetiraom key intermediate III comprises the following steps:
(1) Mixing a compound with a structure shown in a formula V, a compound with a structure shown in a formula E, an alkaline compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a compound with a structure shown in a formula IV;
(2) R in the compound with the structure shown in the formula IV is subjected to deprotection reaction 1 And/or R 2 Radical removal, to give the Resmetiraom key intermediate III.
Preferably, the amino protecting group is t-BuOCO-, phCO-, CH 3 CO-、CF 3 CO-or CCl 3 CO-。
Preferably, in the step (i) and the step (1), the alkaline compound is independently one or more of DBU, 1, 3-tetramethylguanidine, sodium amide, potassium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate, KOH and NaOH; the mol ratio of the compound with the structure shown in the formula V and the alkaline compound is independently 1 (0.5-10);
in the step (i) and the step (1), the molar ratio of the compound with the structure shown in the formula V to the compound with the structure shown in the formula E is independently 1 (1-5);
in the step (i) and the step (1), the temperature of the addition-elimination-double bond shift reaction is independently 0-120 ℃ and the time is independently 1-50 h.
Preferably, when R in formula IV 1 Is t-BuOCO-, R 2 Is H orWhen, or when R in formula IV 1 H, R of a shape of H, R 2 When the acid is not H, the deprotection reaction in the step (2) is an acidic deprotection reaction, and the acid used in the acidic deprotection reaction is selected from hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1, 4-dioxane solution; the temperature of the acidic deprotection reaction is 0-100 ℃.
Preferably, when R in formula IV 1 Is other than H and is other than t-BuOCO-, R 2 In the case of H, the deprotection reaction in the step (2) is alkaline hydrolysis reaction, and alkali used in the alkaline hydrolysis reaction is selected from sodium hydroxide or potassium hydroxide; the mol ratio of the compound with the structure of the formula IV to the alkali is 1 (2-10); the solvent for the alkaline hydrolysis reaction is an organic solvent-water mixed solvent, and the organic solvent in the organic solvent-water mixed solvent is one or more selected from ethanol, methanol, tetrahydrofuran, 1, 4-dioxane and DMSO.
Preferably, when R in formula IV 1 、R 2 Are not H, and R 1 When the acid is not t-BuOCO-, the hydrolysis reaction comprises an acidic deprotection reaction and an alkaline hydrolysis reaction which are sequentially carried out; the acid used in the acidic deprotection reaction is selected from one of hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1, 4-dioxane solution; the acid isThe temperature of the sexual deprotection reaction is 0-100 ℃; the alkali used in the alkaline hydrolysis reaction is selected from sodium hydroxide or potassium hydroxide; the mol ratio of the compound with the structure of the formula IV to the alkali is 1 (2-10); the solvent for the alkaline hydrolysis reaction is an organic solvent-water mixed solvent, and the organic solvent in the organic solvent-water mixed solvent is one or more selected from ethanol, methanol, tetrahydrofuran, 1, 4-dioxane and DMSO.
Preferably, when R in formula V 1 Is not H, R 2 In the case of H, the preparation method of the compound with the structure shown in the formula V comprises the following steps:
mixing a compound with a structure shown in a formula D, a compound with a structure shown in a formula G, a first alkaline compound and an organic solvent for substitution reaction to obtain a compound with a structure shown in a formula VI;
in formula G and formula VI, R 1 The kind of the groups is the same as that in the formula V;
mixing the compound with the structure shown in the formula VI, acetic acid and sodium acetate to carry out substitution-hydrolysis reaction to obtain a compound with the structure shown in the formula V, wherein the structural formula is shown in the formula V-1;
When R in V 1 Is not H, R 2 When the compound is not H, the preparation method of the compound with the structure shown in the formula V comprises the following steps:
mixing a compound with a structure shown in a formula V-1, 3, 4-dihydro-2H-pyrane, acid and an organic solvent for carrying out an amide protection reaction to obtain the compound with the structure shown in the formula V, wherein the structural formula is shown in a formula V-2;
when VR in (B) 1 Is H, R 2 In the case of H, the preparation method of the compound with the structure shown in the formula V comprises the following steps:
mixing a compound with a structure shown in a formula V-1, a second alkaline compound, an organic solvent and water to perform a first hydrolysis reaction to obtain the compound with the structure shown in the formula V, wherein the structural formula is shown in a formula V-3;
in formula V-1: r is R 1 Is PhCO-, CF 3 CO-、CCl 3 CO-or CH 3 CO-；
When R in V 1 Is H, R 2 When the compound is not H, the preparation method of the compound with the structure shown in the formula V comprises the following steps:
mixing a compound with a structure shown in a formula V-2, a third alkaline compound, an organic solvent and water to perform a second hydrolysis reaction to obtain the compound with the structure shown in the formula V, wherein the structural formula is shown in a formula V-4;
in formula V-2: r is R 1 Is PhCO-, CF 3 CO-、CCl 3 CO-or CH 3 CO-。
Preferably, the molar ratio of the compound of the structure shown in the formula D to the compound of the structure shown in the formula G is 1 (1-2);
The first alkaline compound is one or more of alkali metal carbonate, alkali metal hydroxide and organic alkali; the mol ratio of the compound with the structure shown in the formula D to the first alkaline compound is 1 (1-3);
the organic solvent adopted in the substitution reaction is one or more of DMF, DMAc, DMSO, NMP, acetonitrile and 1, 4-dioxane; the temperature of the substitution reaction is 40-120 ℃ and the time is 5-50 h;
the mol ratio of the compound with the structure shown in the formula VI to the sodium acetate is 1 (1-5); the mol ratio of the compound with the structure shown in the formula VI to acetic acid is 1 (10-50);
the temperature of the substitution-hydrolysis reaction is 60-150 ℃ and the time is 2-20 h.
Preferably, in the amide protection reaction, the molar ratio of the compound of the structure shown in the formula V-1 to the acid is 1 (0.05-0.5), and the molar ratio of the compound of the structure shown in the formula V-1 to the 3, 4-dihydro-2H-pyran is 1 (1-4);
the organic solvent adopted in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone and 1, 4-dioxane;
the temperature of the amide protection reaction is 30-80 ℃ and the time is 1-10 h.
Preferably, in the first hydrolysis reaction, the molar ratio of the compound having the structure represented by the formula V-1 to the second basic compound is 1 (2 to 6); the second basic compound is an alkali metal hydroxide;
The solvent used in the first hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran and DMSO;
the temperature of the first hydrolysis reaction is 50-120 ℃ and the time is 1-10 h;
in the second hydrolysis reaction, the mol ratio of the compound with the structure shown in the formula V-2 to the third alkaline compound is 1 (2-6); the third alkaline compound is an alkali metal hydroxide;
the solvent used in the second hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran and DMSO;
the temperature of the second hydrolysis reaction is 50-120 ℃ and the time is 1-10 h.
The invention provides a preparation method of a Resmetiram key intermediate III, wherein R is shown in a formula V 1 And R is 2 When the groups are H, mixing a compound with a structure shown in a formula V, a compound with a structure shown in a formula E, an alkaline compound and an organic solvent to perform addition-elimination-double bond shift reaction, so as to directly obtain a Resmetirom key intermediate III; when R in V 1 And R is 2 When the groups are not simultaneously H,mixing a compound with a structure shown in a formula V, a compound with a structure shown in a formula E, a basic compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a compound with a structure shown in a formula IV, and removing R through deprotection reaction 1 And/or R 2 The group can obtain the key intermediate III. The preparation method of the key intermediate III provided by the invention has the advantages of simple steps, easy operation, no need of using expensive silver nitrate, cesium carbonate, isopropyl magnesium bromide and lithium chloride reagents, high product yield, solid intermediate products, convenient purification, and small solid waste and waste liquid amount, and is beneficial to environmental protection. Further, the compound of the structure represented by formula G used in the present invention is stable in physical properties and hardly oxidized. In conclusion, the method provided by the invention can obviously reduce the production difficulty and the production cost of the key intermediate III, and is more beneficial to industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of Resmetiraom key intermediate III prepared in example 20 of the present invention.
Detailed Description
The invention provides a preparation method of a Resmetiram key intermediate III, which comprises the following steps:
providing a compound of the structure shown in formula V:
in formula V: r is R 1 Is H or an amino protecting group, wherein the carbon number of the amino protecting group is 1-10; r is R 2 Is H or
When R in V 1 And R is 2 And when H is the same time, the preparation method of the Resmetiraom key intermediate III comprises the following steps of:
(i) Mixing a compound with a structure shown in a formula V, a compound with a structure shown in a formula E, an alkaline compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a Resmetiram key intermediate III; the structural formula of the Resmetiram key intermediate III is shown in a formula III;
in formula E: r is R 3 is-NO 2 、-SO 2 Ph、-SO 2 Me、-CN、-CF 3 or-CCl 3 ；
When R in V 1 And R is 2 When the two are not H, the preparation method of the Resmetiraom key intermediate III comprises the following steps:
(1) Mixing a compound with a structure shown in a formula V, a compound with a structure shown in a formula E, an alkaline compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a compound with a structure shown in a formula IV;
(2) R in the compound with the structure shown in the formula IV is subjected to deprotection reaction 1 And/or R 2 Radical removal, to give the Resmetiraom key intermediate III.
The present invention provides a compound of the structure of formula V wherein R in formula V 1 When the amino protecting group is an amino protecting group, the carbon number of the amino protecting group is preferably 2 to 8, and specifically, the amino protecting group is t-BuOCO-, phCO-, CH 3 CO-、CF 3 CO-or CCl 3 CO-。
In the present invention, when R in formula V 1 Is not H, R 2 In the case of H, the preparation method of the Resmetiram intermediate preferably comprises the following steps:
Mixing a compound with a structure shown in a formula D, a compound with a structure shown in a formula G, a first alkaline compound and an organic solvent for substitution reaction to obtain a compound with a structure shown in a formula VI;
in formula G and formula VI, R 1 The kind of the groups is the same as that in the formula V;
mixing the compound with the structure shown in the formula VI, acetic acid and sodium acetate to carry out substitution-hydrolysis reaction to obtain a compound with the structure shown in the formula V, wherein the structural formula is shown in the formula V-1;
when R is 1 Is not H, R 2 In the case of H, the synthetic route for the compound of formula V is as follows:
the invention mixes the compound with the structure shown in the formula D, the compound with the structure shown in the formula G, the first alkaline compound and the organic solvent for substitution reaction to obtain the compound with the structure shown in the formula VI. In the present invention, the molar ratio of the compound of the structure represented by the formula D to the compound of the structure represented by the formula G is preferably 1 (1-2), more preferably 1 (1-1.3); the first basic compound is preferably one or more of an alkali metal carbonate, an alkali metal hydroxide and an organic base; the alkali metal carbonate is preferably one or more of potassium carbonate, sodium carbonate and cesium carbonate; the alkali metal hydroxide is preferably potassium hydroxide and/or sodium hydroxide; the organic base is preferably one or more of sodium methoxide, sodium ethoxide and potassium tert-butoxide; in a specific embodiment of the present invention, the first basic compound is most preferably potassium carbonate; the molar ratio of the compound of the structure represented by the formula D to the first basic compound is preferably 1 (1-3), more preferably 1 (1-2); the organic solvent used in the substitution reaction is preferably one or more of DMF, DMAc, DMSO, NMP (N-methylpyrrolidone), acetonitrile and 1, 4-dioxane, more preferably DMF.
In the present invention, the temperature of the substitution reaction is preferably 40 to 120 ℃, more preferably 50 to 90 ℃, and the time of the substitution reaction is preferably 5 to 50 hours, more preferably 10 to 40 hours.
After the substitution reaction is finished, the obtained substitution reaction liquid is preferably subjected to post-treatment, and the post-treatment method preferably comprises the following steps: mixing the obtained substitution reaction liquid with water, regulating the pH value of the mixed liquid to 11, stirring at room temperature, filtering, washing a solid product with water, and drying to obtain a compound with a structure shown in a formula VI; the reagent used for adjusting the pH value of the mixed solution is preferably liquid alkali; the stirring time at room temperature is preferably 30min.
After the compound with the structure shown in the formula VI is obtained, the compound with the structure shown in the formula VI, acetic acid and sodium acetate are mixed for substitution-hydrolysis reaction to obtain the compound with the structure shown in the formula V, wherein the structural formula is shown in the formula V-1. In the present invention, the molar ratio of the compound of the structure represented by formula VI to sodium acetate is preferably 1 (1 to 5), more preferably 1 (1.5 to 3); the molar ratio of the compound with the structure shown in the formula VI to the acetic acid is preferably 1 (10-50), more preferably 1 (15-30); the acetic acid is preferably glacial acetic acid; the temperature of the substitution-hydrolysis reaction is preferably 60 to 150 ℃, more preferably 90 to 120 ℃, and the time of the substitution-hydrolysis reaction is preferably 2 to 20 hours, more preferably 5 to 15 hours.
After the substitution-hydrolysis reaction is finished, the present invention preferably subjects the obtained substitution-hydrolysis reaction liquid to a post-treatment, which comprises: spin-evaporating the obtained substitution-hydrolysis reaction liquid to dryness under reduced pressure, mixing the remainder with water, stirring at room temperature, filtering, washing the obtained solid product with water, and drying to obtain a compound with a structure shown in formula V (formula V-1); the stirring time at room temperature is preferably 2 hours.
In the present invention, when R in formula V 1 Is not H, R 2 When the compound is not H, the preparation method of the Resmetiraom intermediate shown in the formula V preferably comprises the following steps:
mixing a compound with a structure shown in a formula V-1, 3, 4-dihydro-2H-pyrane, acid and an organic solvent for amide protection reaction to obtain a compound with a structure shown in a formula V, wherein the structural formula is shown in a formula V-2;
when R is 1 Is not H, R 2 When the compound is not H, the synthetic route of the compound with the structure shown in the formula V is as follows:
in the present invention, the preparation method of the compound with the structure shown in the formula V-1 is consistent with the scheme, and is not repeated here; the acid is preferably an organic acid, more preferably one or more of p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid, more preferably p-toluenesulfonic acid; the molar ratio of the compound of the structure represented by the formula V-1 to the acid is preferably 1 (0.05 to 0.5), more preferably 1 (0.05 to 0.3); the molar ratio of the compound of the structure represented by the formula V-1 to 3, 4-dihydro-2H-pyran is preferably 1 (1-4), more preferably 1 (1-2); the organic solvent used in the amide protection reaction is preferably one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone and 1, 4-dioxane, and more preferably tetrahydrofuran; the temperature of the amide protection reaction is preferably 30 to 80 ℃, more preferably 40 to 70 ℃, and the time of the amide protection reaction is preferably 1 to 10 hours, more preferably 3 to 8 hours.
After the completion of the amide protection reaction, the present invention preferably subjects the resulting amide protection reaction liquid to a post-treatment, and the post-treatment method preferably includes: cooling the obtained amide protection reaction liquid to room temperature, mixing with water, regulating the pH value of the obtained mixed liquid to 9, stirring at room temperature, then screwing off an organic solvent, filtering the residual liquid, washing the obtained solid product, and drying to obtain a compound with a structure shown in a formula V (formula V-2); the reagent used for adjusting the pH value of the mixed solution is preferably potassium carbonate; the stirring time at room temperature is preferably 30min; the washing reagent is preferably a mixed solvent of ethyl acetate and heptane, and the volume ratio of the ethyl acetate to the heptane in the mixed solvent is preferably 1:2.
In the present invention, when R in formula V 1 Is H, R 2 In the case of H, the preparation method of the Resmetiraom intermediate shown in the formula V preferably comprises the following steps:
mixing a compound with a structure shown in a formula V-1, a second alkaline compound, an organic solvent and water to perform a first hydrolysis reaction to obtain a compound with a structure shown in a formula V, wherein the structural formula is shown in a formula V-3;
in formula V-1: r is R 1 Is PhCO-, CF 3 CO-、CCl 3 CO-or CH 3 CO-。
When R is 1 Is H, R 2 In the case of H, the synthetic route for the compound of formula V is as follows:
In the present invention, the specific preparation method of the compound with the structure shown in the formula V-1 is the same as the scheme described above, and is not repeated here;
in the present invention, the second alkaline compound is preferably an alkali metal hydroxide, preferably potassium hydroxide and/or sodium hydroxide; the molar ratio of the compound of the structure represented by the formula V-1 to the second basic compound is preferably 1 (2 to 6), more preferably 1 (2.5 to 4); the solvent used in the first hydrolysis reaction is preferably one or more of ethanol, methanol, tetrahydrofuran and DMSO, more preferably ethanol or methanol; the volume ratio of the organic solvent to the water is preferably (1-4): 1; the temperature of the first hydrolysis reaction is preferably 50 to 120 ℃, more preferably 60 to 100 ℃, and the time of the first hydrolysis reaction is preferably 1 to 10 hours, more preferably 3 to 8 hours.
After the first hydrolysis reaction is finished, the obtained first hydrolysis reaction liquid is preferably subjected to post-treatment, and the post-treatment preferably comprises the following steps: the obtained first hydrolysis reaction liquid is cooled to room temperature, then the pH value is regulated to 6 by acid salt, the organic solvent is removed by screwing, the residual liquid is filtered, and the obtained solid product is washed by water and then dried, so as to obtain the compound (formula V-3) with the structure shown in the formula V.
In the present invention, when R in formula V 1 Is H, R 2 When the compound is not H, the preparation method of the Resmetiraom intermediate shown in the formula V preferably comprises the following steps:
mixing a compound with a structure shown in a formula V-2, a third alkaline compound, an organic solvent and water to perform a second hydrolysis reaction to obtain the compound with the structure shown in the formula V, wherein the structural formula is shown in a formula V-4;
in formula V-2: r is R 1 Is PhCO-, CF 3 CO-、CCl 3 CO-or CH 3 CO-。
When R is 1 Is H, R 2 When the compound is not H, the synthetic route of the compound with the structure shown in the formula V is as follows:
in the present invention, the preparation method of the compound with the structure shown in the formula V-2 is the same as that of the above scheme, and will not be described herein.
In the present invention, the third basic compound is preferably an alkali metal hydroxide, preferably potassium hydroxide and/or sodium hydroxide; the molar ratio of the compound of the structure represented by the formula V-2 to the third basic compound is preferably 1 (2 to 6), more preferably 1 (2.5 to 4); the solvent used in the second hydrolysis reaction is preferably one or more of ethanol, methanol, tetrahydrofuran and DMSO, more preferably ethanol or methanol; the volume ratio of the organic solvent to the water is preferably (1-4): 1; the temperature of the second hydrolysis reaction is preferably 50 to 120 ℃, more preferably 60 to 100 ℃, and the time of the second hydrolysis reaction is preferably 1 to 10 hours, more preferably 3 to 8 hours.
After the second hydrolysis reaction is finished, the obtained second hydrolysis reaction liquid is preferably subjected to post-treatment, and the post-treatment preferably comprises the following steps: and cooling the obtained second hydrolysis reaction liquid to room temperature, regulating the pH value to 6 by using acid salts, screwing off most of organic solvents, filtering the residual liquid, and washing the obtained solid product with water to obtain the compound (formula V-4) with the structure shown in the formula V.
In the present invention, when Resmetiraom key intermediate III is prepared using a compound having a structure represented by formula V, R is according to formula V 1 And R is 2 Whether H is the same time, the invention provides two preparation methods, and the two preparation methods are described in detail below.
In the present invention, when R in formula V 1 And R is 2 And when H is the same time, the preparation method of the Resmetiraom key intermediate III comprises the following steps of:
mixing a compound with a structure shown in a formula V (namely a formula V-3), a compound with a structure shown in a formula E (marked as a fourth basic compound) and an organic solvent to perform addition-elimination-double bond shift reaction (marked as a first addition-elimination-double bond shift reaction) so as to obtain a Resmetiram key intermediate III; the structural formula of the Resmetiram key intermediate III is shown in a formula III;
in formula E: r is R 3 is-NO 2 、-SO 2 Ph、-SO 2 Me、-CN、-CF 3 or-CCl 3 。
When R in V 1 And R is 2 And when H is the same time, the synthesis route of the Resmetiraom key intermediate III is as follows:
in the present invention, the fourth basic compound is preferably one or more of DBU, 1, 3-tetramethylguanidine, sodium amide, potassium t-butoxide, sodium hydride, potassium carbonate, sodium carbonate, KOH, naOH, more preferably DBU or sodium amide; the molar ratio of the compound of the structure represented by formula V to the fourth basic compound is preferably 1 (0.5 to 10), more preferably 1 (1 to 5); the molar ratio of the compound of the structure shown in the formula V (namely the formula V-3) to the compound of the structure shown in the formula E is preferably 1 (1-5), more preferably 1 (1.1-3); the organic solvent used in the addition-elimination-double bond shift reaction is preferably one of DMSO, sulfolane, DMF, DMAc, N-methylpyrrolidone, tetrahydrofuran and 1, 4-dioxane, more preferably DMSO; the temperature of the first addition-elimination-double bond shift reaction is preferably 0 to 120 ℃, more preferably 20 to 80 ℃, and the time is preferably 1 to 50 hours, more preferably 5 to 30 hours.
After the first addition-elimination-double bond shift reaction is finished, the invention preferably carries out post-treatment on the obtained first addition-elimination-double bond shift product feed liquid, and the post-treatment preferably comprises the following steps: mixing the obtained first addition-elimination-double bond shift reaction liquid with water, adjusting the pH value of the obtained mixed liquid to 6 by using hydrochloric acid, filtering, and recrystallizing the obtained solid product to obtain a key intermediate III. The solvent for recrystallization is preferably a mixed solvent of acetonitrile and isopropyl ether, and the volume ratio of acetonitrile to isopropyl ether in the mixed solvent is preferably (2-20): 1.
In the present invention, when R in formula V 1 And R is 2 When the two are not H, the preparation method of the Resmetiraom key intermediate III comprises the following steps:
(1) Mixing a compound with a structure shown in a formula V, a compound with a structure shown in a formula E, a basic compound and an organic solvent to perform addition-elimination-double bond shift reaction (marked as second addition-elimination-double bond shift reaction) to obtain a compound with a structure shown in a formula IV;
(2) R in the compound with the structure shown in the formula IV is subjected to deprotection reaction 1 And/or R 2 Radical removal, to give the Resmetiraom key intermediate III.
In the present invention, the steps are as follows(1) The specific conditions for the second addition-elimination-double bond shift reaction are identical to those for the first addition-elimination-double bond shift reaction described in the above scheme, and only the compound of the structure represented by formula V-3 is correspondingly replaced with R 1 And R is 2 The compound of the structure shown in the formula V which is not H at the same time can be obtained, other operation conditions are the same, the type and the dosage of the alkaline compound are the same as those of the fourth alkaline compound, and the description is omitted here.
After the second addition-elimination-double bond shift reaction is completed, the post-treatment method of the obtained second addition-elimination-double bond shift reaction liquid is the same as the post-treatment method of the first addition-elimination-double bond shift reaction liquid, and the compound with the structure shown in the formula IV is obtained.
After obtaining the compound with the structure shown in the formula IV, the invention is based on R 1 And R is 2 And (3) removing protecting groups by selecting acid deprotection reaction and/or alkaline hydrolysis reaction to obtain a Resmetirom key intermediate III. The following is a detailed description.
In the present invention, when R in formula IV 1 Is t-BuOCO-, R 2 Is H orWhen, or when R in formula IV 1 H, R of a shape of H, R 2 When it is not H (denoted as case one), the deprotection reaction in step (2) is preferably an acidic deprotection reaction; the acid used in the acid deprotection reaction is selected from hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1, 4-dioxane solution; in the hydrogen chloride diethyl ether solution, the hydrogen chloride tetrahydrofuran solution or the hydrogen chloride 1, 4-dioxane solution, the mass fraction of the hydrogen chloride is independently preferably 10-50%; the dosage ratio of the compound with the structure shown in the formula IV to the acid is preferably 1g (2-20) mL; the temperature of the acid deprotection reaction is preferably 0 to 100 ℃, more preferably 20 to 80 ℃, and the time of the acid deprotection reaction is preferably 1 to 10 hours.
In the invention, after the acidic deprotection reaction is finished, the obtained reaction solution is preferably spin-dried, the residual solid product is washed by sodium bicarbonate solution and dried in vacuum to obtain a crude product, and the obtained crude product is recrystallized to obtain the Resmetirom key intermediate III; the solvent for recrystallization is preferably a mixed solvent of acetonitrile and isopropyl ether, and the volume ratio of acetonitrile to isopropyl ether in the mixed solvent is preferably (2-20): 1.
In the present invention, when R in formula IV 1 Is other than H and is other than t-BuOCO-, R 2 In the case of H (denoted as case two), the deprotection reaction in the step (2) is an alkaline hydrolysis reaction using a base selected from sodium hydroxide or potassium hydroxide; the molar ratio of the compound of the structure of the formula IV to the base is preferably 1 (2-10), more preferably 1 (3-8); the solvent for the alkaline hydrolysis reaction is preferably an organic solvent-water mixed solvent, wherein the organic solvent in the organic solvent-water mixed solvent is one or more selected from ethanol, methanol, tetrahydrofuran, 1, 4-dioxane and DMSO, and more preferably ethanol or methanol; the volume ratio of the organic solvent to water in the organic solvent-water mixed solvent is preferably (1-4): 1; the temperature of the alkaline hydrolysis reaction is preferably 30 to 130 ℃, more preferably 50 to 110 ℃, and the time of the alkaline hydrolysis reaction is preferably 2 to 20 hours.
In the invention, after the alkaline hydrolysis reaction is finished, the obtained reaction liquid is cooled to room temperature, the organic solvent is preferably removed, ice water is then added, the pH value is regulated to 6 by hydrochloric acid to precipitate a product, the obtained solid product is filtered, then water washing and drying are carried out to obtain a crude product, and the crude product is recrystallized to obtain the Resmetirom key intermediate III; the solvent for recrystallization is the same as the above-described scheme and will not be described in detail here.
In the present invention, when R in formula IV 1 、R 2 Are not H, and R 1 When the catalyst is not t-BuOCO-, the hydrolysis reaction comprises acidic deprotection reaction and alkaline hydrolysis reaction which are sequentially carried out (marked as a third case); the conditions of the acid deprotection reaction in the third case are identical to those in the first case, and are not described in detail herein; the conditions of the alkaline hydrolysis reaction in the third case are consistent with those in the second case, and are not described in detail herein; in the specific embodiment of the invention, after the acidic deprotection reaction is finished, the reaction solution is preferably spin-dried, and then an alkaline hydrolysis reagent is added for alkaline hydrolysis reaction; alkaline hydrolysis reactionThe post-processing method is consistent with the second case, and will not be described in detail here.
The following description of the embodiments of the present invention will clearly and fully describe the technical solutions of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
EXAMPLE 1 preparation of Compounds of formula V-1a
Method 1: 14.9G (100 mmol) of compound D, 26.4G of structural compound G-1 of structural formula (120 mmol), 20.7G of potassium carbonate powder (150 mmol) and 200mL of DMF are added into a reaction bottle, the mixture is heated to 65 ℃ and stirred for reaction for 24 hours, the mixture is poured into 1000mL of water, pH is adjusted to 11 by liquid alkali, stirring is carried out at room temperature for 30min, filtering, washing by 100mL of water and drying are carried out, thus obtaining compound VI-1a; to the resulting product, 120mL of glacial acetic acid and 16.4g of sodium acetate (200 mmol) were added, the temperature was raised to 110℃for reaction for 5 hours, glacial acetic acid was turned off, 150mL of water was added, stirring was carried out at room temperature for 2 hours, filtration, washing with 50mL of water, and drying to give 29.2g of compound V-1a as an off-white solid in 93% yield.
Method 2: 14.9G (100 mmol) of compound D, 24.2G of compound (110 mmol) shown in the structural formula G-1, 21.2G of sodium carbonate powder (200 mmol) and 200mL of DMSO are added into a reaction bottle, the temperature is raised to 75 ℃ and stirred for reaction for 16 hours, the mixture is poured into 1000mL of water, the pH of the mixture is adjusted to 11 by liquid alkali, the mixture is stirred at room temperature for 30min, the mixture is filtered, and the mixture is washed by 100mL of water and dried to obtain a compound VI-1a; to the resulting product, 100mL of glacial acetic acid and 12.3g of sodium acetate (150 mmol) were added, the temperature was raised to 100℃for reaction for 8 hours, the glacial acetic acid was turned off, 150mL of water was added, stirring was carried out at room temperature for 2 hours, filtration, washing with 50mL of water and drying were carried out to obtain 28.3g of an off-white solid compound V-1a in 90% yield.
The nuclear magnetic data of the compound V-1a obtained in the method 1 are as follows: 1 H-NMR(400M，DMSO-d 6 )：12.27(1H，s)，10.30(1H，s)，7.77(2H，s)，7.58(1H，d)，7.07(1H，d)，2.07(3H，s)。
EXAMPLE 2 preparation of Compounds of formula V-1b
14.9G (100 mmol) of compound D, 30.6G of compound (110 mmol) shown in the structural formula G-2, 42.4G of cesium carbonate powder (130 mmol) and 200mL of DMAc are added into a reaction bottle, the temperature is raised to 65 ℃ and stirred for reaction for 24 hours, the mixture is poured into 1000mL of water, the pH of the mixture is adjusted to 11 by liquid alkali, the mixture is stirred for 30 minutes at room temperature, the mixture is filtered, and the mixture is washed by 100mL of water and dried to obtain a compound VI-1b; to the resulting product, 120mL of glacial acetic acid and 16.4g of sodium acetate (200 mmol) were added, the temperature was raised to 110℃for reaction for 5 hours, glacial acetic acid was turned off, 150mL of water was added, stirring was carried out at room temperature for 2 hours, filtration, washing with 50mL of water, and drying to give 30.9g of compound V-1b as an off-white solid in 83% yield. 1 H-NMR(400M，DMSO-d 6 )：12.23(1H，s)，10.09(1H，s)，7.75(2H，s)，7.57(1H，d)，7.01(1H，d)，1.28(9H，s)。
EXAMPLE 3 preparation of Compounds of formula V-1c
14.9G (100 mmol) of compound D, 31.0G of compound (110 mmol) with the structure shown in the formula G-3, 15.7G of potassium tert-butoxide powder (140 mmol) and 200mL of DMF are added into a reaction bottle, the temperature is raised to 65 ℃ and stirred for reaction for 24 hours, the mixture is poured into 1000mL of water, the pH of the mixture is adjusted to 11 by liquid alkali, the mixture is stirred for 30 minutes at room temperature, the mixture is filtered, and the mixture is washed by 100mL of water and dried to obtain a compound VI-1c; to the resulting product, 120mL of glacial acetic acid and 13.1g of sodium acetate (160 mmol) were added, the temperature was raised to 105℃for 8 hours, the glacial acetic acid was turned off, 150mL of water was added, stirring was carried out at room temperature for 2 hours, filtration was carried out, 50mL of water was washed once, and drying was carried out, to obtain 32.7g of an off-white solid compound V-1c in 87% yield. 1 H-NMR(400M，DMSO-d 6 )：12.25(1H，s)，10.26(1H，s)，7.98(2H，m)，7.76(2H，s)，7.63(1H，m)，7.58(1H，d)，7.47(2H，m)，7.05(1H，d)。
EXAMPLE 4 preparation of Compounds of formula V-1d
14.9G (100 mmol) of compound D, 30.1G of compound (110 mmol) with the structure shown in the formula G-4, 20.7G of potassium carbonate powder (150 mmol) and 200mL of DMF are added into a reaction bottle, the temperature is raised to 65 ℃ and stirred for reaction for 24 hours, the mixture is poured into 1000mL of water, the pH of the mixture is adjusted to 11 by liquid alkali, the mixture is stirred for 30 minutes at room temperature, the mixture is filtered, and the mixture is washed by 100mL of water and dried to obtain a compound VI-1D; to the resulting product, 120mL of glacial acetic acid and 13.1g of sodium acetate (160 mmol) were added, the temperature was raised to 105℃for reaction for 8 hours, glacial acetic acid was turned off, 150mL of water was added, stirring was carried out at room temperature for 2 hours, filtration, washing with 50mL of water and drying gave 33.9g of compound V-1d as an off-white solid in 92% yield. 1 H-NMR(400M，DMSO-d 6 )：12.27(1H，s)，10.54(1H，s)，7.85(2H，s)，7.58(1H，d)，7.05(1H，d)。
EXAMPLE 5 preparation of Compounds of formula V-1e
14.9G (100 mmol) of compound D, 34.0G (105 mmol) of compound G-5, 22.1G of potassium carbonate powder (160 mmol) and 200ml of DMAc are added into a reaction bottle, the temperature is raised to 80 ℃ and stirred for reaction for 12 hours, the mixture is poured into 1000ml of water, pH is adjusted to 11 by liquid alkali, the mixture is stirred at room temperature for 30min, and the mixture is filtered and washed by 100ml of water to obtain a compound VI-1e; to the resulting product, 10.7g (130 mmol) of sodium acetate and 80ml of glacial acetic acid were added, the temperature was raised to 100℃for reaction for 8 hours, the glacial acetic acid was turned off, 100ml of water was added, stirring was carried out for 10 minutes, filtration was carried out, 50ml of water was washed, and 38.4g of off-white solid compound V-1e was obtained by drying, with a yield of 92%. 1 H-NMR(400M，DMSO-d 6 )：12.26(1H，s)，10.45(1H，s)，7.83(2H，s)，7.58(1H，d)，7.05(1H，d)。
EXAMPLE 6 preparation of Compounds of formula V-2a
Method 1: 9.42g (30 mmol) of compound V-1a, 3.78g (45 mmol) of 3, 4-dihydro-2H-pyran, 0.52g (3.0 mmol) of p-toluenesulfonic acid and 100mL of tetrahydrofuran were charged into the reaction flask, and the mixture was heated to 60℃for reaction for 5 hours; cooling to room temperature, adding 100mL of water, adjusting the pH to 9 with potassium carbonate, and stirring at room temperature for 30min; the tetrahydrofuran was spun off and a large amount of solids precipitated, filtered, 50mL ethyl acetate: heptane=1:2 solvent washing, oven drying, to give 11.8g of compound V-2a as an off-white solid in 99% yield.
Method 2: 9.42g (30 mmol) of compound V-1a, 5.04g (60 mmol) of 3, 4-dihydro-2H-pyran, 0.77g (8.0 mmol) of methanesulfonic acid and 100mL of acetonitrile were charged into a reaction flask, and the mixture was heated to 70℃to react for 3 hours; cooling to room temperature, adding 100mL of water, adjusting the pH to 9 with potassium carbonate, and stirring at room temperature for 30min; the acetonitrile was spun off, a large amount of solids precipitated, filtered, 50mL ethyl acetate: heptane=1:2 solvent washing, oven drying, gave 11.6g of compound V-2a as an off-white solid in 97% yield.
The nuclear magnetic data of the compound V-2a obtained in the method 1 are as follows: 1 H-NMR(400M，DMSO-d 6 )：10.31(1H，brs)，7.80(2H，s)，7.60(1H，d)，7.17(1H，d)，5.69(1H，dd)，3.79(1H，d)，3.49(1H，t)，2.08(3H，s)，1.49-1.22(6H，m)。
EXAMPLE 7 preparation of Compounds of formula V-2b
11.17g (30 mmol) of compound V-1b, 3.78g (45 mmol) of 3, 4-dihydro-2H-pyran, 0.46g (4.0 mmol) of trifluoroacetic acid and 100mL of ethyl acetate were charged into the reaction flask, and the mixture was heated to 60℃for reaction for 5 hours; cooling to room temperature, adding 100mL of water, adjusting the pH to 9 with potassium carbonate, and stirring at room temperature for 30min; the ethyl acetate was spun off and a large amount of solid precipitated, filtered, 50mL ethyl acetate: heptane=1:2 solvent washing, oven drying, to give 11.6g of compound V-2b as an off-white solid in 85% yield.
1 H-NMR(400M，DMSO-d 6 )：10.09(1h，brs)，7.71(2H，s)，7.55(1H，d)，7.13(1H，d)，5.65(1H，dd)，3.74(1H，m)，3.53(1H，m)，1.58-1.26(15H，m)。
EXAMPLE 8 preparation of Compounds of formula V-2c
11.3g (30 mmol) of compound V-1c, 5.04g (60 mmol) of 3, 4-dihydro-2H-pyran, 1.04g (6.0 mmol) of p-toluenesulfonic acid and 100mL of tetrahydrofuran were charged into a reaction flask, and reacted at 60℃for 5 hours; cooling to room temperature, adding 100mL of water, adjusting the pH to 9 with potassium carbonate, and stirring at room temperature for 30min; the tetrahydrofuran was spun off and a large amount of solids precipitated, filtered, 50mL ethyl acetate: heptane=1:2 solvent washing, oven drying, to give 13.5g of compound V-2c as an off-white solid in 98% yield. 1 H-NMR(400M，DMSO-d 6 )：10.21(1h，brs)，7.98(2H，m)，7.80(2H，s)，7.63(1H，m)，7.56-7.47(3H，m)，7.15(1H，d)，5.65(1H，dd)，3.76(1H，m)，3.53(1H，m)，1.59-1.28(6H，m)。
EXAMPLE 9 preparation of Compounds of formula V-2d
11.0g (30 mmol) of compound V-1d, 5.04g (60 mmol) of 3, 4-dihydro-2H-pyran, 1.39g (8.0 mmol) of p-toluenesulfonic acid and 100mL of acetone were charged into the reaction flask, and the mixture was heated to 60℃for reaction for 5 hours; cooling to room temperature, adding 100mL of water, adjusting the pH to 9 with potassium carbonate, and stirring at room temperature for 30min; the acetone was spun off and a large amount of solids precipitated, filtered, 50mL ethyl acetate: heptane=1:2 solvent washing, oven drying, to give 13.0g of compound V-2d as an off-white solid in 96% yield. 1 H-NMR(400M，DMSO-d 6 )：10.52(1h，brs)，7.85(2H，s)，7.61(1H，d)，7.19(1H，d)，5.66(1H，dd)，3.79(1H，m)，3.54(1H，m)，1.59-1.28(6H，m)。
EXAMPLE 10 preparation of Compounds of formula V-2e
To the reaction flask were added 12.5g (30 mmol) of compound V-1e, 5.04g (60 mmol) of 3, 4-dihydro-2H-pyran, 2.08g (12.0 mmol) of p-toluenesulfonic acid and 100mL of tetrahydrofuran, and the mixture was heated to 60℃for reaction for 5 hours; cooling to room temperature, adding 100mL of water, adjusting the pH to 9 with potassium carbonate, and stirring at room temperature for 30min; the tetrahydrofuran was spun off and a large amount of solids precipitated, filtered, 50mL ethyl acetate: heptane=1:2 solvent washing, oven drying, to give 14.6g of compound V-2e as an off-white solid in 97% yield. 1 H-NMR(400M，DMSO-d 6 )：10.46(1h，brs)，7.84(2H，s)，7.61(1H，d)，7.19(1H，d)，5.65(1H，dd)，3.78(1H，m)，3.52(1H，m)，1.59-1.28(6H，m)。
EXAMPLE 11 preparation of Compounds of formula V-3
Method 1: 9.42g of compound V-1a (30 mmol), 100mL of ethanol, 50mL of water and 5.6g of potassium hydroxide (100 mmol) are added into a reaction bottle, the temperature is raised to 90 ℃ for reaction for 5 hours, the reaction bottle is cooled to room temperature, the pH of the reaction bottle is regulated to 6 by hydrochloric acid, ethanol is removed by screwing, a large amount of solid is separated out, the reaction bottle is filtered, 50mL of water is washed and dried, and 7.83g of brown yellow solid compound V-3 is obtained, and the yield is 96%.
Method 2: 9.42g of compound V-1a (30 mmol), 100mL of tetrahydrofuran, 50mL of water and 4.8g of sodium hydroxide (120 mmol) are added into a reaction bottle, the temperature is raised to 80 ℃ for reaction for 10 hours, the reaction bottle is cooled to room temperature, the pH of hydrochloric acid is adjusted to 6, tetrahydrofuran is screwed off, a large amount of solid is separated out, the filtration and 50mL of water washing are carried out, and the reaction bottle is dried, so that 7.75g of brown yellow solid compound V-3 is obtained, and the yield is 95%.
The nuclear magnetic data of the compound V-3 obtained in the method 1 are as follows: 1 H-NMR(400M，DMSO-d 6 )：12.22(1h，brs)，7.50(1H，d)，7.03(1H，d)，6.68(2H，s)，5.63(2H，brs)。
EXAMPLE 12 preparation of Compounds of formula V-3
11.3g of compound V-1c (30 mmol), 100mL of ethanol, 50mL of water and 6.0g of sodium hydroxide (150 mmol) are added into a reaction bottle, the temperature is raised to 100 ℃ for reaction for 5h, the reaction bottle is cooled to room temperature, the pH of the reaction bottle is regulated to 6 by hydrochloric acid, ethanol is removed by screwing, a large amount of solid is separated out, the reaction bottle is filtered, 50mL of water is washed and dried, and 8.0g of brown yellow solid compound V-3 is obtained, and the yield is 98%. The nuclear magnetic data are consistent with example 11.
EXAMPLE 13 preparation of Compounds of formula V-3
11.0g of compound V-1d (30 mmol), 100mL of ethanol, 50mL of water and 5.6g of potassium hydroxide (100 mmol) are added into a reaction bottle, the temperature is raised to 80 ℃ for reaction for 2 hours, the reaction bottle is cooled to room temperature, the pH of the reaction bottle is regulated to 6 by hydrochloric acid, ethanol is removed by screwing, a large amount of solid is separated out, the reaction bottle is filtered, 50mL of water is washed and dried, and 8.0g of brown yellow solid compound V-3 is obtained, and the yield is 98%. The nuclear magnetic data are consistent with example 11.
EXAMPLE 14 preparation of Compounds of formula V-3
12.5g of compound V-1e (30 mmol), 100mL of tetrahydrofuran, 50mL of water and 8.0g of sodium hydroxide (200 mmol) are added into a reaction bottle, the temperature is raised to 80 ℃ for reaction for 2 hours, the reaction bottle is cooled to room temperature, the pH of hydrochloric acid is adjusted to 6, tetrahydrofuran is screwed off, a large amount of solid is separated out, the filtration and 50mL of water washing are carried out, and drying are carried out, thus obtaining 8.0g of brown yellow solid compound V-3 with the yield of 98%. The nuclear magnetic data are consistent with example 11.
EXAMPLE 15 preparation of Compounds of formula V-4
12.0g of compound V-2a (30 mmol), 100mL of ethanol, 50mL of water and 3.36g of potassium hydroxide (60 mmol) are added into a reaction bottle, the temperature is raised to 90 ℃ for reaction for 6 hours, the reaction bottle is cooled to room temperature, the pH of the reaction bottle is regulated to 6 by hydrochloric acid, ethanol is removed by screwing, a large amount of solid is separated out, the reaction bottle is filtered, 50mL of water is washed and dried, 8.76g of pale yellow solid compound V-4 is obtained, and the yield is 82%. 1 H-NMR(400M，DMSO-d 6 )：7.56(1H，d)，7.15(1H，d)，6.68(2H，s)，5.76(2H，brs)，5.63(1H，dd)，3.78(1H，m)，3.52(1H，m)，1.51-1.25(6H，m)。
EXAMPLE 16 preparation of Compounds of formula V-4
13.8g of compound V-2c (30 mmol), 100mL of methanol, 50mL of water and 4.8g of sodium hydroxide (120 mmol) are added into a reaction bottle, the temperature is raised to 100 ℃ for reaction for 5h, the reaction bottle is cooled to room temperature, the pH of the reaction bottle is regulated to 6 by hydrochloric acid, the methanol is removed by screwing, a large amount of solid is separated out, the reaction bottle is filtered, 50mL of water is washed and dried, and 9.6g of pale yellow solid compound V-4 is obtained, and the yield is 90%. The nuclear magnetic data are consistent with example 15.
EXAMPLE 17 preparation of Compounds of formula V-4
13.6g of compound V-2d (30 mmol), 100mL of ethanol, 50mL of water and 5.04g of potassium hydroxide (90 mmol) are added into a reaction bottle, the temperature is raised to 70 ℃ for reaction for 3h, the reaction bottle is cooled to room temperature, the pH of the reaction bottle is regulated to 6 by hydrochloric acid, ethanol is screwed off, a large amount of solid is separated out, the reaction bottle is filtered, 50mL of water is washed and dried, and 9.7g of pale yellow solid compound V-4 is obtained, and the yield is 91%. The nuclear magnetic data are consistent with example 15.
EXAMPLE 18 preparation of Compounds of formula V-4
15.0g of compound V-2e (30 mmol), 100mL of methanol, 50mL of water and 4.0g of sodium hydroxide (100 mmol) are added into a reaction bottle, the temperature is raised to 70 ℃ for reaction for 3 hours, the reaction bottle is cooled to room temperature, the pH of the reaction bottle is regulated to 6 by hydrochloric acid, the methanol is screwed off, a large amount of solid is separated out, the reaction bottle is filtered, 50mL of water is washed and dried, and 9.6g of pale yellow solid compound V-4 is obtained, and the yield is 90%. The nuclear magnetic data are consistent with example 15.
EXAMPLE 19 preparation of Compounds of formula III
Into the reaction flask were charged 3.14g of Compound V-1a (10 mmol), 1.34g of Compound E-1 (15 mmol), 3.45g of 1, 3-tetramethylguanidine (30 mmol) and 30mL of DMSO, and the mixture was stirred at 50℃for 20 hours; pouring into 120mL of ice water, adjusting the pH to 6 with hydrochloric acid, filtering, and washing once with 20mL of water to obtain the compound IV-1a. To the resulting product was added 20mL of ethanol, 10mL of water and 2.0g of sodium hydroxide (50 mmol), and the mixture was heated to 100℃for reaction for 5 hours; cooling to room temperature, turning off ethanol, adding 20mL of ice water, adjusting pH to 6 with hydrochloric acid, precipitating a large amount of solid, filtering, washing once with 20mL of water, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.54g of compound III as an off-white solid in 81% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 20 preparation of Compounds of formula III
To the reaction flask were added 3.72g of Compound V-1b (10 mmol), 2.2g of Compound E-2 (12 mmol), 1.29g of sodium amide (33 mmol) and 30mL of DMAc, and reacted at 40℃for 15 hours; pouring into 120mL of ice water, adjusting pH to 6 with hydrochloric acid, filtering, washing once with 20mL of water, and vacuum drying to obtain the compound IV-1b. Adding 10mL of hydrogen chloride diethyl ether solution into the obtained product, and stirring at room temperature for reaction for 2h; spin-drying, washing with 20mL sodium bicarbonate solution, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.61g of compound III as an off-white solid in 83% yield. The nuclear magnetic data of the product are as follows: 1 H-NMR(400M，DMSO-d 6 ): 12.12 (1H, s), 7.27 (1H, s), 6.67 (2H, s), 5.61 (2H, brs), 3.03 (1H, m), 1.17 (6H, d); the nuclear magnetic pattern is shown in figure 1.
EXAMPLE 21 preparation of Compounds of formula III
3.76g of Compound V-1c (10 mmol), 1.38g of Compound E-3 (20 mmol), 1.08g of sodium hydride (45 mmol) and 40mL of DMF were added to the reaction flask, and the mixture was stirred at 60℃for 12 hours; 150mL of water and 1.5g of sodium hypochlorite were added, stirred at room temperature for 5 hours, filtered, and washed once with 20mL of water to give compound IV-1c. To the resulting product was added 20mL of methanol, 10mL of water and 2.8g of potassium hydroxide (50 mmol), and the mixture was heated to 90℃for reaction for 8 hours; cooling to room temperature, turning off methanol, adding 20mL of ice water, adjusting pH to 6 with hydrochloric acid, precipitating a large amount of solid, filtering, washing once with 20mL of water, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.51g of compound III as an off-white solid in 80% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 22 preparation of Compounds of formula III
3.68g of Compound V-1d (10 mmol), 1.07g of Compound E-1 (12 mmol), 1.83g of DBU (12 mmol) and 30mL of sulfolane are added into a reaction flask, and stirred at 50 ℃ for reaction for 20h; pouring into 120mL of ice water, adjusting pH to 6 with hydrochloric acid, filtering, and washing once with 20mL of water to obtain the compound VI-1d. To the resulting product was added 20mL of ethanol, 10mL of water and 2.0g of sodium hydroxide (50 mmol), and the mixture was heated to 80℃for 2 hours; cooling to room temperature, turning off ethanol, adding 20mL of ice water, adjusting pH to 6 with hydrochloric acid, precipitating a large amount of solid, filtering, washing once with 20mL of water, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.70g of compound III as an off-white solid in 85% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 23 preparation of Compounds of formula III
Into the reaction flask were charged 4.18g of Compound V-1E (10 mmol), 1.07g of Compound E-1 (12 mmol), 1.83g of DBU (12 mmol) and 30mL of DMSO, and the mixture was stirred at 50℃for 20 hours; pouring into 120mL of ice water, adjusting the pH to 6 with hydrochloric acid, filtering, and washing once with 20mL of water to obtain the compound VI-1e. To the resulting product was added 20mL of ethanol, 10mL of water and 2.0g of sodium hydroxide (50 mmol), and the mixture was heated to 80℃for 2 hours; cooling to room temperature, turning off ethanol, adding 20mL of ice water, adjusting pH to 6 with hydrochloric acid, precipitating a large amount of solid, filtering, washing once with 20mL of water, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.64g of compound III as an off-white solid in 84% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 24 preparation of Compounds of formula III
3.98g of Compound V-2a (10 mmol), 1.34g of Compound E-1 (15 mmol), 3.8g of DBU (15 mmol) and 40mL of DMSO were added into the reaction flask and reacted at 50℃with stirring for 12h; pouring the mixture into 160mL of water, adjusting the pH to 6 with hydrochloric acid, filtering, washing once with 20mL of water, and drying to obtain the compound IV-2a. Adding 10mL of tetrahydrofuran solution of hydrogen chloride into the obtained product, heating to 50 ℃ for reaction for 2h, and spin-drying; then 20mL of ethanol, 10mL of water and 2.4g of sodium hydroxide (60 mmol) are added, and the temperature is raised to 100 ℃ for reaction for 5 hours; cooling to room temperature, turning off ethanol, adding 20mL of ice water, adjusting pH to 6 with hydrochloric acid, precipitating a large amount of solid, filtering, washing once with 20mL of water, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.76g of compound III as an off-white solid in 88% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 25 preparation of Compounds of formula III
Into a reaction flask were charged 4.56g of Compound V-2b (10 mmol), 2.2g of Compound E-2 (12 mmol), 0.86g of sodium amide (22 mmol) and 40mL of DMF, and reacted at room temperature for 10 hours; pouring into 120mL of ice water, adjusting pH to 6 with hydrochloric acid, filtering, washing once with 20mL of water, and vacuum drying to obtain a compound IV-2b; 15mL of hydrogen chloride 1, 4-dioxane solution is added into the obtained product, the temperature is raised to 60 ℃ for reaction for 2 hours, spin drying is carried out, 20mL of sodium bicarbonate solution is used for washing, and vacuum drying is carried out; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.64g of compound III as an off-white solid in 84% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 26 preparation of Compounds of formula III
Into the reaction flask were charged 4.60g of Compound V-2c (10 mmol), 1.79g of Compound E-4 (16 mmol), 0.72g of sodium hydride (30 mmol) and 40mL of DMSO, and reacted at 60℃for 6 hours; pouring into 160mL of ice water, adjusting pH to 6 with hydrochloric acid, filtering, washing once with 20mL of water, and then using 20mL of ethyl acetate: heptane=1:2 solvent washing, oven drying to give compound IV-2c. Adding 20mL of tetrahydrofuran solution of hydrogen chloride into the obtained product, heating to 55 ℃ for reaction for 2h, and spin-drying; then 20mL of ethanol, 10mL of water and 2.4g of sodium hydroxide (60 mmol) are added, and the temperature is raised to 100 ℃ for reaction for 5 hours; cooling to room temperature, turning off ethanol, adding 20mL of ice water, adjusting pH to 6 with hydrochloric acid, precipitating a large amount of solid, filtering, washing once with 20mL of water, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.61g of compound III as an off-white solid in 83% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 27 preparation of Compounds of formula III
Into the reaction flask were charged 4.52g of Compound V-2d (10 mmol), 1.95g of Compound E-6 (16 mmol), 1.01g of sodium amide (26 mmol) and 40mL of DMF, and reacted at 60℃for 6h; pouring into 160mL of ice water, adjusting pH to 6 with hydrochloric acid, filtering, washing once with 20mL of water, and then using 20mL of ethyl acetate: heptane=1:2 solvent washing, oven drying to give compound IV-2d. Adding 20mL of tetrahydrofuran solution of hydrogen chloride into the obtained product, heating to 60 ℃ for reaction for 2h, and spin-drying; then 20mL of ethanol, 10mL of water and 2.4g of sodium hydroxide (60 mmol) are added, and the temperature is raised to 70 ℃ for reaction for 3 hours; cooling to room temperature, turning off ethanol, adding 20mL of ice water, adjusting pH to 6 with hydrochloric acid, precipitating a large amount of solid, filtering, washing once with 20mL of water, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.67g of compound III as an off-white solid in 85% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 28 preparation of Compounds of formula III
Into the reaction flask were charged 5.02g of Compound V-2E (10 mmol), 1.16g of Compound E-1 (13 mmol), 3.8g of DBU (15 mmol) and 40mL of DMSO, and the mixture was stirred at 60℃for 8 hours; pouring the mixture into 160mL of water, adjusting the pH to 6 with hydrochloric acid, filtering, washing once with 20mL of water, and drying to obtain the compound IV-2e. Adding 15mL of hydrogen chloride diethyl ether solution into the obtained product, heating to 40 ℃ for reaction for 4 hours, and spin-drying; then 20mL of methanol, 10mL of water and 2.4g of sodium hydroxide (60 mmol) are added, and the temperature is raised to 70 ℃ for reaction for 3 hours; cooling to room temperature, turning off methanol, adding 20mL of ice water, adjusting pH to 6 with hydrochloric acid, precipitating a large amount of solid, filtering, washing once with 20mL of water, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.83g of compound III as an off-white solid in 90% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 29 preparation of Compounds of formula III
Into a reaction flask were charged 2.72g of Compound V-3 (10 mmol), 1.07g of Compound E-1 (12 mmol), 2.3g of 1, 3-tetramethylguanidine (20 mmol) and 30mL of sulfolane, and reacted at 60℃for 20 hours; pouring into 120mL of ice water, adjusting pH to 6 with hydrochloric acid, filtering, washing once with 20mL of water, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.45g of off-white solid III in 78% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 30 preparation of Compounds of formula III
Into the reaction flask were charged 3.56g of Compound V-4 (10 mmol), 2.42g of Compound E-5 (15 mmol), 0.78g of sodium amide (20 mmol) and 30mL of DMAc, and reacted at 60℃for 8 hours; pouring into 160mL of ice water, adjusting pH to 6 with hydrochloric acid, filtering, washing once with 20mL of water, and vacuum drying to obtain a compound IV-4; adding 15mL of hydrogen chloride 1, 4-dioxane solution into the obtained product, heating to 50 ℃ for reaction for 2 hours, spin-drying, washing with 20mL of sodium bicarbonate solution, and vacuum drying; the crude product obtained was recrystallized from acetonitrile and isopropyl ether to give 2.57g of off-white solid III in 82% yield. Nuclear magnetism identification shows that the product has a target structure.
EXAMPLE 31 preparation of Compounds of formula I
Preparation of Compound II: 3.14g of Compound III (10.0 mmol), 1.72g of Compound A (11.0 mmol) and 60mL of water were added to the reaction flask, and 30mL of hydrochloric acid (37% mass fraction) was added in portions with ice water cooled to 0-10 ℃; maintaining the temperature at 5-10 ℃, dropwise adding a solution prepared from 6.9g of sodium nitrite (100 mmol) and 20mL of water within 30min, and then dropwise adding a solution prepared from 23.0g of sodium acetate (280 mmol) and 90mL of water within 50 min; the ice-water bath was removed, and the reaction was stirred at room temperature for 2 hours, filtered, washed with 30mL of water, then 20mL of isopropyl ether, and dried to give 4.23g of Compound II as a tan solid in 88% yield. 1 H-NMR(400M，DMSO-d 6 )：δ12.26(2H，brs)，10.90(1H，s)，8.00(2H，s)，7.36(1H，s)，4.23(2H，q)，3.07(1H，m)，1.28-1.20(9H，m)。
Preparation of Compound I: 2.41g of Compound II (5.0 mmol), 0.54g of potassium acetate (5.5 mmol) and 20mL of DMF were added to the flask, and the mixture was heated to 110℃for 3 hours; cooling to 80 ℃, adding 1.0mL of glacial acetic acid, and continuously reacting for 2 hours; cooled to room temperature, 100mL of water, potassium carbonate was added to adjust pH to 7, stirred for 5min, filtered, and 20mL of acetonitrile: water = 1:2 to obtain 1.96g of yellow brown solid compound I in 90% yield. 1 H-NMR(400M，DMSO-d 6 )：13.21(1H，brs)，12.261H，brs)，7.81(2H，s)，7.46(1H，s)，3.06(1H，m)，1.18(6H，d)。
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The preparation method of the Resmetirom key intermediate III is characterized by comprising the following steps of:
providing a compound of the structure shown in formula V:
in formula V: r is R 1 Is H or an amino protecting group, wherein the carbon number of the amino protecting group is 1-10; r is R 2 Is H or
When R in V 1 And R is 2 And when H is the same time, the preparation method of the Resmetiraom key intermediate III comprises the following steps of:
(i) Mixing a compound with a structure shown in a formula V, a compound with a structure shown in a formula E, an alkaline compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a Resmetiram key intermediate III; the structural formula of the Resmetiram key intermediate III is shown in a formula III;
In formula E: r is R 3 is-NO 2 、-SO 2 Ph、-SO 2 Me、-CN、-CF 3 or-CCl 3 ；
When R in V 1 And R is 2 When the two are not H, the preparation method of the Resmetiraom key intermediate III comprises the following steps:
(1) Mixing a compound with a structure shown in a formula V, a compound with a structure shown in a formula E, an alkaline compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a compound with a structure shown in a formula IV;
(2) R in the compound with the structure shown in the formula IV is subjected to deprotection reaction 1 And/or R 2 Radical removal, to give the Resmetiraom key intermediate III.
2. The preparation method according to claim 1, wherein the amino protecting group is t-BuOCO-, phCO-, CH 3 CO-、CF 3 CO-or CCl 3 CO-。
3. The method according to claim 1, wherein in the step (i) and the step (1), the basic compound is independently one or more of DBU, 1, 3-tetramethylguanidine, sodium amide, potassium t-butoxide, sodium hydride, potassium carbonate, sodium carbonate, KOH, naOH; the mol ratio of the compound with the structure shown in the formula V and the alkaline compound is independently 1 (0.5-10);
in the step (i) and the step (1), the molar ratio of the compound with the structure shown in the formula V to the compound with the structure shown in the formula E is independently 1 (1-5);
In the step (i) and the step (1), the temperature of the addition-elimination-double bond shift reaction is independently 0-120 ℃ and the time is independently 1-50 h.
4. The process of claim 2, wherein R in formula IV 1 Is t-BuOCO-, R 2 Is H orWhen, or when R in formula IV 1 H, R of a shape of H, R 2 When the acid is not H, the deprotection reaction in the step (2) is an acidic deprotection reaction, and the acid used in the acidic deprotection reaction is selected from hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1, 4-dioxane solution; the temperature of the acidic deprotection reaction is 0-100 ℃.
5. The process of claim 2, wherein R in formula IV 1 Is other than H and is other than t-BuOCO-, R 2 In the case of H, the deprotection reaction in the step (2) is alkaline hydrolysis reaction, and alkali used in the alkaline hydrolysis reaction is selected from sodium hydroxide or potassium hydroxide; the mol ratio of the compound with the structure of the formula IV to the alkali is 1 (2-10); the solvent for the alkaline hydrolysis reaction is an organic solvent-water mixed solvent, and the organic solvent in the organic solvent-water mixed solvent is one or more selected from ethanol, methanol, tetrahydrofuran, 1, 4-dioxane and DMSO.
6. The process of claim 2, wherein R in formula IV 1 、R 2 Are not H, and R 1 When the acid is not t-BuOCO-, the hydrolysis reaction comprises an acidic deprotection reaction and an alkaline hydrolysis reaction which are sequentially carried out; the acid used in the acidic deprotection reaction is selected from one of hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1, 4-dioxane solution; the temperature of the acidic deprotection reaction is 0-100 ℃; the alkali used in the alkaline hydrolysis reactionSelected from sodium hydroxide or potassium hydroxide; the mol ratio of the compound with the structure of the formula IV to the alkali is 1 (2-10); the solvent for the alkaline hydrolysis reaction is an organic solvent-water mixed solvent, and the organic solvent in the organic solvent-water mixed solvent is one or more selected from ethanol, methanol, tetrahydrofuran, 1, 4-dioxane and DMSO.
7. The process of claim 1, wherein R in formula V 1 Is not H, R 2 In the case of H, the preparation method of the compound with the structure shown in the formula V comprises the following steps:
mixing a compound with a structure shown in a formula D, a compound with a structure shown in a formula G, a first alkaline compound and an organic solvent for substitution reaction to obtain a compound with a structure shown in a formula VI;
In formula G and formula VI, R 1 The kind of the groups is the same as that in the formula V;
mixing the compound with the structure shown in the formula VI, acetic acid and sodium acetate to carry out substitution-hydrolysis reaction to obtain a compound with the structure shown in the formula V, wherein the structural formula is shown in the formula V-1;
when R in V 1 Is not H, R 2 When the compound is not H, the preparation method of the compound with the structure shown in the formula V comprises the following steps:
mixing a compound with a structure shown in a formula V-1, 3, 4-dihydro-2H-pyrane, acid and an organic solvent for carrying out an amide protection reaction to obtain the compound with the structure shown in the formula V, wherein the structural formula is shown in a formula V-2;
when R in V 1 Is H, R 2 In the case of H, the preparation method of the compound with the structure shown in the formula V comprises the following steps:
mixing a compound with a structure shown in a formula V-1, a second alkaline compound, an organic solvent and water to perform a first hydrolysis reaction to obtain the compound with the structure shown in the formula V, wherein the structural formula is shown in a formula V-3;
in formula V-1: r is R 1 Is PhCO-, CF 3 CO-、CCl 3 CO-or CH 3 CO-；
When R in V 1 Is H, R 2 When the compound is not H, the preparation method of the compound with the structure shown in the formula V comprises the following steps:
mixing a compound with a structure shown in a formula V-2, a third alkaline compound, an organic solvent and water to perform a second hydrolysis reaction to obtain the compound with the structure shown in the formula V, wherein the structural formula is shown in a formula V-4;
In formula V-2: r is R 1 Is PhCO-, CF 3 CO-、CCl 3 CO-or CH 3 CO-。
8. The preparation method according to claim 7, wherein the molar ratio of the compound of the structure represented by formula D to the compound of the structure represented by formula G is 1 (1-2);
the first alkaline compound is one or more of alkali metal carbonate, alkali metal hydroxide and organic alkali; the mol ratio of the compound with the structure shown in the formula D to the first alkaline compound is 1 (1-3);
the organic solvent adopted in the substitution reaction is one or more of DMF, DMAc, DMSO, NMP, acetonitrile and 1, 4-dioxane; the temperature of the substitution reaction is 40-120 ℃ and the time is 5-50 h;
the mol ratio of the compound with the structure shown in the formula VI to the sodium acetate is 1 (1-5); the mol ratio of the compound with the structure shown in the formula VI to acetic acid is 1 (10-50);
the temperature of the substitution-hydrolysis reaction is 60-150 ℃ and the time is 2-20 h.
9. The process according to claim 7, wherein in the amide protecting reaction, the molar ratio of the compound of the structure represented by the formula V-1 to the acid is 1 (0.05 to 0.5), and the molar ratio of the compound of the structure represented by the formula V-1 to the 3, 4-dihydro-2H-pyran is 1 (1 to 4);
The organic solvent adopted in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone and 1, 4-dioxane;
the temperature of the amide protection reaction is 30-80 ℃ and the time is 1-10 h.
10. The method according to claim 7, wherein in the first hydrolysis reaction, the molar ratio of the compound having the structure represented by the formula V-1 to the second basic compound is 1 (2 to 6); the second basic compound is an alkali metal hydroxide;
the solvent used in the first hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran and DMSO;
the temperature of the first hydrolysis reaction is 50-120 ℃ and the time is 1-10 h;
in the second hydrolysis reaction, the mol ratio of the compound with the structure shown in the formula V-2 to the third alkaline compound is 1 (2-6); the third alkaline compound is an alkali metal hydroxide;
the solvent used in the second hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran and DMSO;
the temperature of the second hydrolysis reaction is 50-120 ℃ and the time is 1-10 h.
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