CN111362893B - Preparation method of tasimelteon intermediate - Google Patents
Preparation method of tasimelteon intermediate Download PDFInfo
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- CN111362893B CN111362893B CN201811589363.8A CN201811589363A CN111362893B CN 111362893 B CN111362893 B CN 111362893B CN 201811589363 A CN201811589363 A CN 201811589363A CN 111362893 B CN111362893 B CN 111362893B
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- CN
- China
- Prior art keywords
- compound
- reaction
- tasimelteon
- preparation
- sodium
- Prior art date
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Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- MKWRRGVTYBMERJ-UHFFFAOYSA-N 2,3-dihydro-1-benzofuran-4-carbaldehyde Chemical compound O=CC1=CC=CC2=C1CCO2 MKWRRGVTYBMERJ-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 239000000126 substance Substances 0.000 claims abstract description 29
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 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 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 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 claims abstract description 14
- 238000006277 sulfonation reaction Methods 0.000 claims abstract description 11
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000007810 chemical reaction solvent Substances 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 7
- 230000002140 halogenating effect Effects 0.000 claims description 7
- XXDAXUSYDPWTPK-UHFFFAOYSA-N 2-(oxo-lambda5-phosphanylidyne)acetic acid Chemical compound P(=O)#CC(=O)O XXDAXUSYDPWTPK-UHFFFAOYSA-N 0.000 claims description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 5
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- 229960000660 tasimelteon Drugs 0.000 claims description 3
- PTOIAAWZLUQTIO-GXFFZTMASA-N tasimelteon Chemical compound CCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1CCO2 PTOIAAWZLUQTIO-GXFFZTMASA-N 0.000 claims description 3
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 3
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 5
- 238000011112 process operation Methods 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 2
- 239000012044 organic layer Substances 0.000 description 42
- 238000010438 heat treatment Methods 0.000 description 26
- 238000001035 drying Methods 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000001816 cooling Methods 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 239000012065 filter cake Substances 0.000 description 15
- 238000001514 detection method Methods 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 10
- 238000002386 leaching Methods 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 9
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 6
- XKVKNLLAHQALQA-GHMZBOCLSA-N (1r,2r)-2-(2,3-dihydro-1-benzofuran-4-yl)-n-methylcyclopropan-1-amine Chemical compound CN[C@@H]1C[C@@H]1C1=CC=CC2=C1CCO2 XKVKNLLAHQALQA-GHMZBOCLSA-N 0.000 description 5
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- -1 lithium aluminum hydride Chemical compound 0.000 description 4
- 239000002994 raw material Substances 0.000 description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- BMIOQCCAVKGDBY-GZMMTYOYSA-N [(1r,2r)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methanol Chemical compound OC[C@@H]1C[C@H]1C1=CC=CC2=C1CCO2 BMIOQCCAVKGDBY-GZMMTYOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 208000013651 non-24-hour sleep-wake syndrome Diseases 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical group CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 2
- JUVHWXZKOCRDDV-VHSXEESVSA-N (1r,2r)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=CC2=C1CCO2 JUVHWXZKOCRDDV-VHSXEESVSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 229940121723 Melatonin receptor agonist Drugs 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 241001516476 Vanda Species 0.000 description 1
- FXYHNSKFBUUONP-GZMMTYOYSA-N [(1r,2r)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methanamine Chemical compound NC[C@@H]1C[C@H]1C1=CC=CC2=C1CCO2 FXYHNSKFBUUONP-GZMMTYOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 150000001540 azides Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of an tasimelteon intermediate, which at least comprises the following steps: 1) carrying out substitution reaction or sulfonation reaction on the compound IV to obtain a compound III; 2) reacting the compound III with hydroxylamine hydrochloride under the condition of an alkaline substance to obtain a compound II; 3) carrying out reduction reaction on the compound II to obtain a compound I; the method has the advantages of high yield, high purity, few reaction byproducts, simple process operation and low overall cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a tasimelteon intermediate.
Background
Tasimelteon is a melatonin receptor agonist developed by Vanda Pharms corporation and approved by the FDA for the treatment of Non-24 h wake-up cycle disorder (Non-24) in patients with complete blindness at 31 days 1/2014, which is the first drug approved by the FDA for this disease, and it was reported at home and abroad that the intermediate [ (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropyl ] methylamine is a key compound for the synthesis of tasimelteon.
At present, three mainstream methods for synthesizing [ (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropyl ] methylamine at home and abroad are available, one (patent CN102675268) is to use (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropane carboxylic acid as a starting material, obtain (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropane carbonyl chloride through chlorination, generate (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropane carboxamide through ammonolysis, and finally obtain the compound through reduction, wherein the starting material of the route is expensive and is not easy to obtain, and the route is as follows;
the second (patent US5856529) uses (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropanemethanol as a starting material, and is oxidized to obtain aldehyde, then reacts with hydroxylamine hydrochloride to generate oxime, and finally is reduced to generate (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropanemethylamine which is a key intermediate, and the route has low yield and high cost and is not beneficial to industrial production, and the route is as follows;
the third (U.S. Pat. No. 6,6214869) uses (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropanemethanol as starting material, then the hydroxyl group is protected by methanesulfonyl group, then methanesulfonyl group is substituted by azide through the action of sodium azide, finally cis-2- (2, 3-dihydrobenzofuran-4-yl) cyclopropanemethylamine is obtained through reduction by lithium aluminum hydride, the process requirement of the method is strict, and high-risk reagent NaN is used3And is not beneficial to industrial scale-up, and the route is as follows:
the [ (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropyl ] methyl alcohol is used as an initial raw material, and is halogenated or sulfonated, ammoniated and reduced to obtain [ (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropyl ] methylamine, so that the method has the advantages of high yield, low overall cost and simple process operation, and is suitable for industrial production. The specific route is as follows:
disclosure of Invention
The [ (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropyl ] methyl alcohol is used as an initial raw material, and is halogenated or sulfonated, ammoniated and reduced to obtain [ (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropyl ] methylamine, so that the method has the advantages of high yield, low overall cost and simple process operation, and is suitable for industrial production.
The invention provides a preparation method of an tasimelteon intermediate, which at least comprises the following steps:
1) the compound IV is subjected to substitution reaction or sulfonation reaction to obtain a compound III
2) Reacting the compound III with hydroxylamine hydrochloride under the condition of an alkaline substance to obtain a compound II;
3) carrying out reduction reaction on the compound II to obtain a compound I;
the chemical reaction formula is as follows:
wherein, X in the compound III at least comprises one of Cl, Br, I, MsO and TsO.
In one embodiment, the substituting reactant in step 1) is a halogenated reactant; the sulfonation reaction reagent is a sulfonation reagent.
In one embodiment, the halogenating agent comprises one or more of thionyl chloride, phosphorus oxychloride, phosphorus tribromide, hydrobromic acid/acetic acid solution, thionyl bromide, carbon tetrabromide/triphenylphosphine, bromine, hydroiodic acid, sodium iodide, iodine/triphenylphosphine; the sulfonation reagent comprises one or more of methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride;
preferably, the halogenating agent comprises one or more of thionyl chloride, phosphorus tribromide, hydrobromic acid/acetic acid solution, dibromosulphoxide, hydroiodic acid and sodium iodide; the sulfonation reagent comprises one or more of methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride;
more preferably, the halogenating agent comprises one of thionyl chloride and phosphorus tribromide; the sulfonation reagent is methanesulfonyl chloride.
In one embodiment, the molar ratio of the compound iv to the halogenating agent is 1: (1-3); preferably, the molar ratio of the compound iv to the halogenating agent is 1: (1-2); more preferably, the molar ratio of said compound iv to said halogenating agent is 1: 1.2.
in one embodiment, the molar ratio of the compound iv to the sulfonating agent is 1: (1-3); preferably, the molar ratio of the compound iv to the sulfonating agent is 1: (1-2); more preferably, the molar ratio of said compound iv to said sulfonating agent is 1: 1.2.
in one embodiment, the reaction solvent in step 1) comprises one or more of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, 1, 4-dioxane; the reaction temperature is 15-35 ℃; the reaction time is 1-5 h;
preferably, the reaction solvent in the step 1) comprises one or more of dichloromethane and 1, 4-dioxane; the reaction temperature is 25-30 ℃; the reaction time is 2-3 h.
In one embodiment, the weight ratio of the compound iv to the reaction solvent is 1: (2-10); preferably, the weight ratio of the compound iv to the reaction solvent is 1: (4-7).
In one embodiment, the alkaline substance in step 2) comprises one or more of sodium bicarbonate, potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, triethylamine and tri-n-propylamine; the reaction solvent comprises one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and water; the reaction time is 1-10 h;
preferably, the alkaline substance in step 2) comprises one or more of sodium bicarbonate, potassium carbonate, sodium carbonate, triethylamine and tri-n-propylamine; the reaction solvent comprises one or more of methanol, ethanol, isopropanol, acetonitrile and water; the reaction time is 1-5 h;
more preferably, the alkaline substance in the step 2) comprises one or more of potassium carbonate, sodium carbonate and triethylamine; the reaction solvent comprises one or more of methanol, ethanol and water; the reaction time is 2-3 h.
In one embodiment, the molar ratio of compound iii to hydroxylamine hydrochloride is 1: (1-3); preferably, the molar ratio of the compound III to the hydroxylamine hydrochloride is 1: (1-2); more preferably, the molar ratio of the compound iii to hydroxylamine hydrochloride is 1: 1.5.
in one embodiment, the molar ratio of compound iii to basic material is; the molar ratio of the compound III to the alkaline substance is 1: (1-5); preferably, the molar ratio of the compound iii to the basic substance is 1: (1-3); the molar ratio of the compound III to the alkaline substance is 1: 2.
in one embodiment, the weight ratio of compound iii to reaction solvent is 1: (5-20); preferably, the weight ratio of the compound iii to the reaction solvent is 1: (8-16).
In one embodiment, the reducing agent in step 3) includes one or more of zinc powder, iron powder, sodium borohydride, potassium borohydride, hydrogen gas and hydrazine hydrate; preferably, the reducing agent is zinc powder.
In one embodiment, the reaction solvent in step 3) comprises one or more of tetrahydrofuran, toluene, chlorobenzene, cyclohexane, acetonitrile, DMF, 1, 4-dioxane, acetone, ethanol, isopropanol, and methanol; the reaction temperature is 15-35 ℃; the reaction time is 1-10 h; preferably, the reaction solvent in step 3) comprises one or more of tetrahydrofuran, acetonitrile, DMF, 1, 4-dioxane; the reaction temperature is 20-30 ℃; the reaction time is 2-5 h; more preferably, the reaction solvent in step 3) is tetrahydrofuran; the reaction temperature is 25-30 ℃; the reaction time is 2-3 h.
In one embodiment, the molar ratio of compound ii to reducing agent is 1: (1-10); preferably, the molar ratio of the compound II to the reducing agent is 1: (2-5); more preferably, the molar ratio of the compound ii to the reducing agent is 1: 3.
in one embodiment, the weight ratio of compound ii to reaction solvent is 1: (1-10); preferably, the weight ratio of the compound II to the reaction solvent is 1: (1-5).
In one embodiment, the method for preparing compound iv comprises the steps of:
carrying out reduction reaction on the compound V to obtain a compound IV;
the chemical reaction formula is as follows:
in one embodiment, the reducing agent in the preparation method of the compound IV comprises one or more of sodium borohydride, potassium borohydride and borane; preferably, the reducing agent in the preparation method of the compound IV is sodium borohydride.
In one embodiment, the reaction solvent comprises one or more of tetrahydrofuran, toluene, chlorobenzene, cyclohexane, acetonitrile, DMF, 1, 4-dioxane, acetone; preferably, the reaction solvent is tetrahydrofuran.
In one embodiment, the molar ratio of compound iv to reducing agent is 1: (0.5-3); preferably, the molar ratio of the compound IV to the reducing agent is 1: (1-2.5); more preferably, the molar ratio of the compound iv to the reducing agent is 1: 2.
in one embodiment, the weight ratio of the compound iv to the reaction solvent is 1: (5-20); preferably, the weight ratio of the compound IV to the reaction solvent is 1: (8-12).
In one embodiment, the method of making compound v comprises the steps of:
reacting the compound VI with a reagent and an alkaline substance to obtain a compound V;
the reagent comprises one or more of phosphoryl acetic acid trimethyl ester, phosphoryl acetic acid tripropyl ester and phosphoryl acetic acid triisopropyl ester; preferably, the reagent is triethyl phosphonoacetate.
The alkaline substance comprises one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-amylate, potassium acetate, sodium acetate, potassium fluoride, cesium carbonate, potassium carbonate and sodium carbonate;
preferably, the basic substance is sodium tert-butoxide.
In one embodiment, the reaction solvent comprises one or more of toluene, chlorobenzene, xylene, acetonitrile, DMF, DMAC; preferably, the reaction solvent is toluene.
In one embodiment, the molar ratio of compound vi to agent is 1: (1-5); preferably, the molar ratio of the compound vi to the agent is 1: (2-3); more preferably, the molar ratio of compound vi to reagent is 1: 2.5.
in one embodiment, the molar ratio of compound vi to basic material is 1: (1-6); preferably, the molar ratio of the compound vi to the agent is 1: (2-4); more preferably, the molar ratio of compound vi to reagent is 1: 3.5.
in one embodiment, the weight ratio of compound vi to reaction solvent is 1: (3-12); preferably, the weight ratio of the compound VI to the reaction solvent is 1: (5-10).
The CAS number of the compound VI in the invention is 252577-77-8; CAS number of compound V is 452324-74-2; the CAS number of compound IV is 2095881-22-2.
The reaction formula is as follows:
the methods and conditions for extraction, drying, concentration, recrystallization described in the present invention may be those conventional in such reactions in the art.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the [ (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropyl ] methyl alcohol is used as an initial raw material, and is halogenated or sulfonated, ammoniated and reduced to obtain [ (1R,2R) -2- (2, 3-dihydrobenzofuran-4-yl) cyclopropyl ] methylamine, so that the method has the advantages of high yield, high purity, few reaction byproducts, simple process operation, low overall cost and suitability for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the present invention, the term "compound represented by the formula X" is sometimes expressed as "compound X", which can be understood by those skilled in the art. The compound shown in formula 1 and the compound 1 are the same compound.
Example 1
The preparation method of the compound V comprises the following steps:
adding 22g of sodium tert-butoxide and 65mL of toluene into a 250mL three-necked flask, slowly dropwise adding 36.6g of triethyl phosphonoacetate, controlling the internal temperature to be less than 20 ℃ in the dropwise adding process, heating to 40 ℃, dropwise adding a solution prepared from 10.6g of the compound VI and 78mL of toluene, controlling the internal temperature to be less than 45 ℃ in the dropwise adding process, heating to 60 ℃ for reaction for 24 hours, stopping heating after TLC detection reaction is finished, cooling to room temperature, washing the reaction solution with 50mL of 3 times of water, and concentrating and drying an organic layer to obtain 15.5g of oily substance compound V.
Example 2
Preparation method of compound IV
Adding 15.5g of the oily compound V obtained in the step 3 and 155mL of THF into a 250mL three-necked flask, stirring and cooling to 0-5 ℃, adding 4.9g of sodium borohydride in batches, controlling the internal temperature not to exceed 5 ℃, slowly adding 1mL of methanol after the addition is finished, controlling the internal temperature to be less than 10 ℃ in the dropwise adding process, heating to room temperature for reacting for 6 hours after the dropwise adding is finished, adding 100mL of water and 100mL of toluene after the TLC detection reaction is completed, stirring for 30min, standing and separating liquid, extracting 50mL of a water layer, combining organic layers, washing the organic layers with 50mL of 3 times of water, and concentrating and drying the organic layers to obtain 11.8g of oily compound IV with the yield of 92.9%.
Example 3
Preparation of Compound I
The chemical reaction formula is as follows:
preparation of Compound III-a
Adding 14.7g of thionyl chloride and 59mL of dichloromethane into a 250mL three-necked flask, cooling to 0-5 ℃, slowly dropwise adding a solution prepared from 11.8g of compound IV and 59mL of dichloromethane, controlling the internal temperature to be less than 5 ℃ in the dropwise adding process, heating to room temperature for reacting for 2 hours after the dropwise adding is finished, after the TLC detection reaction is completed, reducing the reaction to 0-5 ℃, slowly adding 100mL of 5% sodium carbonate aqueous solution, stirring for 30 minutes, standing for liquid separation, extracting with 50mL of dichloromethane of a water layer, combining organic layers, washing with 50mL of 2 times of water, concentrating and drying the organic layer to obtain 12.3g of oily compound III-a, wherein the yield is 95.1%.
MS(ESI):m/z=209.52(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),4.36~4.24(t,J=4.8、2.4Hz,2H),3.52~3.16(m,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Preparation of Compound II
Adding 12.3g of oily compound III-a obtained in the step 1, 6.2g of hydroxylamine hydrochloride, 120mL of ethanol and 60mL of water into a 250mL three-necked bottle, stirring and cooling to 0 ℃, adding 12.5g of sodium carbonate, heating to reflux for 2h, recovering ethanol under reduced pressure after TLC detection reaction is completed, cooling to room temperature, adding 100mL of butyl acetate and 50mL of water, stirring for 10min, standing for liquid separation, extracting with 50mL of butyl acetate in a water layer, combining organic layers, washing with 50mL of 2 times of water in the organic layer, concentrating and drying the organic layer to obtain 11.5g of oily compound II, wherein the yield is 95.0%.
MS(ESI):m/z=206.3(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),4.36~4.24(t,J=4.8、2.4Hz,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.78~2.42(m,2H),2..01(s,1H),1.93(s,1H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Preparation of Compound I
Adding 11.5g of the oily substance compound II obtained in the step 2 and 23mL of THF into a 100mL three-necked flask, cooling to 0-5 ℃, dropwise adding 23mL of 70% formic acid aqueous solution, heating to room temperature, adding 11g of zinc powder in batches, stirring at room temperature for 2h, performing suction filtration after TLC detection reaction is complete, leaching a small amount of THF of a filter cake, adjusting the pH of the filtrate to 8 with concentrated ammonia water, extracting with 50mL of 3 times of dichloromethane, combining organic layers, concentrating and drying the organic layers to obtain 11.3g of oily substance, dissolving the obtained oily substance in 113mL of ethanol, adding 8.5g D-mandelic acid, heating to reflux for 1h, stopping heating, cooling to 0-5 ℃ for crystallization for 2h, performing suction filtration, leaching the filter cake with a small amount of glacial ethanol, adding the obtained wet filter cake into a 250mL three-necked flask, adding 115mL of dichloromethane, 2.5g of sodium hydroxide and 115mL of water to prepare a solution, stirring at room temperature for reaction for 30min, refining, separating, extracting water layer 30mL by 2 times with dichloromethane, mixing organic layers, washing organic layer 30mL by 3 times with water, drying with anhydrous sodium sulfate, filtering, concentrating filtrate, and drying to obtain light yellow oily compound I8.9 g with yield of 83.9%, purity of 99.6%, isomer content of 0.08%, and total yield of 64.6%.
MS(ESI):m/z=190.2(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),5.11(s,2H)4.36~4.24(t,J=4.8、2.4Hz,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.78~2.42(m,2H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Example 4
Preparation of Compound III-b
Adding 10g of methanesulfonyl chloride and 55mL of dichloromethane into a 250mL three-necked bottle, cooling to 0-5 ℃, slowly dropwise adding a solution prepared from 11.8g of compound IV and 55mL of dichloromethane, controlling the internal temperature to be less than 5 ℃ in the dropwise adding process, heating to room temperature for reacting for 2h after the dropwise adding is finished, after the TLC detection reaction is completed, reducing the reaction to 0-5 ℃, slowly adding 100mL of 5% sodium carbonate aqueous solution, stirring for 30min, standing for liquid separation, extracting with 50mL of dichloromethane in a water layer, combining organic layers, washing with 50mL of 2 times of water, concentrating and drying the organic layers to obtain 11.5g of oily compound III-b, wherein the yield is 96.2%.
MS(ESI):m/z=269.4(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),4.36~4.24(t,J=4.8、2.4Hz,2H),3.68~3.16(m,2H),3.13(s,3H),3.05~2.91(t,J=6.4、3.2Hz,2H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Preparation of Compound II
Adding 11.5g of the oily compound III-b obtained in the step 1, 5.8g of hydroxylamine hydrochloride, 112mL of ethanol and 56mL of water into a 250mL three-necked bottle, stirring and cooling to 0 ℃, adding 11.7g of sodium carbonate, heating to reflux for 2h, recovering ethanol under reduced pressure after TLC detection reaction is completed, cooling to room temperature, adding 94mL of butyl acetate and 47mL of water, stirring for 10min, standing for liquid separation, extracting with 47mL of butyl acetate in a water layer, combining organic layers, washing with 47mL of 2 times of water in the organic layer, and concentrating and drying the organic layer to obtain 10.6g of the oily compound II with the yield of 93.7%.
MS(ESI):m/z=206.3(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),4.36~4.24(t,J=4.8、2.4Hz,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.78~2.42(m,2H),2..01(s,1H),1.93(s,1H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Preparation of Compound I
Adding 10.6g of the oily compound II obtained in the step 2 and 21.2mL of THF into a 100mL three-necked flask, cooling to 0-5 ℃, dropwise adding 21.2mL of 70% formic acid aqueous solution, heating to room temperature, adding 10.1g of zinc powder in batches, stirring at room temperature for 2h, after TLC detection reaction is completed, performing suction filtration, leaching a small amount of THF (tetrahydrofuran) of a filter cake, adjusting the pH of a filtrate to 8 with concentrated ammonia water, extracting with 46mL of 3 times of dichloromethane, combining organic layers, concentrating and drying the organic layers to obtain 10.6g of oily matter, dissolving the obtained oily matter into 106mL of ethanol, adding 7.8g D-mandelic acid, heating to reflux for 1h, stopping heating, cooling to 0-5 ℃ for crystallization for 2h, performing suction filtration, leaching a small amount of glacial ethanol of the filter cake, adding the obtained wet filter cake into a 250mL three-necked flask, adding a solution prepared from 106mL of dichloromethane, 2.3g of sodium hydroxide and 106mL of water, stirring at room temperature for reaction for 30min, refining, separating, extracting water layer 30mL with 2 times of dichloromethane, combining organic layers, washing organic layer 30mL with 3 times of water, drying with anhydrous sodium sulfate, filtering, concentrating filtrate, and drying to obtain light yellow oily compound I8.3 g with yield of 85.0%, purity of 99.7%, isomer content of 0.06%, and total yield of 61.3%.
MS(ESI):m/z=190.1(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),5.11(s,2H)4.36~4.24(t,J=4.8、2.4Hz,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.78~2.42(m,2H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Example 5
Preparation of Compound III-c
Adding 30g of phosphorus tribromide and 60mL of dichloromethane into a 250mL three-necked bottle, cooling to 0-5 ℃, slowly dropwise adding a solution prepared from 11.8g of compound IV and 61mL of dichloromethane, controlling the internal temperature to be less than 5 ℃ in the dropwise adding process, heating to room temperature for reacting for 2 hours after the dropwise adding is finished, after the TLC detection reaction is completed, reducing the reaction to 0-5 ℃, slowly adding 103mL of 5% sodium carbonate aqueous solution, stirring for 30 minutes, standing for liquid separation, extracting with 50mL of dichloromethane in a water layer, combining organic layers, washing with 50mL of 2 times of water, concentrating and drying the organic layers to obtain 12.7g of oily compound III-c with the yield of 95.7%.
MS(ESI):m/z=254.1(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),4.36~4.24(t,J=4.8、2.4Hz,2H),3.48~3.15(m,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.01(s,1H),1.93(s,1H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Preparation of Compound II
Adding 12.7g of oily compound III-c obtained in the step 1, 6.4g of hydroxylamine hydrochloride, 120mL of ethanol and 60mL of water into a 250mL three-necked bottle, stirring and cooling to 0 ℃, adding 12.9g of sodium carbonate, heating to reflux for 2h, recovering ethanol under reduced pressure after TLC detection reaction is completed, cooling to room temperature, adding 100mL of butyl acetate and 50mL of water, stirring for 10min, standing for liquid separation, extracting with 50mL of butyl acetate in a water layer, combining organic layers, washing with 50mL of 2 times of water in the organic layer, concentrating and drying the organic layer to obtain 11.8g of oily compound II, wherein the yield is 94.5%.
MS(ESI):m/z=206.2(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),4.36~4.24(t,J=4.8、2.4Hz,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.78~2.42(m,2H),2..01(s,1H),1.93(s,1H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Preparation of Compound I
Adding 11.8g of the oily substance compound II obtained in the step 2 and 23mL of THF into a 100mL three-necked flask, cooling to 0-5 ℃, dropwise adding 23.6mL of 70% formic acid aqueous solution, heating to room temperature, adding 11.3g of zinc powder in batches, stirring at room temperature for 2h, carrying out TLC detection to completely react, carrying out suction filtration, leaching a small amount of THF (tetrahydrofuran) of a filter cake, adjusting the pH of the filtrate to 8 with concentrated ammonia water, extracting with 50mL of 3 times of dichloromethane, combining organic layers, concentrating and drying the organic layers to obtain 11.5g of oily substance, dissolving the obtained oily substance in 113mL of ethanol, adding 8.5g D-mandelic acid, heating to reflux for 1h, stopping heating, cooling to 0-5 ℃ for crystallization for 2h, carrying out suction filtration, leaching a small amount of glacial ethanol of the filter cake, adding the obtained wet filter cake into a 250mL three-necked flask, adding a solution prepared from 115mL of dichloromethane, 2.5g of sodium hydroxide and 115mL of water, stirring at room temperature for 30, refining, separating, extracting water layer 30mL by 2 times with dichloromethane, combining organic layers, washing organic layer 30mL by 3 times with water, drying with anhydrous sodium sulfate, filtering, concentrating filtrate, and drying to obtain light yellow oily compound I9.2 g, yield 84.6%, purity 99.7%, isomer content 0.08%, and total yield 67.9%.
MS(ESI):m/z=190.2(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),5.11(s,2H)4.36~4.24(t,J=4.8、2.4Hz,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.78~2.42(m,2H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Example 6
Preparation of Compound III-a
The same as in example 3;
preparation of Compound II
Adding 12.3g of the oily compound III obtained in the step 1, 6.2g of hydroxylamine hydrochloride, 120mL of ethanol and 60mL of water into a 250mL three-necked bottle, stirring and cooling to 0 ℃, adding 11.9g of triethylamine, heating to reflux and reacting for 2h, recovering ethanol under reduced pressure after TLC detection reaction is completed, cooling to room temperature, adding 100mL of butyl acetate and 50mL of water, stirring for 10min, standing and separating, extracting with 50mL of butyl acetate in a water layer, combining organic layers, washing with 50mL of 2 times of water in the organic layer, concentrating and drying the organic layer to obtain 10.3g of the oily compound II, wherein the yield is 85.1%.
MS(ESI):m/z=206.3(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),4.36~4.24(t,J=4.8、2.4Hz,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.78~2.42(m,2H),2.01(s,1H),1.93(s,1H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Preparation of Compound I
Adding 10.3g of the oily substance compound II obtained in the step 2 and 23mL of THF into a 100mL three-necked flask, cooling to 0-5 ℃, dropwise adding 20.7mL of 70% formic acid aqueous solution, heating to room temperature, adding 9.9g of zinc powder in batches, stirring at room temperature for 2h, carrying out TLC detection to completely react, carrying out suction filtration, leaching a small amount of THF (tetrahydrofuran) of a filter cake, adjusting the pH of the filtrate to 8 with concentrated ammonia water, extracting with 50mL of 3 times of dichloromethane, combining organic layers, concentrating and drying the organic layers to obtain 10.1g of oily substance, dissolving the obtained oily substance into 103mL of ethanol, adding 7.7g D-mandelic acid, heating to reflux reaction for 1h, stopping heating, cooling to 0-5 ℃ for crystallization for 2h, carrying out suction filtration, leaching a small amount of glacial ethanol of the filter cake, adding the obtained wet filter cake into a 250mL three-necked flask, adding a solution prepared from 103mL of dichloromethane, 2.25g of sodium hydroxide and 103mL of water, stirring at room temperature, refining, separating, extracting water layer 30mL by 2 times with dichloromethane, combining organic layers, washing organic layer 30mL by 3 times with water, drying with anhydrous sodium sulfate, filtering, concentrating filtrate, and drying to obtain light yellow oily compound I8.2 g, yield 84.9%, purity 99.8%, isomer content 0.05%, and total yield 60.6%.
MS(ESI):m/z=190.3(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),5.11(s,2H)4.36~4.24(t,J=4.8、2.4Hz,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.78~2.42(m,2H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
Example 5
Preparation of Compound III-a
The same as in example 3.
Preparation of Compound II
The same as in example 3.
Preparation of Compound I
Adding 11.5g of the oily substance compound II obtained in the step 2 and 23mL of THF into a 100mL three-necked flask, cooling to 0-5 ℃, dropwise adding 23mL of 70% formic acid aqueous solution, heating to room temperature, adding 9.4g of iron powder in batches, stirring at room temperature for reaction for 4h, performing TLC detection to detect that the reaction is complete, performing suction filtration, leaching a small amount of THF of a filter cake, adjusting the pH of the filtrate to 8 with concentrated ammonia water, extracting with 50mL of 3 times of dichloromethane, combining organic layers, concentrating and drying the organic layers to obtain 11.5g of oily substance, dissolving the obtained oily substance in 113mL of ethanol, adding 8.5g D-mandelic acid, heating to reflux reaction for 1h, stopping heating, cooling to 0-5 ℃ for crystallization for 2h, performing suction filtration, leaching a small amount of ice ethanol to obtain a filter cake, adding the obtained filter cake into a 250mL three-necked flask, adding 115mL of dichloromethane, 2.5g of sodium hydroxide and 115mL of water into the obtained solution, stirring at room temperature for, refining, separating, extracting water layer 30mL by 2 times with dichloromethane, combining organic layers, washing organic layer 30mL by 3 times with water, drying with anhydrous sodium sulfate, filtering, concentrating filtrate, and drying to obtain light yellow oily compound I7.7 g with yield of 72.6%, purity of 99.1%, isomer content of 0.07%, and total yield of 56.9%.
MS(ESI):m/z=190.4(M+H+);
1H-NMR(400MHz,CDCl3)δ:7.18~7.02(m,1H),6.83~6.72(m,2H),5.11(s,2H)4.36~4.24(t,J=4.8、2.4Hz,2H),3.05~2.91(t,J=6.4、3.2Hz,2H),2.78~2.42(m,2H),1.56~1.42(m,1H),1.33~1.21(m,1H),0.72~0.28(m,2H)。
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A preparation method of a tasimelteon intermediate is characterized by at least comprising the following steps:
1) carrying out substitution reaction or sulfonation reaction on the compound IV to obtain a compound III;
2) reacting the compound III with hydroxylamine hydrochloride under the condition of an alkaline substance to obtain a compound II;
3) carrying out reduction reaction on the compound II to obtain a compound I;
the chemical reaction formula is as follows:
wherein, X in the compound III at least comprises one of Cl, Br, I, MsO and TsO.
2. The method for preparing the tasimelteon intermediate according to claim 1 wherein the substitution reagent in step 1) is a halogenated reagent; the sulfonation reaction reagent is a sulfonation reagent.
3. A process for the preparation of tasimelteon intermediates as in claim 2 where the halogenating agent includes one or more of thionyl chloride, phosphorus oxychloride, phosphorus tribromide, hydrobromic acid/acetic acid solution, dibromosulphoxide, carbon tetrabromide/triphenylphosphine, bromine, hydroiodic acid, sodium iodide, iodine/triphenylphosphine; the sulfonation reagent comprises one or more of methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.
4. The preparation method of the tasimelteon intermediate according to claim 1 wherein the reaction solvent in step 1) comprises one or more of dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, 1, 4-dioxane; the reaction temperature is 15-35 ℃; the reaction time is 1-5 h.
5. The method for preparing the tasimelteon intermediate according to claim 1, wherein the basic substance in step 2) comprises one or more of sodium bicarbonate, potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, triethylamine, tri-n-propylamine; the reaction solvent comprises one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and water; the reaction time is 1-10 h; the molar ratio of the compound III to the hydroxylamine hydrochloride is 1: (1-3); the molar ratio of the compound III to the alkaline substance is 1: (1-5).
6. The method for preparing the tasimelteon intermediate according to claim 1, wherein the reducing agent in step 3) comprises one or more of zinc powder, iron powder, sodium borohydride, potassium borohydride, hydrogen gas, and hydrazine hydrate.
7. The preparation method of the tasimelteon intermediate as described in claim 1, wherein the reaction solvent in step 3) comprises one or more of tetrahydrofuran, toluene, chlorobenzene, cyclohexane, acetonitrile, DMF, 1, 4-dioxane, acetone, ethanol, isopropanol, and methanol; the reaction temperature is 15-35 ℃; the reaction time is 1-10 h; the molar ratio of the compound II to the reducing agent is 1: (1-10).
9. the preparation method of the tasimelteon intermediate according to claim 8, wherein the reducing agent in the preparation method of the compound iv comprises one or more of sodium borohydride, potassium borohydride and borane.
10. The preparation method of the tasimelteon intermediate of claim 8, wherein the compound v is prepared by the steps of:
reacting the compound VI with a reagent and an alkaline substance to obtain a compound V;
the reagent comprises one or more of phosphoryl acetic acid trimethyl ester, phosphoryl acetic acid tripropyl ester and phosphoryl acetic acid triisopropyl ester;
the alkaline substance comprises one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-amylate, potassium acetate, sodium acetate, potassium fluoride, cesium carbonate, potassium carbonate and sodium carbonate;
the reaction formula is as follows:
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WO2016109359A1 (en) * | 2014-12-29 | 2016-07-07 | Auspex Pharmaceuticals, Inc. | Cyclopropyl dihydrobenzofuran modulators of melatonin receptors |
US9944616B2 (en) * | 2016-06-08 | 2018-04-17 | Apotex Inc. | Processes for the preparation of Tasimelteon and intermediates thereof |
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WO2016109359A1 (en) * | 2014-12-29 | 2016-07-07 | Auspex Pharmaceuticals, Inc. | Cyclopropyl dihydrobenzofuran modulators of melatonin receptors |
US9944616B2 (en) * | 2016-06-08 | 2018-04-17 | Apotex Inc. | Processes for the preparation of Tasimelteon and intermediates thereof |
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