CN102942542A - Preparation method of 2, 3-dihydrobenzofuran compound - Google Patents
Preparation method of 2, 3-dihydrobenzofuran compound Download PDFInfo
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- CN102942542A CN102942542A CN2012104729257A CN201210472925A CN102942542A CN 102942542 A CN102942542 A CN 102942542A CN 2012104729257 A CN2012104729257 A CN 2012104729257A CN 201210472925 A CN201210472925 A CN 201210472925A CN 102942542 A CN102942542 A CN 102942542A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- -1 2, 3-dihydrobenzofuran compound Chemical class 0.000 title claims abstract description 17
- HBEDSQVIWPRPAY-UHFFFAOYSA-N dihydro-benzofuran Natural products C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 110
- 239000002994 raw material Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims description 126
- 150000003839 salts Chemical class 0.000 claims description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 229940125898 compound 5 Drugs 0.000 claims description 22
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 20
- 235000010755 mineral Nutrition 0.000 claims description 20
- 239000011707 mineral Substances 0.000 claims description 20
- 150000007530 organic bases Chemical class 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 239000003513 alkali Substances 0.000 claims description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 16
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 14
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 13
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 239000002131 composite material Substances 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 12
- 238000005660 chlorination reaction Methods 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 11
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 238000006555 catalytic reaction Methods 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 6
- OPLYDSLPKIFDAA-UHFFFAOYSA-M [F-].[S+](=O)(=O)=O Chemical compound [F-].[S+](=O)(=O)=O OPLYDSLPKIFDAA-UHFFFAOYSA-M 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000005905 mesyloxy group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- MLIWQXBKMZNZNF-KUHOPJCQSA-N (2e)-2,6-bis[(4-azidophenyl)methylidene]-4-methylcyclohexan-1-one Chemical group O=C1\C(=C\C=2C=CC(=CC=2)N=[N+]=[N-])CC(C)CC1=CC1=CC=C(N=[N+]=[N-])C=C1 MLIWQXBKMZNZNF-KUHOPJCQSA-N 0.000 claims description 4
- WNEYAIJFUGWKBT-UHFFFAOYSA-M S(=O)(=O)=[Cl+].[F-] Chemical compound S(=O)(=O)=[Cl+].[F-] WNEYAIJFUGWKBT-UHFFFAOYSA-M 0.000 claims description 4
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 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 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Chemical group 0.000 claims description 2
- 239000001257 hydrogen Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 153
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 238000003756 stirring Methods 0.000 description 32
- 239000007787 solid Substances 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 21
- 239000010410 layer Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- ZPMNHBXQOOVQJL-UHFFFAOYSA-N prucalopride Chemical compound C1CN(CCCOC)CCC1NC(=O)C1=CC(Cl)=C(N)C2=C1OCC2 ZPMNHBXQOOVQJL-UHFFFAOYSA-N 0.000 description 11
- 229960003863 prucalopride Drugs 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 11
- 0 *c(c(O)c1CC=C)ccc1N Chemical compound *c(c(O)c1CC=C)ccc1N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 230000008030 elimination Effects 0.000 description 7
- 238000003379 elimination reaction Methods 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 description 6
- UJVWPZIWWKDJNH-UHFFFAOYSA-N (4-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound CC(=O)NC1=CC=C([As](O)(O)=O)C(O)=C1 UJVWPZIWWKDJNH-UHFFFAOYSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010010774 Constipation Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000012675 alcoholic extract Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052703 rhodium Inorganic materials 0.000 description 3
- 239000010948 rhodium Substances 0.000 description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 2
- 229960004909 aminosalicylic acid Drugs 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- QKWTXJSLAZKYGV-UHFFFAOYSA-N methyl 4-acetamidobenzoate Chemical compound COC(=O)C1=CC=C(NC(C)=O)C=C1 QKWTXJSLAZKYGV-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- OBSLWIKITOYASJ-AZEWMMITSA-N (2r,3s,4s,5r,6s)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical compound CN[C@@H]1[C@H](O)O[C@@H](CO)[C@H](O)[C@H]1O OBSLWIKITOYASJ-AZEWMMITSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
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- KUCQOJIVYWUYLG-UHFFFAOYSA-N ClC[Si](C)(C)C#CI Chemical group ClC[Si](C)(C)C#CI KUCQOJIVYWUYLG-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
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- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
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- 239000005557 antagonist Substances 0.000 description 1
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- 239000001530 fumaric acid Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 125000006239 protecting group Chemical group 0.000 description 1
- 229950010671 prucalopride succinate Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of a 2, 3-dihydrobenzofuran compound. According to the method, substituent p-amino m-allyl o-hydroxybenzene methyl ester is used as a raw material, and the raw material is subjected to a series of reaction of oxidization, reduction, protection, substitution, cyclization and hydrolyzation to prepare the 2, 3-dihydrobenzofuran compound. The preparation method is simple in reaction, low in costs, high in conversion ratio and simple in aftertreatment, and industrial production is easy to achieve.
Description
Technical field
The invention belongs to the organic synthesis field, be specifically related to prucalopride key intermediate 2, the preparation of 3-Dihydrobenzofuranes compounds.
Background technology
Succsinic acid prucalopride (Prucalopride succinate, chemical name 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxy-propyl)-4-piperidyl]-7-benzofuran carboxamides succinate), by Belgian Movetis company according to (the Johnson ﹠amp of Janssen company; Subsidiary Company under the Johnson) authorization development, in October, 2009, got the Green Light in Europe in October, 2009 in the granted women's chronic constipation that is used for the treatment of of the U.S., and go on the market in Germany in January, 2010, and go on the market trade(brand)name Resolor in March, 2010 in Britain.China ratifies the tablet of Janssen Pharmaceutica N.V. company in the clinical trial of China in April, 2010, is used for the symptomatic treatment of women's chronic constipation that cathartic can't fully alleviate.The succsinic acid prucalopride is the novel serotonin 5-HT4 of the first receptor-selective, high-affinity antagonists, can trigger wriggling, compare with similar drugs, have that the 5-HT4 receptor-selective is high, avidity is strong, rapid-action, untoward reaction is few, the characteristics of better tolerance, in the constipation therapy field wide potential applicability in clinical practice is arranged.
Compound patent US5854260A has announced 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid directly and 1-(3-methoxy-propyl)-4-piperylhydrazine condensation, salify obtain the method for succsinic acid prucalopride.This route steps is simple, and yield is higher, is fit to suitability for industrialized production.
The key intermediate of ambroid acid prucalopride is 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid (compound 1), and synthetic method has following several:
Patent of invention US5374637 is take m-anisidine as raw material; protect through pivaloyl group; hydroxyethylation, cyclization, chloro, bromo under the butyllithium effect obtain 4-amino-5-chloro-2 with carbon dioxide reaction, 3-Dihydrobenzofuranes-7-carboxylic acid at last under the butyllithium effect.This route uses butyllithium twice, needs-78 ℃ of low temperature, and the isomer that chloro produces need be through the column chromatography separation, operation inconvenience, and yield only has 18%.
[Synlett 1993 for document, (4), 269-270] take 4-acetamido-2 hydroxybenzoic acid methyl esters as raw material, cyclization behind chloro, iodo, trimethylsilyl acetylene, hydro-reduction under rhodium catalysis, at last hydrolysis obtains 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid, yield 38% is used silica reagent and the rhodium reagent of high price in the route, be unsuitable for a large amount of preparations.
Document [Chem.Pharm.Bull.1998; 46 (1); 42-52] take para-aminosalicylic acid as raw material; after esterification, acetylize, generate allyl group in the hydroxyl reaction; allyl group moves to the hydroxyl ortho position under heating condition; then alkene is oxidized to the aldehyde of a few carbon atom, becomes alcohol with sodium borohydride reduction again.At catalysis ShiShimonoseki of triphenyl phosphorus ring, slough protecting group after the chlorination and generated 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid.This highway route design is reasonable, and productivity ratio is more satisfactory, but has used hypertoxic perosmic anhydride reagent in the reaction, has the labour protection problem, and in the aftertreatment of reaction of a few step the column chromatography operation is arranged, and is not suitable for suitability for industrialized production.
Document [former friendly will, Deng of man of Tang, Cen Junda. Chinese Journal of Pharmaceuticals 2012; 43 (1); 5-8] take para-aminosalicylic acid as raw material, after esterification, acetylize and chloro, bromo, bromotrifluoromethane, cyclization and hydrolysis, obtain 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid.Operation is easy, mild condition, but productive rate is on the low side, is not suitable for a large amount of productions.
Therefore, the key intermediate of seeking the succsinic acid prucalopride is 4-amino-5-chloro-2, and the synthetic method of 3-Dihydrobenzofuranes-7-carboxylic acid (compound 1) is significant.
Summary of the invention
The object of the invention is to provide a kind of 2, the preparation method of 3-Dihydrobenzofuranes compounds [structure is shown in formula I] is with synthetic 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid (compound 1), for the preparation of the succsinic acid prucalopride, to satisfy the needs of relevant branch of industry.
The present invention also aims to provide the preparation method of another kind of 2,3-Dihydrobenzofuranes compounds [structure is suc as formula shown in the III].
Described 2,3-Dihydrobenzofuranes compounds comprise have formula I, free alkali or its organic acid or the formed salt of mineral acid of the compound shown in formula (I ") and the III.
Purpose of the present invention can reach by following measures:
A kind of 2, the preparation method of 3-Dihydrobenzofuranes compounds, adopting compound 7 be starting raw material, selects ruthenium trichloride or its hydrate/periodate composite catalyst to promote to react, and obtains compound 6; Obtain compound 5 after aldehyde radical in the compound 6 is reduced to hydroxyl, be substituted again reaction and connect upper leavings group Z, proceed ring closure reaction and obtain compound (I), obtain compound 2 through chlorination again, obtain compound 1 finally by hydrolysis reaction,
Wherein, R is C
1-6Straight chained alkyl, benzyl, halogeno-benzyl, C
1-4Alkyl benzyl, diphenyl-methyl or the tertiary butyl are preferably methyl; X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6The straight chained alkyl acyl group is preferably ethanoyl; Z is halogen, tolysulfonyl oxygen base, trimethyl fluoride sulfonyl oxygen base, mesyloxy or phenylsulfonyloxy; Wherein halogen is preferably chlorine.
But starting material compound 7 reference [Chem.Pharm.Bull.1998,46 (1), 42-52] method is made by oneself or is purchased.
In the reaction of preparation compound 6, catalyzer is selected ruthenium trichloride or its hydrate/periodate composite catalyst, and wherein periodate can adopt sodium periodate or potassium periodate.Further, catalyzer is selected ruthenium trichloride/sodium periodate, ruthenium trichloride/potassium periodate, ruthenium trichloride hydrate/sodium periodate or ruthenium trichloride hydrate/potassium periodate composite catalyst.The mole dosage of ruthenium trichloride or its hydrate is 1%～8% of compound 7 in the composite catalyst, preferred 2%～4%; The molar weight of periodate is 1～10 times of compound 7, preferred 3～6 times; This temperature of reaction is 0～80 ℃, and preferred 10 ℃～40 ℃, this reaction times is 1～12h.
The composite catalyst that this reaction is selected, cheap and easy to get, avoided the silica reagent of high price and the Cost Problems that rhodium reagent place brings, avoided simultaneously the harm of using hypertoxic perosmic anhydride reagent that environment is caused.
The present invention also provides the conventional preparation method of compound 5 and compound 4, but is not limited only to following method:
Adopting compound 6 reduce aldehyde radical under the effect of sodium borohydride is hydroxyl, prepares compound 5, and its reaction solvent can be selected methyl alcohol or tetrahydrofuran (THF), and temperature of reaction is 20 ℃～30 ℃, reaction afterwards with acid for adjusting pH value to 5-6.
Adopt compound 5 or its salt and the reactions such as sulfur oxychloride, Tosyl chloride, trimethyl fluoride sulfonyl chlorine, methylsulfonyl chloride or benzene sulfonyl chloride, preparation compound 4 or its salt, reactant preferably adopts sulfur oxychloride or Tosyl chloride, most preferably sulfur oxychloride.Concrete grammar can adopt existing ordinary method, for example with after compound 5 dissolvings, drips sulfur oxychloride or Tosyl chloride under the low temperature, chlorination obtains compound 4, this reaction solvent is DMF or methylene dichloride, and temperature of reaction is 0 ℃～30 ℃.
In the reaction of preparation compound (I), compound 4 carries out ring closure reaction under organic bases or mineral alkali catalysis, preparation compound (I); Wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or the tri-tert amine; The consumption of organic bases or mineral alkali is 1～4 times of compound 4 molar weights.This reaction can be carried out in organic solvent, such as DMF or THF; The temperature of reaction is controlled at room temperature to reflux temperature, preferred 20 ℃～100 ℃.
This reaction changes route in the past, and alcoholic extract hydroxyl group is carried out substitution reaction, and the leavings group that connects closes ring again, and reaction obtains target compound (I).This route closes the ring method than other to be compared, and reaction is simple, and cost is low, and transformation efficiency is high, and aftertreatment is simple, is easy to suitability for industrialized production.
The present invention also provides by compound (I) reaction and has obtained the conventional preparation method of succsinic acid prucalopride key intermediate compound 1, but is not limited only to following method:
Compound (I) and N-chlorosuccinimide are obtained compound 2 30 ℃～100 ℃ lower reactions.Compound 2 reacts under the sodium hydroxide effect, again with acid for adjusting pH value to 6-7, obtain compound 1.For example when R be methyl, when X is ethanoyl, can be with compound 2 and sodium hydroxide 40～100 ℃ of reactions, after the reaction again with acid for adjusting pH value to 6-7, and get final product.
During by compound 5 reaction preparations 2,3-Dihydrobenzofuranes compounds, two kinds of routes are arranged: i.e. the phenolic hydroxyl group contraposition of the derivative of compound 7 can be gone up first chlorine before the ring-closure reaction, also can go up chlorine after closed loop again.After the alcoholic extract hydroxyl group of compound 5 is replaced by leavings group, ring-closure reaction, then the phenolic hydroxyl group contraposition under the effect of the chlorinating agents such as sulfuryl chloride on during chlorine, namely obtain compound (I ").When the alcoholic extract hydroxyl group of compound 5 is replaced by leavings group, then ring-closure reaction obtains compound (I), then under the effect of the chlorinating agents such as N-chlorosuccinimide, the upper chlorine of phenolic hydroxyl group contraposition reaction is obtained compound 2.
Therefore the present invention also provides the preparation method of another kind of 2,3-Dihydrobenzofuranes compounds, adopting compound 7 is starting raw material, selects ruthenium trichloride or its hydrate/periodate composite catalyst to promote reaction, obtains compound 6 or its salt; Obtain compound 5 or its salt after aldehyde radical in compound 6 or its salt is reduced to hydroxyl, again with continue to be substituted reaction after chlorination reagent reacts chlorination and be connected leavings group Z, obtain compound 4 " or its salt; compound 4 " or its salt carry out ring closure reaction and obtain compound (I "); obtain compound 1 finally by hydrolysis reaction
Wherein, the group in various and compound 6, a same route of preparation of 5 and 1.
The invention provides compound 4 " conventional preparation method, but be not limited only to following method:
At preparation compound 4 " process in; compound 5 or its salt carry out chlorination with sulfuryl chloride or N-chlorosuccinimide first; with sulfur oxychloride, Tosyl chloride, trimethyl fluoride sulfonyl chlorine, methylsulfonyl chloride or benzene sulfonyl chloride reaction, leavings group Z in connections prepares compound 4 again ".For example compound 5 and N-chlorosuccinimide carry out chlorination under 50 ℃～90 ℃ with the phenolic hydroxyl group contraposition on chlorine, and then obtain compound 4 with the sulfur oxychloride reaction ".
In the preparation compound I " reaction in, compound 4 " under organic bases or mineral alkali catalysis, carry out ring closure reaction, preparation compound (I "); Wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or the tri-tert amine; The consumption of organic bases or mineral alkali is compound 4 " 1～4 times of molar weight; The temperature of reaction is controlled at room temperature to reflux temperature, and preferred 20 ℃～100 ℃, the reaction times is 1～24h.
The present invention also provides compound 6 " the preparation method; it is characterized in that adopting compound 7 " or its salt be starting raw material, select ruthenium trichloride or its hydrate/periodate composite catalyst to promote reaction, obtain compound 6 "; wherein the mole dosage of ruthenium trichloride or its hydrate is compound 7 " 1%～8%, preferred 2%～4%; The molar weight of periodate is compound 7 " 1～10 times, preferred 3～6 times, this temperature of reaction is 0～100 ℃,
Wherein, X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6The straight chained alkyl acyl group.
Can be with compound 6 " with reference to above-mentioned two kind 2, the preparation method of 3-Dihydrobenzofuranes compounds reacts, and finally obtains compound 1.
Can be to compound 6 " carboxyl protection obtain compound 6, then with reference to above-mentioned two kind 2, the preparation method of 3-Dihydrobenzofuranes compounds finally obtains compound 1.
Also can be with compound 6 " aldehyde radical is reduced into hydroxyl under the effect of the reductive agents such as sodium borohydride, then carboxyl is protected, and obtains compound 5, and then with reference to above-mentioned two kind 2, the preparation method of 3-Dihydrobenzofuranes compounds finally obtains compound 1.
The invention provides another 2, the preparation method of 3-Dihydrobenzofuranes compounds III, it is characterized in that adopting compound ii or its salt is starting raw material, carry out ring closure reaction and obtain the compound III,
Wherein, Y is chlorine or hydrogen; X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6The straight chained alkyl acyl group; Z is halogen, tolysulfonyl oxygen base, trimethyl fluoride sulfonyl oxygen base, mesyloxy or phenylsulfonyloxy.
Compound ii can take off the R group by compound 4 and obtain under the condition of acid, also can pass through compound 6 " through the aldehyde radical reduction reaction, the hydroxyl substitution reaction obtains, but be not limited only to this method.
Compound ii or its salt carry out ring closure reaction under organic bases or mineral alkali catalysis, wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or the tri-tert amine; The consumption of organic bases or mineral alkali is 1～4 times of compound ii molar weight.
" salt " expression among the present invention in compound 7 or its salt, compound 6 or its salt, compound 5 or its salt, compound 4 or its salt does not have or less dysgenic those salt reaction process.This class salt can include but not limited to: the salt that (1) becomes with acid, comprise mineral acid, such as (but being not limited to) hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid such as (but being not limited to) acetic acid, propionic acid, vinylformic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid etc.(2) salt that becomes with metal ion or organic bases, metal ion is alkalimetal ion, alkaline-earth metal ions or aluminum ion for example, organic bases such as thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc.
The present invention by reactions such as a series of oxidation, reduction, protection, replacement, pass ring, hydrolysis, prepares 2,3-Dihydrobenzofuranes compounds to replace allyl group o-hydroxy methyl esters between amino as raw material.Adopt of the present inventionly 2,3-Dihydrobenzofuranes compounds can prepare 4-amino-5-chloro-2 easily, 3-Dihydrobenzofuranes-7-carboxylic acid (compound 1), thus can prepare more easily the succsinic acid prucalopride, to satisfy the needs of medicine industry.This route reaction is simple, and cost is low, and transformation efficiency is high, and aftertreatment is simple, is easy to suitability for industrialized production.
Embodiment
Following examples further describe the present invention, and still, these embodiment only are for explanation the present invention, rather than limitation of the scope of the invention.
Embodiment 12-hydroxyl-3-(2-aldehyde-base)-(preparation of compound 6 ') of 4-acetyl-amino-benzoic acid methyl ester
Chemical equation
Operation steps
In the 10L reaction flask, under the nitrogen protection, add 160g compound 7 ', 6.2g ruthenium trichloride monohydrate, 7.2g benzyltriethylammoinium chloride and 1142ml ethyl acetate; open and stir; drip the mixing solutions of 687g sodium periodate and 7140ml water, between warm 20～30 ℃, drip and finish in the control; react 1.5h under the room temperature; developping agent is carried out in TLC monitoring reaction: petrol ether/ethyl acetate=1/1, the Rf=0.5 of raw material (compound 7 '); the Rf=0.4 of product, TLC show that the raw material primitive reaction is complete.Stopped reaction adds the 3570ml ethyl acetate, stirs 10 minutes, tells ethyl acetate layer, water layer extracts with ethyl acetate 2140ml * 2, combined ethyl acetate layer, water 2140ml * 2 washings, ethyl acetate layer anhydrous sodium sulfate drying, be spin-dried for, get the 142g black solid, be compound 6 '.
The compound 6 ' that obtains is added 2035ml methyl alcohol, stir, be cooled to 0 ℃, add the 52.4g sodium borohydride in batches, finish, between 20～25 ℃, react 15h, developping agent is carried out in TLC monitoring reaction: petrol ether/ethyl acetate=1/1,6 ' Rf=0.4 of compound, product 5 ' Rf=0.3, TLC shows that primitive reaction is complete.Stopped reaction, transfer between its pH value to 5～6 with the 6mol/L aqueous hydrochloric acid under the ice-water bath, continue to stir 1h, the elimination insolubles, filtrate is spin-dried for, and gets enriched material, adds the 8900ml ethyl acetate, water 2700ml * 3 washings, combining water layer extracts once with ethyl acetate 2700ml again, merges the organic layer anhydrous sodium sulfate drying, be spin-dried for, get gray solid, add inwards the 1250ml ethyl acetate and be heated to backflow, slowly add the 2500ml sherwood oil, continue to reflux 10 minutes, then naturally cool to stirring at room crystallization 12h.Suction filtration, filter cake are with 50ml ethyl acetate/petroleum ether=1/2 mixed solution washing, and 40 ℃ of vacuum-dryings get the 121.7g gray solid, be compound 5 ', yield: 75%.
1HNMR(DMSO-d6)：δ11.09(1H,s)、δ9.61(1H,s)、δ7.64(1H,d)、δ7.39(1H,d)、δ5.22(1H,br)、δ3.89(3H,s)、δ3.59(2H,t)、δ2.85(2H,t)、δ2.09(3H,s)；
MS(ESI)：254.1([M+H]
+)，276.1([M+Na]
+)。
Embodiment 2 compounds (I ') 4-acetylaminohydroxyphenylarsonic acid 2, the preparation of 3-Dihydrobenzofuranes-7-carboxylate methyl ester
Chemical equation
Operation steps
In the 500ml four-hole bottle, add 48g compound 5 and ' with 288Ml DMF, stir molten clear.Be cooled to 0～10 ℃, splash into the 22.6g sulfur oxychloride, approximately dripped in 30 minutes and finish.Rise to room temperature reaction 2h, TlC monitors reaction, developping agent: petrol ether/ethyl acetate=1/1, compound 5 ' Rf=0.3, the Rf=0.8 of product, TLC show and to react completely.Stopped reaction, reaction solution is evaporated to dried between 50～60 ℃, get the 51.5g gray solid be compound 4 '.
1HNMR(DMSO-d6)：δ11.14(1H,s)、δ9.57(1H,s)、δ7.68(1H,d)、δ7.22(1H,d)、δ3.90(3H,s)、δ3.69(2H,t)、δ3.12(2H,t)、δ2.11(3H,s)；
MS(ESI)：272.1([M+H]
+)，294.1([M+Na]
+)。
51.5g compound 4 ' is added in the 2L reaction flask, and adding 720ml tetrahydrofuran (THF) and 38.4g triethylamine, stir, be heated to back flow reaction 12h, TlC monitors reaction, developping agent: petrol ether/ethyl acetate=1/1, compound 4 ' Rf=0.8, (Rf=0.2 of I '), the TLC demonstration reacts completely compound.Stopped reaction is cooled to room temperature, the elimination insolubles, and filtrate is spin-dried for, and gets residue, adds inwards the 960ml ethyl acetate, and wash water 360ml, 20% wet chemical 360ml and saturated sodium-chloride water solution 360ml * 2 respectively.Combining water layer, water layer use ethyl acetate 360ml * 2 to extract again, and the combined ethyl acetate layer with 20g activated carbon decolorizing 1h, is used anhydrous sodium sulfate drying again.The filtering siccative, filtrate is spin-dried for, and gets the 45g solid-liquid.Add inwards the 80ml ethyl acetate, being heated to refluxes makes its dissolving, slowly adds the 96ml sherwood oil, finishes again insulation backflow 5 minutes, then naturally cools to room temperature, changes stirring and crystallizing 10h between 3～8 ℃ over to again.Suction filtration, filter cake washs with the cold ethyl acetate/petroleum ether of 30ml=1/1 mixed solution, and 40 ℃ of vacuum-dryings get 37.9g off-white color solid, are compound (I '), yield 85%.
1HNMR(DMSO-d6)：δ9.54(1H,s)、δ7.56(1H,d)、δ7.41(1H,d)、δ4.63(2H,t)、δ3.75(3H,s)、δ3.15(2H,t)、δ2.10(3H,s)；
MS(ESI)：236.1([M+H]
+)，258.1([M+Na]
+)。
Embodiment 34-amino-5-chloro-2, the preparation of 3-Dihydrobenzofuranes-7-carboxylic acid (compound 1)
Chemical equation
Operation steps
In the 2L four-hole boiling flask, add 140g 4-acetylaminohydroxyphenylarsonic acid 2,3-Dihydrobenzofuranes-7-carboxylate methyl ester and 78.4g N-chlorosuccinimide, and 840ml DMF.Open to stir, be warming up to 70 ℃ of reactions, developping agent is carried out in TLC monitoring reaction: petrol ether/ethyl acetate=1/2, compound (Rf=0.3 of I '), compound 2 ' Rf=0.6.Behind the reaction 3h, the TLC demonstration reacts completely.Stopped reaction, the reaction solution decompression steams approximately 600mlDMF.Be warming up to 70 ℃, slowly add 840ml water, slowly cool to 10-15 ℃ of stirring and crystallizing 2h behind 70 ℃ of stirring 30min, suction filtration, an amount of frozen water washing leaching cake, 45 ℃ of vacuum-drying 12h, obtain the 114.8g yellow solid, be 4-acetylaminohydroxyphenylarsonic acid 5-chloro-2,3-Dihydrobenzofuranes-7-carboxylate methyl ester (compound 2 '), yield 70%.
In the 5L four-hole boiling flask, add 112g 4-acetylaminohydroxyphenylarsonic acid 5-chloro-2,3-Dihydrobenzofuranes-7-carboxylate methyl ester and 1120ml methyl alcohol, open and stir, slowly add 8mol/LNaOH aqueous solution 1120ml, be warming up to back flow reaction, TLC monitoring reaction is carried out, developping agent: petrol ether/ethyl acetate=1/2, compound 2 ' Rf=0.6, the Rf=0.0 of compound 1.Behind the reaction 10h, TLC shows that raw material reaction is complete.Stopped reaction is cooled to 5～10 ℃ and transfers its pH value to 6-7 with the 8mol/L HCl aqueous solution, and insulated and stirred 1h separates out solid again.Suction filtration, 50ml frozen water washing leaching cake, 45 ℃ of vacuum-drying 12h.Filtrate is spin-dried for to get solid, adds the 500ml ethyl acetate, is warming up to 50 ℃ and stirs 30min, is cooled to room temperature, suction filtration.Filter cake is 50 ℃ of approximately 300ml water stirrings of lower adding, then be cooled to stirring and crystallizing 2h between 10～15 ℃, suction filtration, 20ml frozen water washing leaching cake, 45 ℃ of vacuum-drying 12h merge twice solid and obtain the 78.7g gray solid, are succsinic acid prucalopride key intermediate 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid (compound 1), yield: 89%.
1HNMR(DMSO-d6)：δ11.99(1H,s)、δ7.43(1H,s)、δ5.93(2H,s)、δ4.60(2H,t)、δ2.98(2H,t)；
MS(ESI)：212.1([M-H]
+)。
Embodiment 4 compounds (12) 4-acetylaminohydroxyphenylarsonic acid 2, the preparation of 3-Dihydrobenzofuranes-7-carboxylic acid
Chemical equation
Operation steps
In the 10L reaction flask; under the nitrogen protection; add 160g compound 8,6.2g ruthenium trichloride monohydrate, 7.2g benzyltriethylammoinium chloride and 1142ml ethyl acetate; open and stir; drip the mixing solutions of 727g sodium periodate and 7140ml water under the room temperature; drip and finish; react 2h under the room temperature, stopped reaction adds 3570ml, 2140ml * 2 ethyl acetate extraction; the combined ethyl acetate layer; water 2140ml * 2 washings, the ethyl acetate layer anhydrous sodium sulfate drying is spin-dried for; get the 110g black solid, be compound 9.
The compound 9 that obtains is added 2035ml methyl alcohol, stir, be cooled to 0 ℃, add the 43.3g sodium borohydride in batches, finish, in room temperature reaction 15h.Stopped reaction is transferred between its pH value to 5～6 with the 6mol/L aqueous hydrochloric acid under the ice-water bath, continues to stir 1h, the elimination insolubles, filtrate is spin-dried for, and gets enriched material, add the 8900ml ethyl acetate, water 2700ml * 3 washings, combining water layer, extract once with ethyl acetate 2700ml again, merge organic layer, anhydrous sodium sulfate drying, be spin-dried for, get gray solid, add inwards the 1250ml ethyl acetate and be heated to backflow, then naturally cool to stirring at room crystallization 12h.Suction filtration, filter cake washs with the 50ml ethyl acetate, and 40 ℃ of vacuum-dryings get the 97.6g gray solid, are compound 10, yield: 60%.MS(ESI)：240.1([M+H]
+)。
In the 1000ml four-hole bottle, add 97.6g compound 10 and 580MLDMF, stir molten clear.Be cooled to 0～10 ℃, add the 77.7g Tosyl chloride in batches, finish.Rise to room temperature reaction 2h.Stopped reaction, reaction solution is evaporated to dried between 50～60 ℃, gets the 160.5g gray solid, uses methylene dichloride: the moving phase of methyl alcohol=5:1 is crossed pillar, gets solid 40.2g, is compound 11.
40g compound 11 is added in the 1L reaction flask, and add 400ml tetrahydrofuran (THF) and 20.6g triethylamine, stir, be heated to back flow reaction 12h.Stopped reaction is cooled to room temperature, the elimination insolubles, and filtrate is spin-dried for, and gets residue, adds inwards the 250ml ethyl acetate, and wash water 100ml, 15% aqueous hydrochloric acid 100ml and saturated sodium-chloride water solution 100ml * 2 respectively.Ethyl acetate layer is used anhydrous sodium sulfate drying again with 8g activated carbon decolorizing 1h.The filtering siccative, filtrate is spin-dried for, and gets residue.Add inwards 80ml ethyl acetate reflux, then naturally cool to room temperature, suction filtration, filter cake washs with cold ethyl acetate, and 40 ℃ of vacuum-dryings get 15.1g off-white color solid, are compound (12), yield 69%.MS(ESI)：222.08([M+H]
+)。
Embodiment 5 compounds (17) 4-benzyloxycarbonyl amino-2, the preparation of 3-Dihydrobenzofuranes-7-carboxylic acid, ethyl ester
Chemical equation
Operation steps
In the 10L reaction flask; under the nitrogen protection; add 160g compound 13,6.2g ruthenium trichloride monohydrate, 7.2g benzyltriethylammoinium chloride and 1142ml ethyl acetate; open and stir; drip the mixing solutions of 481g sodium periodate and 5100ml water under the room temperature; drip and finish; react 2h under the room temperature, stopped reaction adds 3570ml, 2140ml * 2 ethyl acetate extraction; the combined ethyl acetate layer; water 2140ml * 2 washings, the ethyl acetate layer anhydrous sodium sulfate drying is spin-dried for; get the 120g black solid, be compound 14.
The compound 14 that obtains is added 2035ml methyl alcohol, stir, be cooled to 0 ℃, add the 34.1g sodium borohydride in batches, finish, in room temperature reaction 15h.Stopped reaction is transferred between its pH value to 5～6 with the 6mol/L aqueous hydrochloric acid under the ice-water bath, continues to stir 1h, the elimination insolubles, filtrate is spin-dried for, and gets enriched material, add the 8900ml ethyl acetate, water 2700ml * 3 washings, combining water layer, extract once with ethyl acetate 2700ml again, merge the organic layer anhydrous sodium sulfate drying, be spin-dried for, get gray solid, add inwards the 1250ml ethyl acetate and be heated to backflow, then naturally cool to stirring at room crystallization 12h.
Suction filtration, filter cake washs with the 50ml ethyl acetate, and 40 ℃ of vacuum-dryings get the 102g gray solid, are compound 15, yield: 63%.MS(ESI)：360.1([M+H]
+)。
In the 1000ml four-hole bottle, add 102g compound 15 and 580MLDMF, stir molten clear.Be cooled to 0～10 ℃, splash into the 33.8g sulfur oxychloride, drip and finish.Rise to room temperature reaction 2h.Stopped reaction, reaction solution is evaporated to dried between 50～60 ℃, gets the 107g gray solid and is compound 16.MS(ESI)：378.1([M+H]
+)。
107g compound 16 is added in the 2L reaction flask, and add 1500ml tetrahydrofuran (THF) and 57.3g triethylamine, stir, be heated to back flow reaction 12h.Stopped reaction is cooled to room temperature, the elimination insolubles, and filtrate is spin-dried for, and gets residue, adds inwards the 1000ml ethyl acetate, and wash water 300ml, 20% wet chemical 300ml and saturated sodium-chloride water solution 300ml * 2 respectively.Ethyl acetate layer is used anhydrous sodium sulfate drying again with 20g activated carbon decolorizing 1h.The filtering siccative, filtrate is spin-dried for, and gets residue.Add inwards 80ml ethyl acetate reflux, then naturally cool to room temperature, suction filtration, filter cake washs with cold ethyl acetate, and 40 ℃ of vacuum-dryings get 63g off-white color solid, are compound (17), yield 65%.MS(ESI)：342.1([M+H]
+)。
Embodiment 64-acetylaminohydroxyphenylarsonic acid 5-chloro-2, the 3-Dihydrobenzofuranes-7-carboxylate methyl ester (preparation of compound 2 ')
Chemical equation
Operation steps
In the 2L four-hole boiling flask, add 140g compound 5 ' and 73.8g N-chlorosuccinimide, and 840ml DMF.Open and stir, be warming up to 70 ℃ of reaction 3h.Stopped reaction, removal of solvent under reduced pressure adds 840ml water in residue, stirring and crystallizing 2h under the room temperature, suction filtration, the suitable quantity of water washing leaching cake, 45 ℃ of vacuum-drying 12h obtain the 87.5g yellow solid, are compound 18, yield 55%.MS(ESI)：288.1([M+H]
+)。
In the 1000ml four-hole bottle, add 87.5g compound 18 and 500MLDMF, stir molten clear.Be cooled to 0～10 ℃, splash into the 36.2g sulfur oxychloride, drip and finish.Rise to room temperature reaction 2h.Stopped reaction, reaction solution is evaporated to dried between 50～60 ℃, gets the 93.1g gray solid and is compound 19.MS(ESI)：306.1([M+H]
+)。
93.1g compound 19 is added in the 2L reaction flask, and add 1400ml tetrahydrofuran (THF) and 61.5g triethylamine, stir, be heated to back flow reaction 12h.Stopped reaction is cooled to room temperature, the elimination insolubles, and filtrate is spin-dried for, and gets residue, adds inwards the 1000ml ethyl acetate, and wash water 300ml, 20% wet chemical 300ml and saturated sodium-chloride water solution 300ml * 2 respectively.Ethyl acetate layer is used anhydrous sodium sulfate drying again with 20g activated carbon decolorizing 1h.The filtering siccative, filtrate is spin-dried for, and gets residue.Add inwards 80ml ethyl acetate reflux, then naturally cool to room temperature, suction filtration, filter cake washs with cold ethyl acetate, and 40 ℃ of vacuum-dryings get 55.7g off-white color solid, are compound (2 '), yield 68%.MS(ESI)：270.1([M+H]
+)。
Embodiment 72-hydroxyl-3-(2-aldehyde-base)-(preparation of compound 6 ') of 4-acetyl-amino-benzoic acid methyl ester
Chemical equation
Operation steps
In the 10L reaction flask, under the nitrogen protection, add 91.5g compound 20,3.5g ruthenium trichloride monohydrate, 3.6g benzyltriethylammoinium chloride and 600ml methylene dichloride; open and stir; drip the mixing solutions of 344g sodium periodate and 3600ml water, between warm 20～30 ℃, drip and finish in the control; react 2h under the room temperature; developping agent is carried out in TLC monitoring reaction: methyl alcohol oil ether/methylene dichloride=1/10, the Rf=0.7 of raw material (compound 20); the Rf=0.5 of product, TLC show that the raw material primitive reaction is complete.Stopped reaction, the hydrochloric acid soln that adds 1700ml ethyl acetate, 200ml10% stirred 10 minutes, tell organic layer, water layer extracts with ethyl acetate 1000ml * 2, merges organic layer, water 800ml * 2 washings, the ethyl acetate layer anhydrous sodium sulfate drying, be spin-dried for, get the 68g black solid, be compound 6 '.MS(ESI)：252.1([M+H]
+)。
Claims (13)
1. one kind 2, the preparation method of 3-Dihydrobenzofuranes compounds, it is characterized in that adopting compound 7 or its salt is starting raw material, selects ruthenium trichloride or its hydrate/periodate composite catalyst to promote reaction, obtains compound 6 or its salt; Obtain compound 5 or its salt after aldehyde radical in compound 6 or its salt is reduced to hydroxyl, be substituted again the upper leavings group Z of reaction connection and obtain compound 4 or its salt, compound 4 or its salt are proceeded ring closure reaction obtain compound (I), obtain compound 2 through chlorination again, obtain compound 1 finally by hydrolysis reaction
Wherein, R is C
1-6Straight chained alkyl, benzyl, halogeno-benzyl, C
1-4Alkyl benzyl, diphenyl-methyl or the tertiary butyl; X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6The straight chained alkyl acyl group; Z is halogen, tolysulfonyl oxygen base, trimethyl fluoride sulfonyl oxygen base, mesyloxy or phenylsulfonyloxy.
2. method according to claim 1 is characterized in that described R is methyl; X is ethanoyl; Z is chlorine.
3. method according to claim 1 is characterized in that preparing in the reaction of compound 6, and the mole dosage of ruthenium trichloride or its hydrate is 1%～8% of compound 7 in the composite catalyst, and preferred 2%～4%; The molar weight of periodate is 1～10 times of compound 7, preferred 3～6 times; This temperature of reaction is 0～80 ℃, preferred 10 ℃～40 ℃; Described periodate is potassium periodate and sodium periodate.
4. method according to claim 1 is characterized in that preparing in the reaction of compound 5 or its salt, and the employing sodium borohydride is reductive agent; Compound 5 or its salt and sulfur oxychloride, Tosyl chloride, trimethyl fluoride sulfonyl chlorine, methylsulfonyl chloride or benzene sulfonyl chloride reaction, preparation compound 4 or its salt.
5. method according to claim 1 is characterized in that compound 4 carries out ring closure reaction under organic bases or mineral alkali catalysis, preparation compound (I); Wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or the tri-tert amine; The consumption of organic bases or mineral alkali is 1～4 times of compound 4 molar weights; Temperature of reaction is controlled at room temperature to reflux temperature, preferred 20 ℃～100 ℃.
6. method according to claim 1 is characterized in that compound (I) and N-chlorosuccinimide obtain compound 2 30 ℃～100 ℃ lower reactions; Compound 2 under the sodium hydroxide effect in 40～100 ℃ of lower reactions, again with acid for adjusting pH value to 6-7, obtain compound 1.
7. one kind 2, the preparation method of 3-Dihydrobenzofuranes compounds, it is characterized in that adopting compound 7 or its salt is starting raw material, selects ruthenium trichloride or its hydrate/periodate composite catalyst to promote reaction, obtains compound 6 or its salt; Obtain compound 5 or its salt after aldehyde radical in compound 6 or its salt is reduced to hydroxyl, again with continue to be substituted reaction after chlorination reagent reacts chlorination and be connected leavings group Z, obtain compound 4 " or its salt; compound 4 " or its salt carry out ring closure reaction and obtain compound (I "); obtain compound 1 finally by hydrolysis reaction
Wherein, R is C
1-6Straight chained alkyl, benzyl, halogeno-benzyl, C
1-4Alkyl benzyl, diphenyl-methyl or the tertiary butyl; X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6The straight chained alkyl acyl group; Z is halogen, tolysulfonyl oxygen base, trimethyl fluoride sulfonyl oxygen base, mesyloxy or phenylsulfonyloxy.
8. method according to claim 7 is characterized in that compound 4 " under organic bases or mineral alkali catalysis, carry out ring closure reaction, the preparation compound (I "); Wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or the tri-tert amine; The consumption of organic bases or mineral alkali is compound 4 " 1～4 times of molar weight.
9. method according to claim 7, the temperature of reaction that it is characterized in that preparing compound (I ") is controlled at room temperature to reflux temperature, preferred 20 ℃～100 ℃; Compound 5 or its salt carry out chlorination with sulfuryl chloride or N-chlorosuccinimide first, again with sulfur oxychloride, Tosyl chloride, trimethyl fluoride sulfonyl chlorine, methylsulfonyl chloride or benzene sulfonyl chloride reaction, leavings group Z in the connection, preparation compound 4 ".
10. compound 6 " the preparation method, it is characterized in that adopting compound 7 " or its salt be starting raw material, select ruthenium trichloride or its hydrate/periodate composite catalyst to promote reaction, obtain compound 6 " or its salt;
Wherein, X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6The straight chained alkyl acyl group.
11. method according to claim 10 is characterized in that at preparation compound 6 " in the used composite catalyst mole dosage of ruthenium trichloride or its hydrate be compound 7 " 1%～8%, preferred 2%～4%; The molar weight of periodate is compound 7 " 1～10 times, preferred 3～6 times.
12. one kind 2, the preparation method of 3-Dihydrobenzofuranes compounds III, it is characterized in that adopting compound ii or its salt is starting raw material, carry out ring closure reaction and obtain the compound III,
Wherein, Y is chlorine or hydrogen; X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6The straight chained alkyl acyl group; Z is halogen, tolysulfonyl oxygen base, trimethyl fluoride sulfonyl oxygen base, mesyloxy or phenylsulfonyloxy.
13. method according to claim 12 is characterized in that compound ii or its salt carry out ring closure reaction under organic bases or mineral alkali catalysis, preparation compound III; Wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or the tri-tert amine; The consumption of organic bases or mineral alkali is 1～4 times of compound ii molar weight.
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| CN103664912A (en) * | 2013-12-31 | 2014-03-26 | 南京正大天晴制药有限公司 | Synthesis process of prucalopride |
| CN103804211A (en) * | 2014-03-12 | 2014-05-21 | 天津市炜杰科技有限公司 | Synthetic method of 4-(acetyl amino)-2-hydroxy-3-(2-carbonyl ethyl) methyl benzoate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103664912A (en) * | 2013-12-31 | 2014-03-26 | 南京正大天晴制药有限公司 | Synthesis process of prucalopride |
| CN103664912B (en) * | 2013-12-31 | 2015-11-25 | 南京正大天晴制药有限公司 | A kind of synthesis technique of prucalopride |
| CN103804211A (en) * | 2014-03-12 | 2014-05-21 | 天津市炜杰科技有限公司 | Synthetic method of 4-(acetyl amino)-2-hydroxy-3-(2-carbonyl ethyl) methyl benzoate |
| CN103804211B (en) * | 2014-03-12 | 2016-04-06 | 天津市炜杰科技有限公司 | The synthetic method of 4-(acetylamino)-2-hydroxyl-3-(2-carbonylethyl) methyl benzoate |
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