CN110950802A - Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride - Google Patents
Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride Download PDFInfo
- Publication number
- CN110950802A CN110950802A CN201911352624.9A CN201911352624A CN110950802A CN 110950802 A CN110950802 A CN 110950802A CN 201911352624 A CN201911352624 A CN 201911352624A CN 110950802 A CN110950802 A CN 110950802A
- Authority
- CN
- China
- Prior art keywords
- lorcaserin
- reaction
- compound
- hydrochloric acid
- lorcaserin hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ITIHHRMYZPNGRC-QRPNPIFTSA-N lorcaserin hydrochloride Chemical compound Cl.C[C@H]1CNCCC2=CC=C(Cl)C=C12 ITIHHRMYZPNGRC-QRPNPIFTSA-N 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000008569 process Effects 0.000 title claims abstract description 26
- 229960003283 lorcaserin hydrochloride Drugs 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 17
- 229940079593 drug Drugs 0.000 title claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 48
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 36
- -1 hydrochloric acid lorcaserin racemate Chemical class 0.000 claims abstract description 12
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 9
- 238000006467 substitution reaction Methods 0.000 claims abstract description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 7
- SRXFXCKTIGELTI-UHFFFAOYSA-N 2-(4-chlorophenyl)ethanamine Chemical compound NCCC1=CC=C(Cl)C=C1 SRXFXCKTIGELTI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 230000003579 anti-obesity Effects 0.000 claims abstract description 5
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 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 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 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 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 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 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 229960005060 lorcaserin Drugs 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000011968 lewis acid catalyst Substances 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005516 engineering process Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 230000021736 acetylation Effects 0.000 claims description 3
- 238000006640 acetylation reaction Methods 0.000 claims description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 239000006227 byproduct Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims description 2
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000004721 Polyphenylene oxide Chemical group 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 239000002635 aromatic organic solvent Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 150000004714 phosphonium salts Chemical group 0.000 claims description 2
- 229920000570 polyether Chemical group 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
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 230000000397 acetylating effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000010933 acylation Effects 0.000 abstract description 5
- 238000005917 acylation reaction Methods 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 229960002631 carbazochrome Drugs 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 13
- 230000008901 benefit Effects 0.000 description 7
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- 208000008589 Obesity Diseases 0.000 description 5
- AXZNIFHZRQTQDM-UHFFFAOYSA-N chlorobenzene ethanamine Chemical compound C(C)N.ClC1=CC=CC=C1 AXZNIFHZRQTQDM-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 235000020824 obesity Nutrition 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- JEQDSBVHLKBEIZ-REOHCLBHSA-N (2s)-2-chloropropanoyl chloride Chemical compound C[C@H](Cl)C(Cl)=O JEQDSBVHLKBEIZ-REOHCLBHSA-N 0.000 description 3
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- HXITXNWTGFUOAU-UHFFFAOYSA-N dihydroxy-phenylborane Natural products OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000002912 waste gas Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000005937 allylation reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RULQUTYJXDLRFL-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)boronic acid Chemical compound COC1=CC(B(O)O)=CC(OC)=C1OC RULQUTYJXDLRFL-UHFFFAOYSA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZYPGRYUBFLTFOC-UHFFFAOYSA-N 1h-1-benzazepine;hydrochloride Chemical compound Cl.N1C=CC=CC2=CC=CC=C12 ZYPGRYUBFLTFOC-UHFFFAOYSA-N 0.000 description 1
- CDPKJZJVTHSESZ-UHFFFAOYSA-N 4-chlorophenylacetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1 CDPKJZJVTHSESZ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 238000010917 Friedel-Crafts cyclization Methods 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- XJQDSZGDDUJVHC-UHFFFAOYSA-N chlorobenzene;ethanol Chemical compound CCO.ClC1=CC=CC=C1 XJQDSZGDDUJVHC-UHFFFAOYSA-N 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002083 iodinating effect Effects 0.000 description 1
- 229940102253 isopropanolamine Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Child & Adolescent Psychology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis process of an antiobesity drug lorcaserin hydrochloride intermediate (compound V), which is characterized by comprising the following steps of: p-chlorophenylethylamine is used as a raw material, acetic anhydride is used for protecting amino through acylation, and then the hydrochloric acid lorcaserin racemate is obtained through allyl substitution, Friedel-crafts alkylation and hydrochloric acid deprotection. The invention has simple synthesis and preparation and high yield, and is a green-carbazochrome hydrochloride intermediate synthesis process suitable for industrial mass production.
Description
Technical Field
The invention relates to a novel synthesis process of an intermediate of an antiobesity drug, namely lorcaserin hydrochloride, and belongs to the technical field of drug synthesis.
Background
Obesity is a multifactorial chronic metabolic disease in which a human body eats more calories than is consumed, and the excess calories are stored in the body in the form of fat, and when the fat in the body is accumulated excessively or is distributed abnormally, the weight of the fat exceeds 20% of the standard weight loss. There is a great deal of relevant evidence that when the body stores too much energy in the form of fat, i.e., beyond normal physiological needs, it can have adverse effects on longevity and health. With the age, the body fat correspondingly increases, which can increase the risk of cardiovascular diseases, influence the endocrine and digestive systems and increase the probability of cancer occurrence.
The world health organization listed obesity as a disease in 1997 and is one of four major medical societal problems in the world. From the 80 s of the last century, with the rapid development of economy and technology to improve the physical living standard of people and to make the dietary structure unreasonable, obesity spreads like epidemic diseases and has a tendency to continue to expand. The incidence of obesity in China is also increasing year by year, especially in adolescent groups. Therefore, the research on the drugs for treating obesity is receiving more and more attention.
The latest large-scale phase III clinical test result shows that the hydrochloric acid Lvcardelin has the weight-losing effect, and has no influence on heart valves and pulmonary arteries; in contrast, unlike other anti-obesity agents, lorcaserin improves heart rate, blood pressure, and low density lipoprotein cholesterol (LDL-C) levels while reducing weight. The advantageous well for losing weight of the lorcaserin hydrochloride is not in curative effect, but is obviously better than the existing medicines in safety, has clear benefits for the II-type diabetes mellitus and the people with cardiovascular risk factors, is approved by the United states Food and Drug Administration (FDA) to be on the market in 2012, and therefore has good market prospect for developing the lorcaserin hydrochloride.
Lorcaserin hydrochloride is known under the english name Lorcaserin hydrochloride, CAS number: 846589-
98-8, Chinese alias: (R) -8-chloro-1-methyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride, the English alias: (R) -8-Chloro-1-methyl-2,3,4, 5-tetrahydroxy-1H-3-
benzazepine hydrochloride, molecular formula: c11H14Hcl, molecular structural formula as follows:
the hydrochloric acid green Carlsbergine racemate (V) and its free base-green Carlsbergine racemate (VI) are key intermediates for synthesizing the hydrochloric acid green Carlsbergine (I), and according to the literature reports, the following routes are mainly formed:
route one: the synthesis method reported in CN101123955 takes p-chlorobenzene ethylamine as a raw material, and prepares the lorcaserin racemate through six steps of reactions such as trifluoroacetic anhydride acylation protection of amino, iodo, allylation, Heck reaction, hydrogenation reduction, sodium hydroxide hydrolysis and the like. The route is a typical laboratory or pilot plant synthesis method and has the defects of long process route, low atom utilization rate, low total yield and the like. In addition, trifluoroacetic anhydride, an iodinating reagent and a palladium metal reagent which are expensive are used in the reaction, so that the production cost is high.
And a second route: CN105367497 and CN106496122 report that p-chlorophenylethylamine is used as a raw material, and the chlorocarbanilide racemate (VI) is prepared by four-step reactions such as Boc anhydride acylation to protect amino, allylation, deprotection, friedel-crafts reaction (ring closing) and the like. Although the route is short, the Boc anhydride used is expensive, and the removal of Boc protecting group requires the use of HCl saturated ethyl acetate solution, which generates a large amount of waste gas and waste acid, thus being unfavorable for equipment maintenance.
In the third route, US20090143576 reports that racemic lucarniline (VI) is obtained by bromination, amination, chlorination and Friedel-crafts reaction (cyclization) by taking p-chlorobenzene ethanol as a starting material. Although the route only has four-step reaction and the price of the starting raw materials is low, the used brominating reagents such as phosphorus tribromide and thionyl chloride are corrosive hazardous chemicals, and have the advantages of large molecular weight, large relative dosage, high cost, more waste gas and waste acid, and great industrial pollution; meanwhile, during substitution, secondary substitution side reaction is easy to occur, and the total yield is low.
And a fourth route: WO2008070111 reports that 4-chlorophenylacetic acid is used as a starting material, condensed with isopropanolamine under the catalysis of a condensing agent 3,4, 5-trimethoxyphenylboronic acid, and subjected to amide reduction, chlorination and Friedel-crafts cyclization to obtain racemic lorcaserin (VI). The phenylboronic acid condensing agent used in the first step of the route is expensive, the post-treatment period is long, and the workload is large; dangerous sodium borohydride or borane reducing agents are used for reducing the second step of amide, and a large amount of ether solvents such as tetrahydrofuran and the like are used, so that the reaction explosion risk is high, and the reaction solvent is expensive and is not beneficial to recycling. Thionyl chloride generates a large amount of waste gas and waste acid, which is not beneficial to environmental protection.
And a fifth route: WO2005019179 reports that racemic lorcaserin (VI) is obtained by reacting p-chlorobenzene ethylamine serving as a starting material with 2-chloropropionyl chloride and then carrying out Friedel-crafts alkylation and reduction. Although the reaction route is short, the price of the 2-chloropropionyl chloride and the borane is high, and the operation of the 2-chloropropionyl chloride and the borane is inconvenient. The ring closing reaction adopts the reaction temperature which is higher than 150 ℃ and the time is long, so that more impurities are generated, and the separation and purification difficulty is high; and a large amount of ether solvents such as tetrahydrofuran and the like are used in the third step of reaction, and the solvents are high in price, flammable and explosive and are not beneficial to recycling and reusing.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a synthesis process of an intermediate of the weight-reducing drug lorcaserin hydrochloride, which has the advantages of simple process, safety, reliability, stable quality, low cost and high yield, is suitable for industrial mass production and has great social, economic and environmental benefits.
In order to solve the technical problems, the invention adopts the following technical scheme:
the invention discloses a synthesis process of an antiobesity drug lorcaserin hydrochloride intermediate (compound V). The synthesis process comprises the steps of taking p-chlorphenethylamine as a raw material, substituting cheap acetic anhydride for Boc anhydride or trifluoroacetic anhydride adopted in the traditional route, protecting amino by acylation, and then obtaining lorcaserin hydrochloride racemate by allyl substitution, Friedel-crafts alkylation and hydrochloric acid deprotection. The invention has simple synthetic route, low production cost and high yield, and is a hydrochloric acid lorcaserin intermediate synthetic process suitable for industrial mass production.
Further, the method sequentially comprises the following steps:
first step acetylation
① adding p-chlorobenzene ethylamine dropwise into acetic anhydride, and reacting at a certain temperature;
② post-treatment, namely distilling off excessive acetic anhydride and byproduct acetic acid after the reaction is finished, adding an aromatic organic solvent, washing with water, and directly putting the organic phase of the compound II into the next reaction without concentration;
the second step is that: substitution
① adding a certain amount of alkali into the organic phase obtained in the previous step,
② adding a certain amount of phase transfer catalyst into the organic phase obtained in the previous step
③ dropping a certain amount of allyl halogenated hydrocarbon, and reacting for a period of time while keeping the temperature after dropping;
④ post-treatment, filtering to remove residual alkali after the reaction is finished, washing with water, and concentrating under reduced pressure to obtain compound III.
The third step: closing ring
① putting the compound III and Lewis acid catalyst into halohydrocarbon solvent, and carrying out Friedel-crafts reaction at a certain temperature;
② post-treatment, namely washing with 1% dilute hydrochloric acid and water after the reaction is finished, standing for layering, and concentrating the organic phase under reduced pressure to obtain a compound IV;
the fourth step: deprotection of the amino acid
① adding hydrochloric acid into a reaction kettle containing compound IV, deprotecting at a certain temperature and simultaneously reacting to form a salt;
② post-treatment, adding alkali metal hydroxide or alkali metal carbonate for neutralization after the reaction is finished, extracting by organic solvent, introducing HCl gas for crystallization, filtering and drying to obtain the hydrochloric acid lorcaserin racemate.
Further, in the first step, the feeding molar ratio of the p-chlorobenzene ethylamine to the acetic anhydride is 1: 1-5;
further, in the first step, the aromatic hydrocarbon solvent is toluene or xylene, etc.;
further, in the first step, the reaction temperature is 30-130 ℃;
further, in the first step, the reaction time is kept at 0.5-4 hours.
Further, in the second step, the alkali is one or a mixture of any two of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride, calcium hydride, potassium tert-butoxide, sodium methoxide or sodium ethoxide;
further, in the second step, the feeding molar ratio of the compound II to the alkali is 1: 1-5;
further, in the second step, the phase transfer catalyst is quaternary ammonium salt, quaternary phosphonium salt or polyether catalyst;
further, in the second step, the feeding molar ratio of the compound II to the phase transfer catalyst is 1: 0.01-0.2;
further, in the second step, the allyl chlorohydrocarbon is one of allyl chloride and allyl bromide;
further, in the second step, the feeding molar ratio of the compound II to the allyl chlorohydrocarbon is 1: 1-5;
further, in the second step, the reaction temperature is 20-100 ℃;
further, in the second step, the reaction time is 2-20 hours.
Further, in the third step, the halogenated hydrocarbon solvent for the ring closure reaction is any one or a mixture of any two of dichloromethane, dichloroethane, chlorobenzene, o-dichlorobenzene and the like;
further, in the third step, the lewis acid catalyst for the ring closing reaction is ferric trichloride, aluminum trichloride, boron trifluoride, titanium tetrachloride, stannic chloride or zinc chloride;
further, in the third step, the feeding molar ratio of the compound III to the Lewis acid catalyst is 1: 1-5;
further, in the third step, the ring closing reaction time is 1-8 hours;
further, in the third step, the ring closing reaction temperature is 50-150 ℃;
further, in the fourth step, the feeding molar ratio of the compound IV to the HCl is 1: 2-8;
further, in the fourth step, the deprotection reaction temperature is 50-150 ℃;
further, in the fourth step, the deprotection reaction time is 1-12 hours;
further, in the fourth step, the alkali metal hydroxide or alkali metal carbonate used for neutralization is lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, or the like;
in the fourth step, the organic solvent used for extraction is an organic solvent commonly used in laboratories and industry, such as dichloromethane, trichloromethane, cyclohexane, toluene, xylene, methyl tert-butyl ether, ethyl acetate, butyl acetate and the like.
Further: the racemate (V) of the hydrochloric acid green Carlsbergine prepared by the synthesis process of the intermediate of the hydrochloric acid green Carlsbergine is subjected to manual resolution to obtain the weight-reducing medicine green Carlsbergine hydrochloride;
further: a novel oral weight-reducing medicine is prepared by manually splitting the obtained hydrochloric acid lorcaserin racemate (V) to obtain weight-reducing medicine hydrochloric acid lorcaserin, and preparing the weight-reducing medicine suitable for oral administration by using the conventional technology and auxiliary materials.
In summary, the invention has the following advantages:
(1) the invention provides a synthesis process of a new antiobesity drug lorcaserin hydrochloride intermediate (compound V). Acylation with acetic anhydride to give intermediate 1 (compound II); the synthetic routes adopted by the intermediate 2 (compound III) and the intermediate 3 (compound IV) are not reported in the literature, and the synthetic process of the invention is simple to operate.
(2) The compound can be used for synthesizing lorcaserin hydrochloride, and then is prepared into a weight-reducing medicine suitable for oral administration by using the traditional technology and auxiliary materials.
(3) The invention achieves the aim of the invention, overcomes the defects in the prior art, and provides the intermediate synthesis process of the weight-reducing medicine lorcaserin hydrochloride, which has the advantages of simple process, safety, reliability, high yield, stable intermediate and finished product quality, suitability for industrial mass production and great social, economic and environmental benefits.
Drawings
FIG. 1 is the H-NMR spectrum of the racemic modification of lorcaserin hydrochloride (V).
Detailed Description
The technical solution of the present invention will be described in detail with reference to the following embodiments.
The first step is as follows: acetylation
Adding 7.4kg of acetic anhydride into a 50L reaction kettle in sequence, then dropwise adding 7.5kg of p-chlorobenzene ethylamine, starting stirring and heating, heating to 50-60 ℃ for reaction for 2 hours, and sampling and sending to HPLC (high performance liquid chromatography) for central control; after the reaction is finished, evaporating excessive acetic anhydride and byproduct acetic acid under reduced pressure; 20kg of toluene and water are added for washing, and after standing and layering, the organic phase directly enters the next allyl substitution reaction.
The second step is that: substitution
Adding 3.0kg of tetrabutylammonium bromide, 11.4kg of allyl bromide, 19.6kg of potassium carbonate and 26.5kg of potassium hydroxide into a 100L reaction kettle, starting stirring, and heating to 50-60 ℃ for reaction for 10-12 hours; filtering, and washing a filter cake with a small amount of toluene; and washing the filtrate with water, and concentrating to obtain a compound III.
The third step: closing ring
Adding 57.5 kg of o-dichlorobenzene into a dry 200L reaction kettle, starting stirring, adding 9.7kg of anhydrous aluminum trichloride, uniformly mixing 11.5 kg of compound III and 11.5 kg of o-dichlorobenzene, pumping into an overhead tank for dropwise adding, after dropwise adding, keeping the temperature at 120-130 ℃ for reaction for 3.0-4.0 hours; after the reaction is finished, washing the reaction product by using 1% hydrochloric acid and water in sequence; the organic phase is decompressed and concentrated to obtain the compound IV.
The fourth step: deprotection of the amino acid
Adding 38.7kg of industrial concentrated hydrochloric acid into the 200L reaction kettle filled with the compound IV, starting stirring and heating, and heating for reflux reaction for 8-10 hours; after the reaction is finished, adjusting the pH value with sodium carbonate, extracting with 62kg of toluene, introducing hydrogen chloride gas into the organic phase for crystallization, filtering and drying to obtain 9.1kg of hydrochloric acid lorcaserin racemate. HPLC purity 99.49%.
The above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and do not limit the concept and the protection scope of the present invention, and the ordinary skilled person of the present invention can modify the technical solutions of the present invention or substitute the equivalent without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.
Claims (10)
1. A synthesis process of an antiobesity drug lorcaserin hydrochloride intermediate comprises the following steps: using p-chlorophenylethylamine as a raw material, acylating acetic anhydride to protect amino, namely acetylating, then performing allyl substitution, Friedel-crafts alkylation, namely ring closing, and hydrochloric acid deprotection to obtain a hydrochloric acid lorcaserin intermediate, namely hydrochloric acid lorcaserin racemate; the reaction formula is as follows:
2. the process for synthesizing a lorcaserin hydrochloride intermediate according to claim 1,
first step acetylation
Dropwise adding p-chlorophenylethylamine into acetic anhydride, wherein the reaction temperature is 30-130 ℃; the reaction time is kept at 0.5-4 hours;
② post-treatment, namely distilling off excessive acetic anhydride and byproduct acetic acid after the reaction is finished, adding an aromatic organic solvent, washing with water, and directly putting the organic phase containing the compound II into the next reaction without concentration.
3. The process for the synthesis of the lorcaserin hydrochloride intermediate according to claim 1, characterized in that in the second step: substitution
①, adding a certain amount of alkali into the organic phase obtained in the previous step, wherein the feeding molar ratio of the compound II to the alkali is 1: 1-5;
② adding a certain amount of phase transfer catalyst into the organic phase obtained in the previous step, wherein the feeding molar ratio of the compound II to the phase transfer catalyst is 1: 0.01-0.2;
③, dropwise adding a certain amount of allyl halogenated hydrocarbon, wherein the feeding molar ratio of the compound II to the allyl chlorinated hydrocarbon is 1: 1-5, and after dropwise adding, the reaction temperature is 20-100 ℃;
the reaction time is 2-20 hours;
④ post-treatment, filtering to remove residual alkali after the reaction is finished, washing with water, and concentrating under reduced pressure to obtain compound III.
4. The process for synthesizing a lorcaserin hydrochloride intermediate according to claim 1, wherein the third step comprises: closing ring
①, putting a compound III and a Lewis acid catalyst into a halogenated hydrocarbon solvent, wherein the feeding molar ratio of the compound III to the Lewis acid catalyst is 1: 1-5, the ring closing reaction temperature is 50-150 ℃, and the ring closing reaction time is 1-8 hours;
② post-treatment, washing with 1% dilute hydrochloric acid and water, standing for layering, and concentrating under reduced pressure to obtain compound IV.
5. The process for synthesizing a lorcaserin hydrochloride intermediate according to claim 1, wherein the fourth step comprises: deprotection of the amino acid
① adding hydrochloric acid into a reaction kettle filled with a compound IV, wherein the feeding molar ratio of the compound IV to the HCl is 1: 2-8, deprotecting at 50-150 ℃, and reacting for 1-12 hours;
② post-treatment, adding alkali metal hydroxide or alkali metal carbonate for neutralization after the reaction is finished, extracting by organic solvent, introducing HCl gas for crystallization, filtering and drying to obtain the hydrochloric acid lorcaserin racemate.
6. The synthesis process of the intermediate of lorcaserin hydrochloride as claimed in claim 2, wherein in the first step, the feeding molar ratio of p-chlorophenylethylamine to acetic anhydride is 1: 1-5; the aromatic hydrocarbon solvent includes toluene or xylene.
7. The process for synthesizing the lorcaserin hydrochloride intermediate according to claim 3, wherein: in the second step, the alkali is one or the mixture of any two of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride, calcium hydride, potassium tert-butoxide, sodium methoxide or sodium ethoxide;
the phase transfer catalyst is quaternary ammonium salt, quaternary phosphonium salt or polyether catalyst;
the allyl chlorohydrocarbon is one of allyl chloride and allyl bromide.
8. The process for synthesizing the lorcaserin hydrochloride intermediate according to claim 4, wherein: in the third step, the halogenated hydrocarbon solvent for the ring closing reaction comprises any one or a mixture of any two of dichloromethane, dichloroethane or chlorobenzene and o-dichlorobenzene;
the Lewis acid catalyst for the ring closing reaction is ferric trichloride, aluminum trichloride, boron trifluoride, titanium tetrachloride, stannic chloride or zinc chloride.
9. The process for synthesizing the lorcaserin hydrochloride intermediate according to claim 5, wherein: in the fourth step, the alkali metal hydroxide or alkali metal carbonate used for neutralization comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate;
the organic solvent used for extraction comprises dichloromethane, chloroform, cyclohexane, toluene, xylene, methyl tert-butyl ether, ethyl acetate and butyl acetate.
10. The lorcaserin hydrochloride racemate (V) prepared by the lorcaserin hydrochloride intermediate synthesis process according to claim 1 is manually split to obtain the weight-reducing drug lorcaserin hydrochloride;
and/or the obtained hydrochloric acid lorcaserin racemate (V) is manually split to obtain the weight-reducing medicine hydrochloric acid lorcaserin, and the weight-reducing medicine suitable for oral administration is prepared by using the traditional technology and auxiliary materials.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911352624.9A CN110950802A (en) | 2019-12-25 | 2019-12-25 | Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911352624.9A CN110950802A (en) | 2019-12-25 | 2019-12-25 | Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110950802A true CN110950802A (en) | 2020-04-03 |
Family
ID=69983931
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911352624.9A Pending CN110950802A (en) | 2019-12-25 | 2019-12-25 | Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110950802A (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5561233A (en) * | 1993-10-28 | 1996-10-01 | Hoffmann-La Roche Inc. | Process for the preparation of an intermediate of a benzo[a]quinolizinone derivative |
CN105348197A (en) * | 2015-11-23 | 2016-02-24 | 中国药科大学 | Preparation method of lorcaserin hydrochloride |
CN105367497A (en) * | 2014-08-08 | 2016-03-02 | 中国药科大学 | Preparation method of weigh reducing drug lorcaserin hydrochloride and intermediate thereof |
-
2019
- 2019-12-25 CN CN201911352624.9A patent/CN110950802A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5561233A (en) * | 1993-10-28 | 1996-10-01 | Hoffmann-La Roche Inc. | Process for the preparation of an intermediate of a benzo[a]quinolizinone derivative |
CN105367497A (en) * | 2014-08-08 | 2016-03-02 | 中国药科大学 | Preparation method of weigh reducing drug lorcaserin hydrochloride and intermediate thereof |
CN105348197A (en) * | 2015-11-23 | 2016-02-24 | 中国药科大学 | Preparation method of lorcaserin hydrochloride |
Non-Patent Citations (3)
Title |
---|
JÉRÔMECLUZEAU等: "Development and optimization of a new synthetic process for lorcaserin", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
QIHUA ZHU等: "Novel Synthesis of Antiobesity Drug Lorcaserin Hydrochloride", 《ORG. PROCESS RES. DEV.》 * |
何光超等: "盐酸绿卡色林的工艺研究", 《中国现代应用药学》 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN114085181B (en) | Synthetic method and application of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane | |
CN102925528B (en) | Method for producing intermediate of levo-praziquantel and levo-praziquantel | |
CN101607955B (en) | Preparation method for low-residue lipoic acid | |
CN1164588C (en) | Preparation of berberine and its salts | |
CN103333111A (en) | Preparation method of lorcaserin hydrochloride | |
CN106748825A (en) | A kind of synthesis of Dapoxetine hydrochloride, resolving and purifying and salifying method | |
CN111499506A (en) | Green production process of 2, 4-dichloro-5-fluorobenzoyl chloride | |
CN105153137A (en) | Preparation method of empagliflozin | |
CN1709888A (en) | Improved systhesizing process for dicyclohexyl-18-crown-6 | |
CN110950802A (en) | Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride | |
CN113264814B (en) | Process for preparing hydroxytyrosol | |
CN1810775B (en) | Preparation process of 4-amino-2-trifluoromethyl benzonitrile | |
CN101643439A (en) | Method for preparing ethylmethylamino formyl chloride | |
CN112047851B (en) | Preparation method of D-panthenol | |
CN108892659A (en) | A kind of canagliflozin impurity and preparation method thereof | |
CN106478377B (en) | A kind of synthetic method of 2,3- Difluoro-5-Bromophenol | |
CN106748630A (en) | A kind of synthetic method of antalgesic intermediate Bromomethylcyclobutane | |
CN103360264A (en) | Synthesizing method of indacaterol amino fragment 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride | |
CN107698647A (en) | A kind of improved method for reclaiming the underproof fulvestrant of isomer proportion | |
CN113943231A (en) | Preparation method of 1-hydroxymethyl cyclopropyl acetonitrile | |
CN104628584A (en) | High-purity dapoxetine preparation method suitable for industrialization | |
CN105017137B (en) | One kind prepares vitamin B by malic acid6Method | |
CN117402053A (en) | Synthesis method of halogenated malonic acid | |
CN115611740B (en) | Production method of ethyl 8-chlorooctoate | |
CN116178307B (en) | Synthesis method of 1- (2, 3-dichlorophenyl) piperazine hydrochloride |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200403 |