CN103333111A - Preparation method of lorcaserin hydrochloride - Google Patents
Preparation method of lorcaserin hydrochloride Download PDFInfo
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- CN103333111A CN103333111A CN2013102360454A CN201310236045A CN103333111A CN 103333111 A CN103333111 A CN 103333111A CN 2013102360454 A CN2013102360454 A CN 2013102360454A CN 201310236045 A CN201310236045 A CN 201310236045A CN 103333111 A CN103333111 A CN 103333111A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- ITIHHRMYZPNGRC-QRPNPIFTSA-N lorcaserin hydrochloride Chemical compound Cl.C[C@H]1CNCCC2=CC=C(Cl)C=C12 ITIHHRMYZPNGRC-QRPNPIFTSA-N 0.000 title abstract 5
- 229960003283 lorcaserin hydrochloride Drugs 0.000 title abstract 4
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- 230000002829 reductive effect Effects 0.000 claims abstract description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 3
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 37
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 34
- 239000000460 chlorine Substances 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 33
- 229910052801 chlorine Inorganic materials 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 27
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- -1 4-Chlorophenylacetic acid ester Chemical class 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 229940117389 dichlorobenzene Drugs 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- YKDZEZDQPMEHGB-UHFFFAOYSA-N n-(2-hydroxypropyl)acetamide Chemical compound CC(O)CNC(C)=O YKDZEZDQPMEHGB-UHFFFAOYSA-N 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 229940095064 tartrate Drugs 0.000 claims description 5
- RKSJALDVDDPATL-UHFFFAOYSA-N N-(2-chloropropyl)acetamide Chemical compound CC(=O)NCC(C)Cl RKSJALDVDDPATL-UHFFFAOYSA-N 0.000 claims description 4
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-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
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003586 protic polar solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical group [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940116298 l- malic acid Drugs 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 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
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- KEUPLGRNURQXAR-UHFFFAOYSA-N (4-chlorophenyl) acetate Chemical compound CC(=O)OC1=CC=C(Cl)C=C1 KEUPLGRNURQXAR-UHFFFAOYSA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 abstract 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 abstract 1
- 238000007098 aminolysis reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 229940102253 isopropanolamine Drugs 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- YGLDQFWPUCURIP-UHFFFAOYSA-N 3h-3-benzazepine Chemical compound C1=CNC=CC2=CC=CC=C21 YGLDQFWPUCURIP-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 229940063656 aluminum chloride Drugs 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- CDPKJZJVTHSESZ-UHFFFAOYSA-N 4-chlorophenylacetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1 CDPKJZJVTHSESZ-UHFFFAOYSA-N 0.000 description 1
- 229940116892 5 Hydroxytryptamine 2B receptor antagonist Drugs 0.000 description 1
- 102100024956 5-hydroxytryptamine receptor 2B Human genes 0.000 description 1
- 101710138092 5-hydroxytryptamine receptor 2B Proteins 0.000 description 1
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 description 1
- 101710138093 5-hydroxytryptamine receptor 2C Proteins 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 229940055858 aluminum chloride anhydrous Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000021407 appetite control Nutrition 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
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical class Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 1
- 229960005060 lorcaserin Drugs 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of lorcaserin hydrochloride, namely (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. The method comprises the following steps: taking p-chlorophenyl acetate as raw material, performing aminolysis with isopropanol amine, then performing chlorination, reduction and Friedel-Crafts alkylation, further splitting by L-tartaric acid, and performing salt formation to get the lorcaserin hydrochloride. The invention provides the preparation method of the lorcaserin hydrochloride. The method has the advantages of low cost, simplicity in operation and higher product purity; according to the process disclosed by the invention, the continuous operation can be performed, and the production cycle is greatly reduced; meanwhile a reagent is low in price and easy to obtain, the operation is simple, and the post-treatment is simple and convenient, so that the preparation method is a brand new and economic synthesis method which can realize industrial production.
Description
Technical field
The present invention relates to chemical pharmacy field, in particular to a kind of preparation method of diet pill chlorine Ka Selin hydrochloride.
Background technology
Chlorine Ka Selin hydrochloride formula (I), English name Lorcaserin, chemical name (R)-8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine hydrochloride, be applied to the obesity patient, developed by U.S. Arena Pharm Inc in 2005, on June 27th, 2012, at first ratified to go on the market in the U.S. by FDA (Food and Drug Adminstration), its specificity target spot is 5-HT2C, for control appetite very strong effect is arranged, for 5-HTM or the then not effect of 5-HT2B acceptor, therefore compare the side effect that has still less with diet pill in the past, meanwhile, chlorine Ka Selin can also improve heart rate, blood pressure and low-density lipoprotein cholesterol level in fat-reducing.
The synthetic route of having reported at present has following method:
Circuit one:
Circuit two:
Circuit three:
In disclosed file WO2005003096, reported the synthetic method of route one, being starting raw material to chlorobenzene ethamine, react with the 2-chlorpromazine chloride, again through paying the gram alkylation, reduction splits and obtains chlorine Ka Selin, though this route had only for four steps, starting raw material is few to the chlorobenzene ethamine market requirement, be unconventional industrial chemicals, therefore expensive.
The synthetic chlorine Ka Selin of US20090143576 has adopted the method for route two, be starting raw material with what be easy to get relatively to chlorophenethylol, through bromination, replace, pay the gram alkylation, fractionation obtains product, and this route uses dangerous big phosphorus tribromide, and industrial pollution is big, aftertreatment produces a large amount of hydrogen bromides, when replacing, be easy to generate polysubstituted product simultaneously, reaction requires harsh.
Along with the research to chlorine Ka Selin, bibliographical information the has been arranged synthetic method of route three, be starting raw material with the 4-Chlorophenylacetic acid that more is easy to get, carry out condensation with Yi Bingchunan, back reducing amide, chloro, pay the gram alkylation, split and obtain product, but at synthetic 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) in the process of ethanamide formula V, the condensation reagent costliness, improved production cost greatly, purifying products difficulty behind the condensing agent of perhaps application cheapness, WO2008070111 is, and condensation reaction improves, adopt boric acid, the mode of phenylo boric acid catalysis is carried out condensation, greatly reduces reaction cost, but this reaction needed divides water just can carry out fully for a long time, reaction is to the moisture requirement height, and the production cycle is long.
Summary of the invention
The invention solves deficiency of the prior art, provide a kind of with low cost, the preparation method of brand-new synthesis of high purity chlorine Ka Selin hydrochloride simple to operate.
Concrete synthetic route of the present invention is summarized as follows:
The invention provides a kind of preparation method of chlorine Ka Selin hydrochloride, comprise following a few step:
(1) 2-(4-chloro-phenyl-)-and the N-(2-hydroxypropyl) preparation of ethanamide:
In the 4-Chlorophenylacetic acid ester solution, add Yi Bingchunan, react completely, obtain the 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) ethanamide;
(2) 2-(4-chloro-phenyl-)-and the N-(2-chloropropyl) preparation of ethanamide:
With the 2-(4-chloro-phenyl-that obtains in the step (1))-the N-(2-hydroxypropyl) add halide reagent in the acetamide solution, obtain the 2-(4-chloro-phenyl-after the complete reaction)-the N-(2-chloropropyl) ethanamide;
(3) 2-chloro-N-(4-chlorobenzene ethyl)-preparation of propane-1-amine:
With the 2-(4-chloro-phenyl-that obtains in the step (2))-the N-(2-chloropropyl) acetamide solution adds and to go back original reagent or system, obtains 2-chloro-N-(4-chlorobenzene ethyl after the complete reaction)-propane-1-amine;
(4) 8-chloro-1-methyl-2,3,4, the preparation of 5-tetrahydrochysene-1H-3-benzazepine:
The 2-chloro-N-(4-chlorobenzene ethyl that step (3) is obtained)-propane-1-amine aqueous solution adds Lewis acid, obtains 8-chloro-1-methyl-2,3,4 after the complete reaction, 5-tetrahydrochysene-1H-3-benzazepine;
(5) preparation of chlorine Ka Selin:
With the 8-chloro-1-methyl-2 that obtains in the step (4), 3, add resolving agent in 4,5-tetrahydrochysene-1H-3-benzazepine solution, crystallization obtains tartrate, recrystallization again, free, salify obtains (R)-8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine hydrochloride is chlorine Ka Selin hydrochloride.
Preferably, the Yi Bingchunan described in the step (1) is 1.01:1~2:1 with the ratio of 4-Chlorophenylacetic acid ester amount of substance.
Preferably, solvent in the step (1) in the 4-Chlorophenylacetic acid ester solution is protic solvent and non-protonic solvent, described protic solvent is a kind of or its mixture in methyl alcohol, ethanol, Virahol, propyl alcohol, butanols, the trimethyl carbinol, isopropylcarbinol and the ethylene glycol, described non-protonic solvent is a kind of or its mixture in dioxane, dimethyl formamide and the dimethyl sulfoxide (DMSO), and the mass ratio of the quality of described solvent and described 4-Chlorophenylacetic acid ester is 1:1~10:1.
Preferably, 2-(4-chloro-phenyl-in the step (2))-the N-(2-hydroxypropyl) solvent of acetamide solution is a kind of or its mixture in methylene dichloride, chloroform, toluene and the dimethylbenzene, described solvent and 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) mass ratio of ethanamide is 1:1~10:1.
Preferably, it is characterized in that, halide reagent described in the step (2) is a kind of or its mixture chlorination reagent or the bromide reagent in sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride and the phosphorus tribromide, the temperature that adds described halide reagent is 0~100 ℃, described halide reagent and 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) amount of substance of ethanamide is than for 0.5:1~2.0:1, and temperature of reaction is 0~150 ℃.
Preferably, 2-(4-chloro-phenyl-in the step (3))-and the N-(2-chloropropyl) solvent in the acetamide solution is a kind of or its mixture in toluene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, chlorobenzene and the dichlorobenzene; Described solvent and 2-(4-chloro-phenyl-)-the N-(2-chloropropyl) mass ratio of ethanamide is 1:1~10:1.
Preferably, reductive agent described in the step (3) is one or more in Lithium Aluminium Hydride, sodium borohydride, POTASSIUM BOROHYDRIDE and the red aluminium, described reductive agent and 2-(4-chloro-phenyl-)-the N-(2-chloropropyl) the amount of substance ratio of ethanamide is 0.6~3, the temperature control of described reaction is at 30~150 ℃.The favourable raising speed of response of control temperature of reaction.
Preferably, 2-chloro-N-(4-chlorobenzene ethyl in the step (4))-solvent in propane-1-amine aqueous solution is chlorobenzene or dichlorobenzene, described solvent and 2-chloro-N-(4-chlorobenzene ethyl)-mass ratio of propane-1-amine is 3:1~15:1.
Preferably, Lewis acid described in the step (4) is one or more in aluminum chloride, tin protochloride, tin chloride and the zinc chloride, described Lewis acid and 2-chloro-N-(4-chlorobenzene ethyl)-the amount of substance ratio of propane-1-amine is 0.8~2, the temperature control of described reaction is at 60~160 ℃.The favourable raising speed of response of control temperature of reaction.
Preferably, 8-chloro-1-methyl-2 described in the step (5), 3,4,5-tetrahydrochysene-1H-3-benzazepine solution solvent be methyl alcohol, ethanol, in water and the acetone one or more, described solvent and 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine mass ratio is 5:1~30:1, described resolving agent is L-tartrate or L MALIC ACID, described resolving agent and 8-chloro-1-methyl-2,3,4, the amount of substance of 5-tetrahydrochysene-1H-3-benzazepine is than being 0.2:1~0.5:1, and described recrystallization temperature is 0~30 ℃, and the described crystallization time is 1~24 hour.
The preparation method of a kind of chlorine Ka Selin hydrochloride provided by the invention, this method is with low cost, simple to operate and to obtain the purity of product higher, but technology operate continuously of the present invention, reduce the production cycle greatly, reagent is cheap and easy to get simultaneously, simple to operate, aftertreatment is easy, but therefore is a kind of synthetic method of brand-new, economic suitability for industrialized production.
Embodiment
In order to make those skilled in the art person understand the present invention better, and above-mentioned advantage of the present invention can be become apparent more, the present invention is further detailed explanation below in conjunction with specific embodiment.
Embodiment 1
(1) 2-(4-chloro-phenyl-)-and the N-(2-hydroxypropyl) preparation of ethanamide formula V
Add methyl alcohol 900ml in the there-necked flask of 3000ml, Yi Bingchunan 82.6g(1.1mol), the back that stirs adds p-chlorophenyl acetate 184.6g(1mol), be heated to 50 ℃, be incubated after 6 hours, decompression and solvent recovery adds the 5L process water, 20~25 ℃ of crystallizatioies of temperature control, filter, filtration cakes torrefaction obtains the 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) the ethanamide formula V, white solid 223g, yield 97.9%.
(2) 2-(4-chloro-phenyl-)-and the N-(2-chloropropyl) preparation of ethanamide formula (IV)
Add toluene 500ml in the there-necked flask of 1000ml, the 2-(4-chloro-phenyl-)-and the N-(2-hydroxypropyl) ethanamide formula V 114g(0.5mol), stirring and dissolving, ice-water bath is cooled to 0~5 ℃, slow dripping thionyl chloride 90g(0.6mol), after dropwising, add the 5ml triethylamine, 10~20 ℃ of temperature controls, reacted 2~3 hours, reclaim solvent, add 2-methyltetrahydrofuran 500ml again, the sodium hydroxide solution 200ml of 1mol/L, separatory, the organic phase anhydrous sodium sulfate drying filters, and filtrate is directly carried out next step reaction.
(3) 2-chloro-N-(4-chlorobenzene ethyl)-preparation of propane-1-amine formula (III)
The solution 500ml that last step reaction obtains, add sodium borohydride 38g, drip boron trifluoride tetrahydrofuran solution 50ml, after dropwising, be warming up to 60~65 ℃, insulation adds the hydrochloric acid 100ml of 2mol/L to reacting completely, reflux after 30 minutes, separatory, water is regulated P hour to 10 with saturated sodium carbonate, adds the 200ml ethyl acetate extraction, organic phase adds the saturated hydrogenchloride ethyl acetate of 50ml, 0~5 ℃ of temperature control is separated out white solid, 2-chloro-N-(4-chlorobenzene ethyl)-propane-1-amine formula (III) hydrochloride, 107.4g, two step yields 80.2%.
(4) 8-chloro-1-methyl-2,3,4, the preparation of 5-tetrahydrochysene-1 hour-3-benzazepine formula (II)
Add 2-chloro-N-(4-chlorobenzene ethyl in the there-necked flask of 3000ml)-propane-1-amine formula (III) hydrochloride 200g, aluminum chloride 150g, dichlorobenzene 1L, slowly be warming up to 120~125 ℃, insulation is cooled to 20 ℃ to reacting completely, add the 500ml frozen water, separatory, water is regulated P hour to 12, the toluene extraction, organic layer reclaims solvent and gets grey crude product solid 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1 hour-3-benzazepine formula (II) need not to be further purified.
(5) preparation of chlorine Ka Selin hydrochloride formula (I)
Add in the there-necked flask of 1000ml and go up the 8-chloro-1-methyl-2,3 that the step reaction obtains, 4,5-tetrahydrochysene-1 hour-3-benzazepine crude product adds acetone 600ml, is heated to backflow, added the 20g activated carbon decolorizing 20 minutes, filter the back and add the tartaric aqueous solution of L-(28gL-tartrate is dissolved in the 50ml water), be cooled to 0~5 ℃, crystallization 3 hours, filter, filter cake joins in the 200ml water behind recrystallization, regulates P hour to 10 with salt of wormwood, ethyl acetate extraction, the organic layer drying feeds hour Cl gas to saturated, 0~5 ℃ of crystallization of temperature control 6 hours, filter, dry white crystal (R)-8-chloro-1-methyl-2,3,4 of getting, 5-tetrahydrochysene-1 hour-the 3-benzazepine is chlorine Ka Selin hydrochloride formula (I) 56.6g, two step yields 38.5%, the enantiomorph relative content is greater than 99%, and purity is greater than 99.5%.
Embodiment 2
(1) 2-(4-chloro-phenyl-)-and the N-(2-hydroxypropyl) preparation of ethanamide formula V
Add ethanol 1000ml in the there-necked flask of 3000ml, Yi Bingchunan 82.6g(1.1mol), the back that stirs adds p-chlorophenyl acetate 184.6g(1mol), be heated to 70 ℃, be incubated after 4 hours, decompression and solvent recovery adds the 5L process water, 20~25 ℃ of crystallizatioies of temperature control, filter, filtration cakes torrefaction obtains the 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) the ethanamide formula V, white solid 224g, yield 98.3%.
(2) 2-(4-chloro-phenyl-)-and the N-(2-chloropropyl) preparation of ethanamide formula (IV)
Add methylene dichloride 500ml in the there-necked flask of 1000ml, the 2-(4-chloro-phenyl-)-and the N-(2-hydroxypropyl) ethanamide formula V 114g(0.5mol), stirring and dissolving, ice-water bath is cooled to 0~5 ℃, slowly add phosphorus pentachloride 52g(0.25mol), after adding finishes, 30~40 ℃ of temperature controls reacted 2~3 hours, reclaimed solvent, add 2-methyltetrahydrofuran 600ml again, the sodium hydroxide solution 200ml of 1N, separatory, organic phase anhydrous sodium sulfate drying, filter, filtrate is directly carried out next step reaction.
(3) 2-chloro-N-(4-chlorobenzene ethyl)-preparation of propane-1-amine formula (III)
The solution 550ml that last step reaction obtains adds sodium borohydride 38g, adds iodine 254g, after adding, be warming up to 60~65 ℃, insulation is to reacting completely, add the hydrochloric acid 100ml of 2N, reflux after 30 minutes separatory, water is regulated P hour to 10 with saturated sodium carbonate, adds the extraction of 200ml first uncle ether, and organic phase feeds hydrogenchloride to saturated, 0~5 ℃ of temperature control, separate out white solid, 2-chloro-N-(4-chlorobenzene ethyl)-propane-1-amine formula (III) hydrochloride 111.3g, two step yields 83.1%.
(4) 8-chloro-1-methyl-2,3,4, the preparation of 5-tetrahydrochysene-1 hour-3-benzazepine formula (II)
Add 2-chloro-N-(4-chlorobenzene ethyl in the there-necked flask of 3000ml)-propane-1-amine formula (III) hydrochloride 200g, Zinc Chloride Anhydrous 180g, dichlorobenzene 1L, slowly be warming up to 110~120 ℃, insulation is cooled to 20 ℃ to reacting completely, add the 500ml frozen water, separatory, water is regulated P hour to 12, chloroform extraction, organic layer reclaims solvent and gets grey crude product solid 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1 hour-3-benzazepine formula (II) need not to be further purified.
(5) preparation of chlorine Ka Selin hydrochloride formula (I)
Add in the there-necked flask of 1000ml and go up the 8-chloro-1-methyl-2,3 that the step reaction obtains, 4,5-tetrahydrochysene-1 hour-3-benzazepine crude product adds methyl alcohol 600ml, is heated to backflow, added the 20g activated carbon decolorizing 20 minutes, filter the back and add the tartaric aqueous solution of L-(32gL-tartrate is dissolved in the 50ml water), be cooled to 0~5 ℃, crystallization 3 hours, filter, filter cake joins in the 200ml water behind recrystallization, regulates P hour to 10 with salt of wormwood, ethyl acetate extraction, the organic layer drying feeds hour Cl gas to saturated, 0~5 ℃ of crystallization of temperature control 6 hours, filter, dry white crystal (R)-8-chloro-1-methyl-2,3,4 of getting, 5-tetrahydrochysene-1 hour-the 3-benzazepine is chlorine Ka Selin hydrochloride formula (I) 54.4g, two step yields 37.1%, the enantiomorph relative content is greater than 99%, and purity is greater than 99.5%.
Embodiment 3
(1) 2-(4-chloro-phenyl-)-and the N-(2-hydroxypropyl) preparation of ethanamide formula V
Add dioxane 1000ml in the there-necked flask of 3000ml, Yi Bingchunan 82.6g(1.1mol), the back that stirs adds p-chlorophenyl acetate 184.6g(1mol), be heated to 70 ℃, be incubated after 5 hours, decompression and solvent recovery adds the 5L process water, 20~25 ℃ of crystallizatioies of temperature control, filter, filtration cakes torrefaction obtains the 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) the ethanamide formula V, white solid 223.8g, yield 98.0%.
(2) 2-(4-chloro-phenyl-)-and the N-(2-bromopropyl) preparation of ethanamide formula (IV)
Add methylene dichloride 500ml in the there-necked flask of 1000ml, the 2-(4-chloro-phenyl-)-and the N-(2-hydroxypropyl) ethanamide formula V 114g(0.5mol), stirring and dissolving, ice-water bath is cooled to 0~5 ℃, slowly add phosphorus tribromide 68g(0.25mol), after adding finishes, 30~40 ℃ of temperature controls reacted 2~3 hours, reclaimed solvent, add 2-methyltetrahydrofuran 600ml again, the sodium hydroxide solution 200ml of 1mol/L, separatory, organic phase anhydrous sodium sulfate drying, filter, filtrate is directly carried out next step reaction.
(3) 2-bromo-N-(4-chlorobenzene ethyl)-preparation of propane-1-amine formula (III)
The solution 550ml that last step reaction obtains adds sodium borohydride 38g, adds zinc chloride 200g, after adding, be warming up to 60~65 ℃, insulation is to reacting completely, add the hydrochloric acid 100ml of 2mol/L, reflux after 30 minutes separatory, water is regulated P hour to 10 with saturated sodium carbonate, adds the 200ml ethyl acetate extraction, and organic phase feeds hydrogenchloride to saturated, 0~5 ℃ of temperature control, separate out white solid, 2-bromo-N-(4-chlorobenzene ethyl)-propane-1-amine formula (III) hydrochloride 111.3g, two step yields 79.2%.
(4) 8-chloro-1-methyl-2,3,4, the preparation of 5-tetrahydrochysene-1 hour-3-benzazepine formula (II)
Add 2-chloro-N-(4-chlorobenzene ethyl in the there-necked flask of 3000ml)-propane-1-amine formula (III) hydrochloride 200g, Aluminum chloride anhydrous 180g, dichlorobenzene 1L, slowly be warming up to 110-120 ℃, insulation is cooled to 20 ℃ to reacting completely, add the 500ml frozen water, separatory, water is regulated P hour to 12, chloroform extraction, organic layer reclaims solvent and gets grey crude product solid 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1 hour-3-benzazepine formula (II) need not to be further purified.
(5) preparation of chlorine Ka Selin hydrochloride formula (I)
Add in the there-necked flask of 1000ml and go up the 8-chloro-1-methyl-2,3 that the step reaction obtains, 4,5-tetrahydrochysene-1 hour-3-benzazepine crude product adds ethanol 600ml, is heated to backflow, added the 20g activated carbon decolorizing 20 minutes, filter the back and add the tartaric aqueous solution of L-(30gL-tartrate is dissolved in the 50ml water), be cooled to 0~5 ℃, crystallization 3 hours, filter, filter cake joins in the 200ml water behind recrystallization, regulates P hour to 10 with salt of wormwood, ethyl acetate extraction, the organic layer drying feeds hour Cl gas to saturated, 0~5 ℃ of crystallization of temperature control 6 hours, filter, dry white crystal (R)-8-chloro-1-methyl-2,3,4 of getting, 5-tetrahydrochysene-1 hour-the 3-benzazepine is chlorine Ka Selin hydrochloride formula (I) 52.4g, two step yields 35.1%, the enantiomorph relative content is greater than 99%, and purity is greater than 99.5%.
The above; be the specific embodiment of the present invention only, protection scope of the present invention is not limited thereto, and anyly is familiar with those skilled in the art in the technical scope that the present invention discloses; the variation that can expect easily or replacement all should be encompassed within protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain that claim was defined.
Claims (10)
1. the preparation method of a chlorine Ka Selin hydrochloride is characterized in that, comprises following a few step:
(1) 2-(4-chloro-phenyl-)-and the N-(2-hydroxypropyl) preparation of ethanamide:
In the 4-Chlorophenylacetic acid ester solution, add Yi Bingchunan, react completely, obtain the 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) ethanamide;
(2) 2-(4-chloro-phenyl-)-and the N-(2-chloropropyl) preparation of ethanamide:
With the 2-(4-chloro-phenyl-that obtains in the step (1))-the N-(2-hydroxypropyl) add halide reagent in the acetamide solution, obtain the 2-(4-chloro-phenyl-after the complete reaction)-the N-(2-chloropropyl) ethanamide;
(3) 2-chloro-N-(4-chlorobenzene ethyl)-preparation of propane-1-amine:
With the 2-(4-chloro-phenyl-that obtains in the step (2))-the N-(2-chloropropyl) acetamide solution adds and to go back original reagent or system, obtains 2-chloro-N-(4-chlorobenzene ethyl after the complete reaction)-propane-1-amine;
(4) 8-chloro-1-methyl-2,3,4, the preparation of 5-tetrahydrochysene-1H-3-benzazepine:
The 2-chloro-N-(4-chlorobenzene ethyl that step (3) is obtained)-propane-1-amine aqueous solution adds Lewis acid, obtains 8-chloro-1-methyl-2,3,4 after the complete reaction, 5-tetrahydrochysene-1H-3-benzazepine;
(5) preparation of chlorine Ka Selin:
With the 8-chloro-1-methyl-2 that obtains in the step (4), 3, add resolving agent in 4,5-tetrahydrochysene-1H-3-benzazepine solution, crystallization obtains tartrate, recrystallization again, free, salify obtains (R)-8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine hydrochloride is chlorine Ka Selin hydrochloride.
2. the preparation method of chlorine Ka Selin hydrochloride according to claim 1 is characterized in that, the Yi Bingchunan described in the step (1) is 1.01:1~2:1 with the ratio of 4-Chlorophenylacetic acid ester amount of substance.
3. the preparation method of chlorine Ka Selin hydrochloride according to claim 1, it is characterized in that, solvent in the step (1) in the 4-Chlorophenylacetic acid ester solution is protic solvent and non-protonic solvent, described protic solvent is a kind of or its mixture in methyl alcohol, ethanol, Virahol, propyl alcohol, butanols, the trimethyl carbinol, isopropylcarbinol and the ethylene glycol, described non-protonic solvent is a kind of or its mixture in dioxane, dimethyl formamide and the dimethyl sulfoxide (DMSO), and the mass ratio of the quality of described solvent and described 4-Chlorophenylacetic acid ester is 1:1~10:1.
4. the preparation method of chlorine Ka Selin hydrochloride according to claim 1, it is characterized in that, 2-(4-chloro-phenyl-in the step (2))-the N-(2-hydroxypropyl) solvent of acetamide solution is a kind of or its mixture in methylene dichloride, chloroform, toluene and the dimethylbenzene, described solvent and 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) mass ratio of ethanamide is 1:1~10:1.
5. according to the preparation method of claim 1 or 4 each described chlorine Ka Selin hydrochlorides, it is characterized in that, halide reagent described in the step (2) is a kind of or its mixture chlorination reagent or the bromide reagent in sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride and the phosphorus tribromide, the temperature that adds described halide reagent is 0~100 ℃, described halide reagent and 2-(4-chloro-phenyl-)-the N-(2-hydroxypropyl) amount of substance of ethanamide is than for 0.5:1~2.0:1, and temperature of reaction is 0~150 ℃.
6. the preparation method of chlorine Ka Selin hydrochloride according to claim 1, it is characterized in that 2-(4-chloro-phenyl-in the step (3))-the N-(2-chloropropyl) solvent in the acetamide solution is a kind of or its mixture in toluene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, chlorobenzene and the dichlorobenzene; Described solvent and 2-(4-chloro-phenyl-)-the N-(2-chloropropyl) mass ratio of ethanamide is 1:1~10:1.
7. the preparation method of chlorine Ka Selin hydrochloride according to claim 6, it is characterized in that, reductive agent described in the step (3) is one or more in Lithium Aluminium Hydride, sodium borohydride, POTASSIUM BOROHYDRIDE and the red aluminium, described reductive agent and 2-(4-chloro-phenyl-)-the N-(2-chloropropyl) the amount of substance ratio of ethanamide is 0.6~3, the temperature control of described reaction is at 30~150 ℃.
8. according to the preparation method of the chlorine Ka Selin hydrochloride described in the claim 1, it is characterized in that, 2-chloro-N-(4-chlorobenzene ethyl in the step (4))-solvent in propane-1-amine aqueous solution is chlorobenzene or dichlorobenzene, described solvent and 2-chloro-N-(4-chlorobenzene ethyl)-mass ratio of propane-1-amine is 3:1~15:1.
9. the preparation method of the chlorine Ka Selin hydrochloride described in according to Claim 8, it is characterized in that, Lewis acid described in the step (4) is one or more in aluminum chloride, tin protochloride, tin chloride and the zinc chloride, described Lewis acid and 2-chloro-N-(4-chlorobenzene ethyl)-the amount of substance ratio of propane-1-amine is 0.8~2, the temperature control of described reaction is at 60~160 ℃.
10. the preparation method of chlorine Ka Selin hydrochloride according to claim 1, it is characterized in that, 8-chloro-1-methyl-2 described in the step (5), 3,4,5-tetrahydrochysene-1H-3-benzazepine solution solvent be methyl alcohol, ethanol, in water and the acetone one or more, described solvent and 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine mass ratio is 5:1~30:1, and described resolving agent is L-tartrate or L MALIC ACID, described resolving agent and 8-chloro-1-methyl-2, the amount of substance of 3,4,5-tetrahydrochysene-1H-3-benzazepine is than being 0.2:1~0.5:1, described recrystallization temperature is 0~30 ℃, and the described crystallization time is 1~24 hour.
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103601645A (en) * | 2013-11-07 | 2014-02-26 | 上海适济生物科技有限公司 | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof |
CN103755635A (en) * | 2014-01-20 | 2014-04-30 | 中国计量学院 | Synthesis methods of lorcaserin derivative and salt thereof |
CN104130188A (en) * | 2014-08-05 | 2014-11-05 | 南京工业大学 | Preparation method of 8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine |
CN104730167A (en) * | 2015-03-24 | 2015-06-24 | 南京昂谷医药科技有限公司 | Lorcaserin enantiomer detection method and quality control standard of lorcaserin enantiomer |
WO2015170346A1 (en) | 2014-05-09 | 2015-11-12 | Council Of Scientific & Industrial Research | A process for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-benzo[d]azepine its enantiomers |
CN105348196A (en) * | 2015-10-23 | 2016-02-24 | 湖北朗昕生化药业有限公司 | Lorcaserin hydrochloride hemihydrate preparation method |
CN106957237A (en) * | 2017-03-24 | 2017-07-18 | 苏州汇和药业有限公司 | A kind of method for synthesizing bromfenac sodium |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005019179A2 (en) * | 2003-06-17 | 2005-03-03 | Arena Pharmaceuticals, Inc. | Benzazepine derivatives useful for the treatment of 5ht2c receptor associated diseases |
CN1805938A (en) * | 2003-06-17 | 2006-07-19 | 艾尼纳制药公司 | Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases |
WO2007120517A2 (en) * | 2006-04-03 | 2007-10-25 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates related thereto |
CN101547892A (en) * | 2006-12-05 | 2009-09-30 | 艾尼纳制药公司 | Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof |
-
2013
- 2013-06-14 CN CN2013102360454A patent/CN103333111A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005019179A2 (en) * | 2003-06-17 | 2005-03-03 | Arena Pharmaceuticals, Inc. | Benzazepine derivatives useful for the treatment of 5ht2c receptor associated diseases |
CN1805938A (en) * | 2003-06-17 | 2006-07-19 | 艾尼纳制药公司 | Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases |
WO2007120517A2 (en) * | 2006-04-03 | 2007-10-25 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates related thereto |
CN101466684A (en) * | 2006-04-03 | 2009-06-24 | 艾尼纳制药公司 | Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates related thereto |
CN101547892A (en) * | 2006-12-05 | 2009-09-30 | 艾尼纳制药公司 | Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof |
Non-Patent Citations (2)
Title |
---|
钟杭: "绿卡色林", 《中国药物化学杂志》 * |
黄敏: "绿卡色林的合成及生产工艺的研究", 《杭州师范大学硕士论文》 * |
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CN103601645B (en) * | 2013-11-07 | 2016-05-25 | 上海适济生物科技有限公司 | The preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt |
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WO2015170346A1 (en) | 2014-05-09 | 2015-11-12 | Council Of Scientific & Industrial Research | A process for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-benzo[d]azepine its enantiomers |
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CN104130188B (en) * | 2014-08-05 | 2016-08-31 | 南京工业大学 | Preparation method of 8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine |
CN104730167A (en) * | 2015-03-24 | 2015-06-24 | 南京昂谷医药科技有限公司 | Lorcaserin enantiomer detection method and quality control standard of lorcaserin enantiomer |
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