CN112824378A - Preparation method of tamsulosin hydrochloride - Google Patents
Preparation method of tamsulosin hydrochloride Download PDFInfo
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- CN112824378A CN112824378A CN201911119198.4A CN201911119198A CN112824378A CN 112824378 A CN112824378 A CN 112824378A CN 201911119198 A CN201911119198 A CN 201911119198A CN 112824378 A CN112824378 A CN 112824378A
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- tamsulosin
- hydrochloride
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- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229960003198 tamsulosin hydrochloride Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims description 23
- 229960002613 tamsulosin Drugs 0.000 claims abstract description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 229930188012 Bromoether Natural products 0.000 claims abstract description 3
- HJCMMOODWZOXML-UHFFFAOYSA-N bromo hypobromite Chemical compound BrOBr HJCMMOODWZOXML-UHFFFAOYSA-N 0.000 claims abstract description 3
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 claims description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000007670 refining Methods 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract description 5
- 150000001412 amines Chemical class 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000012458 free base Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000009901 transfer hydrogenation reaction Methods 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 18
- -1 2-ethoxyphenyloxy Chemical group 0.000 description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 16
- IOYHGBZPUZBUTJ-UHFFFAOYSA-N 1-(2-bromoethoxy)-2-ethoxybenzene Chemical compound CCOC1=CC=CC=C1OCCBr IOYHGBZPUZBUTJ-UHFFFAOYSA-N 0.000 description 14
- 230000003287 optical effect Effects 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- KYRRNJIOCLALJQ-OGFXRTJISA-N 5-[(2r)-2-aminopropyl]-2-methoxybenzenesulfonamide;hydrochloride Chemical compound Cl.COC1=CC=C(C[C@@H](C)N)C=C1S(N)(=O)=O KYRRNJIOCLALJQ-OGFXRTJISA-N 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- ZZIZZTHXZRDOFM-XFULWGLBSA-N tamsulosin hydrochloride Chemical compound [H+].[Cl-].CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-XFULWGLBSA-N 0.000 description 3
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 2
- WFWKNGZODAOLEO-UHFFFAOYSA-N 1-(4-Methoxyphenyl)-2-propanone Chemical compound COC1=CC=C(CC(C)=O)C=C1 WFWKNGZODAOLEO-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical group [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- NEGYEDYHPHMHGK-MRVPVSSYSA-N (2r)-1-(4-methoxyphenyl)propan-2-amine Chemical compound COC1=CC=C(C[C@@H](C)N)C=C1 NEGYEDYHPHMHGK-MRVPVSSYSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- LJSCVNJEBIWYLD-UHFFFAOYSA-N 1-ethoxy-2-(2-iodoethoxy)benzene Chemical compound CCOC1=CC=CC=C1OCCI LJSCVNJEBIWYLD-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- MQQJFLHZXQRKKJ-UHFFFAOYSA-N 2-methoxy-5-(2-oxopropyl)benzenesulfonamide Chemical compound COC1=CC=C(CC(C)=O)C=C1S(N)(=O)=O MQQJFLHZXQRKKJ-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- IORITYIZDHJCGT-UHFFFAOYSA-N 5-(2-aminopropyl)-2-methoxybenzenesulfonamide Chemical compound COC1=CC=C(CC(C)N)C=C1S(N)(=O)=O IORITYIZDHJCGT-UHFFFAOYSA-N 0.000 description 1
- ZIDMEUOHWXPUFW-SSDOTTSWSA-N 5-[(2r)-2-aminopropyl]-2-methoxybenzenesulfonic acid Chemical compound COC1=CC=C(C[C@@H](C)N)C=C1S(O)(=O)=O ZIDMEUOHWXPUFW-SSDOTTSWSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940093334 flomax Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention belongs to the technical field of chemical synthesis, and relates to a method for synthesizing tamsulosin hydrochloride. The synthesis method comprises the steps of firstly reacting benzenesulfonamide shown in a formula (II) with bromoether shown in a formula (III) to obtain a condensate intermediate shown in a formula (IV), carrying out transfer hydrogenation reaction on the intermediate shown in the formula (IV) in the presence of ammonium formate and a catalyst to obtain R-tamsulosin free base shown in a formula (V), and carrying out salt-forming reaction on the R-tamsulosin free base and hydrochloric acid in an organic solvent to obtain tamsulosin hydrochloride shown in a formula (I). Characterized in that the reaction of the formula (II) with the formula (III) is carried out in a solvent containing water. Through the synthetic route of the invention, the reaction process of the obtained tamsulosin hydrochloride does not have the phenomenon that two molecules of bromide react with amine to generate disubstituted by-products, and the obtained tamsulosin hydrochloride has the advantages of good product purity, stable quality and high yield.
Description
Technical Field
The invention belongs to the technical field of pharmacy, relates to a preparation method of a high-selectivity alpha LA-receptor antagonist for treating benign prostatic hyperplasia, and particularly relates to a method for preparing stable tamsulosin hydrochloride.
Background
Tamsulosin (Tamsu)losin Hydrochloride), also known as tamsulosin, the Hydrochloride salt of which is used clinically and has the chemical name: 5- [ (2R) -2- [ [2- (2-ethoxyphenoxy) ethyl group]Amino group]Propyl radical]-2-methoxybenzenesulphonamide hydrochloride with the chemical name in english: 5- [ (2R) -2- [ [2- (2-ethoxyphenyloxy) ethyl]amino]propyl]-2-methoxybenzzene-sulfonimide hydrochloride, CAS: 106463-17-6; molecular formula C20H28N2O5S.hcl, molecular weight: 444.97 of; 1 chiral carbon atom exists in the tamsulosin hydrochloride molecular structure, and the clinically used medicine is in the R configuration;
the chemical structural formula of tamsulosin hydrochloride is as follows:
。
tamsulosin hydrochloride is a third-generation super-selective long-acting alpha LA-adrenoceptor antagonist, which is successfully developed in Japan and approved by FDA in 1992 in 7 months under the trade name of Harnal (Hale). Tamsulosin hydrochloride was thereafter marketed with Boringer Vargohne, Yapek company under the name Flomax, approved by the FDA in 1997. The medicine can specifically inhibit the contraction of prostate smooth muscle, quickly relieve BPH clinical symptoms, and has good curative effect and few adverse reactions.
The prior art discloses a plurality of preparation methods of tamsulosin or salts thereof, and the main methods are as follows:
the tamsulosin synthesis route disclosed in EP0380144 is:
the route is a patent disclosed by the original research, 5-acetonyl-2-methoxybenzenesulfonamide is used as a raw material, is hydrogenated with alpha- (+) -phenethylamine under the condition of platinum dioxide to form salt, 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride is obtained, then (R) -5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride is obtained by palladium-carbon hydrogenation, and finally the hydrochloride is condensed with o-ethoxy phenoxyethyl bromide to obtain tamsulosin free alkali.
In the method, two molecules of bromide and amine react to generate a disubstituted byproduct when the bromide reacts with the amine, so that the product quality is influenced.
WO2006061549 discloses the following route:
the method takes R-alpha-phenylethylamine and p-methoxy phenyl acetone as raw materials to prepare (R) -1- (4-methoxy phenyl) -N- ((R) -1-phenylethyl) propyl-2-amine hydrochloride; then condensing with chlorosulfonic acid to prepare 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonic acid; hydrogenating to obtain (R) -5- (2-aminopropyl) -2-methoxy benzenesulfonic acid; then condensing with o-ethoxy phenoxyethyl bromide, acylating by thionyl chloride, and aminolyzing to obtain tamsulosin.
The method firstly forms benzenesulfonic acid, and then forms amido bond through acylation and aminolysis, which is more complex; in addition, the method also has the problem that two molecules of bromide react with amine to generate disubstituted byproducts, which affects the quality of products.
CN103508928 used the route as follows:
in the method, R-alpha-phenylethylamine and p-methoxy phenyl acetone are used as raw materials, and sodium triacetoxyborohydride is used as a reducing agent to prepare (R) -1- (4-methoxyphenyl) -N- ((R) -1-phenylethyl) propyl-2-amine hydrochloride; then condensed with chloracyl acid, ammonolyzed and salified to obtain 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride; then (R) -5- (2-aminopropyl) -2-methoxyl benzene sulfonamide hydrochloride is obtained by hydrogenation under the catalysis of palladium carbon; finally condensing with o-ethoxy phenoxyethyl bromide and salifying with hydrochloric acid to obtain tamsulosin salt.
CN102898336, CN106478467 use the same route, as follows:
both of the two patents use (R) - (-) -5- (2-aminopropyl) -2-methoxybenzenesulphonamide hydrochloride and o-ethoxy phenoxyethyl bromide to condense in alkaline aqueous solution to obtain tamsulosin free alkali; and salifying the tamsulosin free alkali with hydrochloric acid to obtain tamsulosin hydrochloride. In addition, in the patent CN106478467, KI is added to an alkaline aqueous solution.
The following route is used in WO2007031823a 1:
calcium oxide is used as an acid-binding agent, reflux reaction is carried out in an alcohol solution, and after post-treatment and salt formation, the product (I) is obtained, wherein the yield is 44.7-57.7%. The requirement in the patent is that the functional group Z is-OSO2CH3，-OSO2C6H4CH3，-F，-Br，-Cl，-I。
The following route is used in WO 2004087623:
the route uses free (R) -5- (2-aminopropyl) -2-methoxybenzenesulphonamide hydrochloride and o-ethoxyphenoxyethyl bromide to react in KHCO3 and KI as acid-binding agents in acetonitrile or DMF or butanone to obtain tamsulosin free base; and (3) in methanol, regulating the pH value by using isopropanol hydrochloride to salify to obtain tamsulosin hydrochloride.
CN103508928, CN102898336, CN106478467 and WO2007031823A1 all have the problem that two molecules of bromide react with amine to generate disubstituted by-products, which affects the product quality.
The route used in WO2004016582 is as follows:
the route uses 5- (2-aminopropyl) -2-methoxybenzenesulphonamide to react with benzaldehyde, amino is protected firstly, then the amino reacts with o-ethoxyphenoxyethyl iodide to form quaternary ammonium salt, and finally the quaternary ammonium salt is hydrolyzed to obtain tamsulosin free alkali.
CN103497126 uses the route as follows:
in the route, 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride and o-ethoxyphenoxyethyl bromide are subjected to condensation reaction in an aprotic polar solvent in the presence of an acid-binding agent to form a tertiary amine condensate intermediate, the condensate intermediate is subjected to hydrogenation removal of ethylbenzene in an organic solvent under palladium-carbon to obtain tamsulosin free alkali, and finally the tamsulosin hydrochloride is salified with concentrated hydrochloric acid to obtain tamsulosin hydrochloride.
In the above-mentioned route, the reaction conditions are severe, such as involving hydrogen in the reaction, the risk factor is high, the chemical purity or optical purity of the obtained product is low, or the product quality is unstable, so it is necessary to develop a new process to solve the problems existing in the prior art.
Disclosure of Invention
The invention aims to overcome the defects of complex synthesis process, high cost and impure products of tamsulosin hydrochloride in the prior art, and provides a preparation method of tamsulosin hydrochloride with high optical purity and high chemical purity.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a method for synthesizing tamsulosin hydrochloride represented by the formula (1), said method comprising the steps of: a) performing condensation reaction on benzenesulfonamide shown as a formula (II) and bromoether shown as a formula (III) in water as a solvent under an alkaline condition to obtain a condensate intermediate shown as a formula (IV); b) carrying out hydrogenation reaction on the condensation compound intermediate in an organic solvent under the conditions that Pb/C is used as a catalyst and ammonium formate is used as a hydrogen source to obtain a tamsulosin crude product shown as a formula (V); refining the obtained tamsulosin crude product shown in the formula (V) to obtain tamsulosin shown in the formula (V); c) carrying out salt forming reaction on tamsulosin shown in formula (V) and a hydrochloric acid solution in an organic solvent to obtain tamsulosin hydrochloride shown in formula (I).
Wherein the base in the alkaline condition in step a) is an inorganic base or an organic base, and the inorganic base is selected from the group consisting of: one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide; the organic base is selected from one or more of triethylamine and N, N-diisopropylethylamine.
In some embodiments, the reaction is catalyzed by adding a suitable amount of sodium iodide or potassium iodide to step a).
The volume weight ratio of the water to the 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II) in the step a) is 5-25: 1, preferably 10-20: 1, more preferably 10-15: 1.
wherein the molar ratio of the 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II) to the o-ethoxyphenoxyethyl bromide (III) in the step a) is 1: 0.8-3.0, preferably 1: 1-2, more preferably 1:1 to 1.5.
Wherein the molar ratio of the 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II) to the alkaline substance in the step a) is 1: 0.5-4, preferably 1:1 to 4.
In the step b), the organic solvent is C1-C4 alcohol, preferably one or more of methanol, ethanol and isopropanol.
Wherein the weight ratio of the organic solvent to the condensate Intermediate (IV) in the step b) is 5-20: 1, preferably 5-15: 1, and further preferably 10-15: 1, more preferably 8: 1.
Wherein in the step b), the palladium carbon catalyst accounts for 0.5-20%, preferably 5-10% of the weight of the condensate Intermediate (IV); the molar ratio of the ammonium formate to the condensate Intermediate (IV) is 2-10: 1, preferably 3-5: 1, more preferably 3: 1; the reaction temperature is 20-60 ℃.
Wherein in the step b), the solvent adopted for refining is isopropanol. The weight-volume ratio of the tamsulosin crude product to the isopropanol is 1: 8-1: 15.
Wherein the organic solvent in the step c) is one or more selected from methanol, ethanol and isopropanol; and adjusting the pH value to 1-4, preferably 2-3, in the salt forming reaction.
The reaction formula of the invention is as follows:
it is another object of the present invention to provide a tamsulosin hydrochloride having stable quality, a stable tamsulosin hydrochloride, which is prepared according to the above method.
Research shows that the melting point, chemical purity and optical purity of the tamsulosin hydrochloride prepared by the method have no obvious change when examined under the condition of a high-temperature influence factor test (60 ℃), and the tamsulosin hydrochloride prepared by the method in reference example 7 has the melting point of 230.0-230.5 ℃ in 0 day, the chemical purity of 99.987%, the optical purity of 99.96%, the melting point of 229.8-230.2 ℃ in 10 days, the chemical purity of 99.980% and the optical purity of 99.96%.
The detection method of tamsulosin hydrochloride related substances and optical purity can be detected according to a detection method in the tamsulosin hydrochloride official draft disclosed in 2018, 8, 13 days of the national pharmacopoeia committee.
Compared with the prior art, the preparation method is simpler to operate, water is used as a solvent in the condensation reaction, so that the prior art is prevented from using an organic solvent as a reaction solvent, and the preparation method is low in cost and environment-friendly; the hydrogenation reaction avoids the use of hydrogen in the prior art, and can be carried out under the normal pressure condition by adopting transfer hydrogenation, so that the safety coefficient is high; is more suitable for industrial production. The preparation method has high yield, and the product tamsulosin hydrochloride has high optical purity and chemical purity, the yield of the adopted method is stable, the optical purity and the chemical purity in the optimal embodiment are both more than 99.95%, and the product quality is stable.
Drawings
FIG. 1 Hydrogen spectrum of compound (IV) of example 1.
FIG. 2 Hydrogen spectrum of Compound (V) of example 4
FIG. 3 heavy Water exchange Hydrogen Spectrum of Compound (V) of example 4
FIG. 4 example 5 chemical purity spectrum of tamsulosin
FIG. 5 chemical purity spectrum of tamsulosin hydrochloride of example 7
FIG. 6 optical purity spectrum of tamsulosin hydrochloride of example 7
FIG. 7 optical purity spectrum of tamsulosin hydrochloride of example 8
FIG. 8 chemical purity spectrum of tamsulosin hydrochloride of example 8
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the invention thereto.
Example 15 preparation of- [ (R) -2- [ [2- (2-ethoxyphenoxy) ethyl ] [ (R) -1-phenylethyl ] amino ] propyl ] -2-methoxybenzenesulfonamide (IV)
30.8 g (80 mmol) of 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II), 29.4 g of o-ethoxyphenoxyethyl bromide (III) and 13.4 g of sodium bicarbonate are added into 460mL of water, the mixture is subjected to heat preservation reaction at 90 ℃, after the reaction is finished, the mixture is cooled to room temperature, 500mL of ethyl acetate is added for extraction, liquid separation is carried out, an organic phase is washed by 400mL of saturated NaCl solution, dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain 51.3g of light yellow oily matter.
Example 25 preparation of- [ (R) -2- [ [2- (2-ethoxyphenoxy) ethyl ] [ (R) -1-phenylethyl ] amino ] propyl ] -2-methoxybenzenesulfonamide (IV)
Adding 56.2g of 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II), 71.6g of o-ethoxyphenoxyethyl bromide (III), 6g of sodium hydroxide and 19.4g of potassium iodide into 1400mL of water, carrying out heat preservation reaction at 100 ℃, cooling to room temperature after the reaction is finished, adding 1000mL of ethyl acetate for extraction, carrying out liquid separation, washing an organic phase with water and a saturated NaCl solution, drying 100g of anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 95.3g of light yellow oily matter.
Example preparation of 35- [ (R) -2- [ [2- (2-ethoxyphenoxy) ethyl ] [ (R) -1-phenylethyl ] amino ] propyl ] -2-methoxybenzenesulfonamide (IV)
19.3g of 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II), 13.5 g of o-ethoxyphenoxyethyl bromide (III) and 25g of N, N-diisopropylethylamine are added into 100g of water, the mixture is kept at 95 ℃, after the reaction is finished, the mixture is cooled to room temperature, 300mL of ethyl acetate is added for extraction, liquid separation is carried out, an organic phase is washed by water and a saturated NaCl solution, anhydrous sodium sulfate is dried, and the mixture is concentrated under reduced pressure to obtain 26.1g of light yellow oily matter.
Example 4 preparation of tamsulosin (V)
51.3g of the oily condensate (IV) of example 1 was dissolved in 400 g of methanol, and 0.3g of 10% Pd/C and 18.8 g of ammonium formate were added thereto, followed by stirring at room temperature to complete the reaction; filtering, concentrating the filtrate to dry to obtain crude tamsulosin, refining the crude tamsulosin by isopropanol, and drying to obtain 25g of white solid tamsulosin, wherein the yield is 76.5% and the chemical purity is 99.910% calculated by 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II).
Example 5 preparation of tamsulosin (V)
95.3g of the oily condensate (IV) of example 2 was dissolved in 1230 g of isopropanol, and 9.5g of 5% Pd/C and 70.3g of ammonium formate were added and reacted at 50 ℃ to complete the reaction; filtering, concentrating the filtrate under reduced pressure to dry to obtain crude tamsulosin, refining the crude tamsulosin by isopropanol, and drying to obtain white solid tamsulosin, wherein the yield is 75.4% and the chemical purity is 99.906% calculated by 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II).
Example 6 preparation of tamsulosin (V)
26.1g of the oily condensate (IV) in example 3 is dissolved in 250g of ethanol, and then 5.2g of 10% Pd/C and 28g of ammonium formate are added to react at 35 ℃ to complete the reaction; filtering, concentrating the filtrate under reduced pressure to dry to obtain crude tamsulosin, refining the crude tamsulosin by isopropanol, and drying to obtain white solid tamsulosin, wherein the yield is 73.5% and the chemical purity is 99.900% calculated by 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II).
Example 7 preparation of tamsulosin hydrochloride (I)
25g of tamsulosin (V) from example 4 was dissolved in 125 g of ethanol, concentrated hydrochloric acid was slowly added to a pH of 3 to precipitate a white solid, which was then subjected to suction filtration, washing with purified water, and drying to obtain 26.0g of tamsulosin hydrochloride (I) having a chemical purity of 99.987%, an optical purity of 99.96%, and a yield of 96.4%.
Example 8 preparation of tamsulosin hydrochloride (I)
30g of tamsulosin (V) from example 5 was taken, dissolved in 240 g of methanol, and 25% hydrochloric acid was slowly added to a pH of 2 to precipitate a white solid, which was then subjected to suction filtration, washing with purified water, and drying to obtain 30g of tamsulosin hydrochloride (I) having a chemical purity of 99.946%, an optical purity of 99.94% and a yield of 91.8%.
Example 9 preparation of tamsulosin hydrochloride (I)
Taking 10 g of tamsulosin (V) of example 6, dissolving with 100g of isopropanol, slowly adding concentrated hydrochloric acid until the pH value is 3, precipitating white solid, filtering, washing with purified water, and drying to obtain 10.4g of tamsulosin hydrochloride (I), wherein the chemical purity is 99.952%, the optical purity is 99.95%, and the yield is 95.5%.
Comparative examples
50g of 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II), 31.8g of o-ethoxyphenoxyethyl bromide (III) and 10.9g of potassium hydroxide are added into 250g of acetonitrile, and the mixture is subjected to heat preservation reaction at 40 ℃ for 15h, after the reaction is finished, the mixture is cooled to room temperature, filtered and concentrated under reduced pressure to obtain 76g of a light yellow oily substance (condensate IV). Dissolving 76g of the obtained condensation compound with 230g of ethanol, transferring the solution to a hydrogenation reaction kettle, adding 3.8g of 5% palladium carbon catalyst, replacing 3 times with nitrogen and hydrogen, heating to 30 ℃, introducing hydrogen to react under the pressure of 0.5Mpa for 10h, cooling, filtering to remove the catalyst, decompressing and concentrating the filtrate to obtain solid, pulping with water, filtering and drying to obtain 35.8g of tamsulosin (V), wherein the yield is 62% and the chemical purity is 95% calculated by 5- [ [ (2R) -2- [ (1R) -N- (1-methylbenzyl) ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride (II). Taking 30g of the obtained tamsulosin hydrochloride, the tamsulosin hydrochloride obtained in reference example 7 has a melting point of 224.6-227.3 ℃.
Claims (10)
1. A method for preparing tamsulosin, comprising the steps of: a) performing condensation reaction on benzenesulfonamide shown as a formula (II) and bromoether shown as a formula (III) in water as a solvent under an alkaline condition to obtain a condensate intermediate shown as a formula (IV); b) carrying out hydrogenation reaction on the condensation compound intermediate shown as the formula (IV) in an organic solvent under the conditions that palladium carbon is used as a catalyst and ammonium formate is used as a hydrogen source to obtain a tamsulosin crude product shown as the formula (V); refining the obtained tamsulosin crude product shown in the formula (V) to obtain tamsulosin shown in the formula (V)
2. A method for preparing tamsulosin hydrochloride, said method comprising reacting tamsulosin prepared according to claim 1 with a hydrochloric acid solution in an organic solvent to form a salt, thereby obtaining tamsulosin hydrochloride represented by formula (I)
3. Tamsulosin hydrochloride prepared according to the process of claim 2.
4. The preparation method according to claim 1 or 2, wherein the volume weight ratio of the water in the step a) to the benzene sulfonamide shown in the formula (II) is 5-25: 1, preferably 10 to 20: 1.
5. the preparation method according to claim 1 or 2, wherein the molar ratio of the benzene sulfonamide shown in the formula (II) to the bromine ether shown in the formula (III) in the step a) is 1: 0.8-3, preferably 1:1 to 2.
6. The preparation method according to claim 1 or 2, wherein the alkali in the alkaline condition in the step a) is an inorganic alkali or an organic alkali, and the inorganic alkali is one or more selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide; the organic base is selected from one or more of triethylamine and N, N-diisopropylethylamine; the molar ratio of the benzenesulfonamide represented by the formula (II) to the base is 1:0.5 to 4.
7. The preparation method according to claim 1 or 2, wherein the organic solvent in step b) is a C1-C4 alcohol, preferably one or more of methanol, ethanol and isopropanol; the weight ratio of the organic solvent to the condensate intermediate shown in the formula (IV) is 5-20: 1, preferably 10-15: 1.
8. The preparation method according to claim 1 or 2, wherein the palladium carbon catalyst in the step b) is 0.5 to 20%, preferably 5 to 10% of the weight of the condensate intermediate shown in the formula (IV); the molar ratio of the ammonium formate to the condensate intermediate shown as the formula (IV) is 2-10: 1, preferably 3-5: 1; the reaction temperature is 20-60 ℃.
9. The production method according to claim 1 or 2, wherein the solvent used for the purification in step b) is isopropyl alcohol.
10. The preparation method according to claim 2, wherein the organic solvent is selected from one or more of methanol, ethanol and isopropanol; and adjusting the pH value to 1-4, preferably 2-3, in the salt forming reaction.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999043657A1 (en) * | 1998-02-27 | 1999-09-02 | F. Hoffmann-La Roche Ag | 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives as muscarinic receptor antagonists |
| CN103497126A (en) * | 2013-09-30 | 2014-01-08 | 台州市华鼎化工有限公司 | Synthesis method of tamsulosin hydrochloride |
| CN106478467A (en) * | 2016-10-13 | 2017-03-08 | 深圳万和制药有限公司 | The method for preparing stable tamsulosin hydrochloride |
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2019
- 2019-11-20 CN CN201911119198.4A patent/CN112824378A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1999043657A1 (en) * | 1998-02-27 | 1999-09-02 | F. Hoffmann-La Roche Ag | 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives as muscarinic receptor antagonists |
| CN103497126A (en) * | 2013-09-30 | 2014-01-08 | 台州市华鼎化工有限公司 | Synthesis method of tamsulosin hydrochloride |
| CN106478467A (en) * | 2016-10-13 | 2017-03-08 | 深圳万和制药有限公司 | The method for preparing stable tamsulosin hydrochloride |
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