CN104447509A - Tirofiban hydrochloride preparation process - Google Patents
Tirofiban hydrochloride preparation process Download PDFInfo
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- CN104447509A CN104447509A CN201310426751.5A CN201310426751A CN104447509A CN 104447509 A CN104447509 A CN 104447509A CN 201310426751 A CN201310426751 A CN 201310426751A CN 104447509 A CN104447509 A CN 104447509A
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- 229960004929 tirofiban hydrochloride Drugs 0.000 title claims abstract description 19
- HWAAPJPFZPHHBC-FGJQBABTSA-N tirofiban hydrochloride Chemical compound O.Cl.C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 HWAAPJPFZPHHBC-FGJQBABTSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 5
- 230000005494 condensation Effects 0.000 claims abstract description 5
- 238000006722 reduction reaction Methods 0.000 claims abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Substances [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 8
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- AOTNPGUCQAQUBT-UHFFFAOYSA-N 4-(4-iodobutyl)piperidine Chemical compound N1CCC(CC1)CCCCI AOTNPGUCQAQUBT-UHFFFAOYSA-N 0.000 claims description 3
- LAXKLKKRQAGCTR-UHFFFAOYSA-N ClC(=O)CCCC1=CC=NC=C1 Chemical compound ClC(=O)CCCC1=CC=NC=C1 LAXKLKKRQAGCTR-UHFFFAOYSA-N 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- BRQSTCCSCAFAQC-UHFFFAOYSA-N 4-(4-iodobutyl)pyridine Chemical compound C1(=CC=NC=C1)CCCCI BRQSTCCSCAFAQC-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 230000026045 iodination Effects 0.000 claims description 2
- 238000006192 iodination reaction Methods 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
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 4
- 125000002346 iodo group Chemical group I* 0.000 claims 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- 239000007859 condensation product Substances 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 229910000000 metal hydroxide Inorganic materials 0.000 claims 1
- 150000004692 metal hydroxides Chemical class 0.000 claims 1
- 238000005649 metathesis reaction Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
- 238000003756 stirring Methods 0.000 description 42
- 239000007787 solid Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 229960000583 acetic acid Drugs 0.000 description 17
- 238000001914 filtration Methods 0.000 description 12
- 238000001291 vacuum drying Methods 0.000 description 12
- 238000010792 warming Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 235000009518 sodium iodide Nutrition 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000010907 mechanical stirring Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- 229960003425 tirofiban Drugs 0.000 description 5
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 3
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- -1 butyl bromide compound Chemical class 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- QLPZEDHKVHQPAD-UHFFFAOYSA-N 2,2,2-trifluoro-n-trimethylsilylacetamide Chemical compound C[Si](C)(C)NC(=O)C(F)(F)F QLPZEDHKVHQPAD-UHFFFAOYSA-N 0.000 description 1
- VWMFGNDEHGWCLR-UHFFFAOYSA-N 2-(4-chlorobutyl)pyridine hydrochloride Chemical compound Cl.ClCCCCC1=CC=CC=N1 VWMFGNDEHGWCLR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the field of medicine and chemical industry. According to the present invention, the tirofiban hydrochloride prepared through substitution, condensation, reduction, salification and other reactions has characteristics of high yield, good quality and good stability, and the preparation process of the present invention provides a synthesis process suitable for the practical industrial mass production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, particularly a kind of preparation technology preparing Tirofiban hydrochloride.
Background technology
Tirofiban hydrochloride chemistry is called " S-N-(normal-butyl nitroxyl)-O-[4-(4-pyridyl) butyl]-TYR hydrochloride monohydrate ".From Tirofiban hydrochloride by after U.S. MerK Developed, its pharmacologically active is remarkable and enjoy the concern of numerous investigators, and its synthesis technique, preparation are especially by research widely and report.CN1050832C, US5206373 disclose a kind of synthetic route of improvement, with 4-picoline and the bromo-3-chloropropane of 1-for raw material, generate 4-chlorobutyl pyridine hydrochloride under n-Butyl Lithium effect.Another TYR through two (TMS) trifluoroacetamide (BSTFA) the silicon etherification protection of N, O-, with positive fourth SULPHURYL CHLORIDE sulfonylation and Deprotection N-(fourth alkylsulfonyl)-TYR.Generation alkylated reaction obtains product and obtain Tirofiban hydrochloride monohydrate after the reduction of palladium charcoal, salify.Patent US522756, EP478328 etc. disclose another synthetic method of this compound; with 4-piperidines-2-ethanol for starting raw material; through the obtained 4-(4-N-t-butyloxycarbonyl piperidyl of five step reactions) butyl bromide compound; acylation reaction is carried out under NaH/DMF effect; the reaction such as esterification under alkaline condition, deprotection, amination, hydrolysis, salify obtains target product Tirofiban hydrochloride monohydrate; this synthesis technique relates to the first-class toxicity of iodate and comparatively strengthens compound; processing step reaches more than ten steps simultaneously; and yield is lower, be unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is to provide one to prepare Tirofiban hydrochloride method, and this technique starting raw material is easy to get, and reaction conditions is gentle, yield is higher, and be easy to suitability for industrialized production, present method comprises following processing step:
A, 4-(4-pyridyl) Butyryl Chloride 2 " original position " are converted into 4-(4 pyridyl) butyl iodide 3, be directly used in the next step;
B, TYR ethyl ester 4 sulphonyl turn to N-normal-butyl alkylsulfonyl-TYR ethyl ester 5, and compound 5 directly carries out next step building-up reactions for oily liquids without the need to purifying;
C, 4-(4-piperidyl) butyl iodide 3 and N-normal-butyl alkylsulfonyl-TYR ethyl ester 5 condensation in the basic conditions, obtain compound 6;
D, N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR 6 is reduced into compound 7;
Compound 7 is converted into target product Tirofiban hydrochloride 1
Operational path is as follows:
The operation of concrete technology step is as follows:
4-(4-pyridyl) Butyryl Chloride is converted into 4-(4 pyridyl by step a) butyl iodide, object improves its activity, iodination reagent used in step is NaI or KI, and the solvent adopted is DMSO or DMF, and temperature of reaction is preferably carried out at 0 DEG C ~ 80 DEG C.
TYR ethyl ester sulphonyl is turned to N-normal-butyl alkylsulfonyl-TYR ethyl ester by step b; alkali used is one or more in alkaline hydrated oxide, alkali hydride or basic carbonate, comprises sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, Quilonum Retard, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus.The solvent adopted is the one in ethyl acetate, methyl acetate, ethyl formate, acetone, butanone, methyl iso-butyl ketone (MIBK), temperature of reaction 20 DEG C ~ 80 DEG C.
Step c is by 4-(4-piperidyl) butyl iodide and N-normal-butyl alkylsulfonyl-TYR ethyl ester condensation in the basic conditions; preparation N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR; basic cpd used is the one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood; the solvent adopted is one or more in DMSO, DMF, temperature of reaction 0 DEG C ~ 80 DEG C.
Steps d is that N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR is reduced into Tirofiban, the reductive agent adopted in steps d is one or more in Pd/C, Raney [Ni], Na/EtOH, and the solvent of employing is one or more in acids, alcohols, ester class; Such as formic acid, acetic acid, ethanol, ethyl acetate, isopropyl acetate, or its mixture; Temperature of reaction 20 DEG C ~ 80 DEG C in steps d.Pressure 0.1 ~ 5.0MPa.
That Tirofiban is converted into Tirofiban hydrochloride in step e.
Advantage of the present invention: 1) muriate of pyridine ring is converted into iodide and 5 and carries out condensation reaction, 2) this technological reaction mild condition, total recovery is high, be suitable for suitability for industrialized production, and patent US522756, EP478328 etc. disclose another synthetic method of this compound, with 4-piperidines-2-ethanol for starting raw material, through the obtained 4-(4-N-t-butyloxycarbonyl piperidyl of five step reactions) butyl bromide compound, acylation reaction is carried out under NaH/DMF effect, esterification under alkaline condition, deprotection, amination, hydrolysis, the reaction such as salify obtains target product Tirofiban hydrochloride monohydrate, this synthesis technique relates to the first-class toxicity of iodate and comparatively strengthens compound, processing step reaches more than ten steps simultaneously, and yield is lower, be unfavorable for suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the present invention is further described in detail, the embodiment provided only in order to illustrate the present invention, instead of in order to limit the scope of the invention.
Case study on implementation 1
The preparation of N-normal-butyl alkylsulfonyl-TYR ethyl ester 5
Compound 4 (450.5 grams, 2.2 moles) be dissolved in ethyl acetate 3 liters, add sodium bicarbonate (1.1 kilograms, 13.1 moles), normal-butyl SULPHURYL CHLORIDE (407 grams, 2.6 moles), stir at being warming up to 40 DEG C after 5 hours and filter, filtrate uses 1.0 mol/L dilute hydrochloric acid (750 milliliters), saturated aqueous common salt (750 milliliters), water (750 milliliter * 2) to wash successively, filter after anhydrous sodium sulfate drying, concentrated filtrate, residuum, through re crystallization from toluene, obtains off-white color pressed powder 5 (581.0 grams, yield is 82.0%).
The preparation of N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR 6
Compound 2(620.0 gram, 4.0 moles) join in dimethyl sulfoxide (DMSO) 5.6 liters, add sodium iodide (7.5 grams subsequently, 0.05 mole), room temperature vigorous stirring is after 4 hours, add compound 5 (1.18 kilograms, 3.6 moles), potassium hydroxide aqueous solution (4 mol/L are dripped under stirring, 2.2 liters), react 15 hours at being warming up to 65 ~ 70 DEG C after dropwising, be chilled to room temperature after completion of the reaction, add water (6.0 liters) and isopropyl ether (4.0 liters), mechanical stirring 1 hour, 4.2 liters ~ 4.5 liters, the Glacial acetic acid of 50% is dripped in aqueous phase after separatory, measure pH value 4.8 ~ 5.0 ~ 5 DEG C and continue stirring 4 hours, purified water drip washing after filtering, vacuum-drying 16 hours at 50 DEG C, obtain off-white color solid (1200.1g, 76.1%), fusing point: 137.1 ~ 139.9 DEG C
The preparation of Tirofiban hydrochloride 1
Compound 6 (500.0 grams, 1.1 moles) and 10% palladium charcoal (25.0 grams) are dissolved in acetic acid (5.0 liters, the weight of 5%), stirring reaction 6h under hydrogen pressure 1.50MPa and 60 DEG C condition.Filtration of catalyst, filtrate is concentrated into dry, adds acetic acid (500 milliliters) and water (500 milliliters), stir 1 hour in residuum, filters, obtains white solid (471.0 grams), fusing point: 221.0 ~ 223.0 DEG C.
Above-mentioned solid is dissolved in ethyl formate (5.0 liters), drips concentrated hydrochloric acid (150 milliliters), drip off rear stirred at ambient temperature 6 hours under stirring.Filter, filter cake is vacuum-drying 10 hours at 45 DEG C after ethyl acetate washing, obtains white solid (507.g, 94.0%), fusing point: 130.0 ~ 131.2 DEG C.
Case study on implementation 2
The preparation of N-normal-butyl alkylsulfonyl-TYR ethyl ester 5
Compound 4 (450.5 grams, 2.2 moles) be dissolved in ethyl acetate 3 liters, add (1.8 kilograms, salt of wormwood, 13.1 moles), normal-butyl SULPHURYL CHLORIDE (407 grams, 2.6 moles), stir at being warming up to 40 DEG C after 5 hours and filter, filtrate uses 1.0 mol/L dilute hydrochloric acid (750 milliliters), saturated aqueous common salt (750 milliliters), water (750 milliliter * 2) to wash successively, filter after anhydrous sodium sulfate drying, concentrated filtrate, residuum, through re crystallization from toluene, obtains off-white color pressed powder 5 (583.1 grams, yield is 82.3%).
The preparation of N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR 6
Compound 2(620.0 gram, 4.0 moles) join in dimethyl sulfoxide (DMSO) 5.6 liters, add sodium iodide (7.5 grams subsequently, 0.05 mole), room temperature vigorous stirring is after 4 hours, add compound 5 (1.18 kilograms, 3.6 moles), aqueous sodium carbonate (5 mol/L are dripped under stirring, 3.0 liters), react 18 hours at being warming up to 65 ~ 70 DEG C after dropwising, be chilled to room temperature after completion of the reaction, add water (6.0 liters) and methyl tertiary butyl ether (5.0 liters), mechanical stirring 1 hour, 4.0 liters ~ 4.3 liters, the Glacial acetic acid of 50% is dripped in aqueous phase after separatory, measure pH value 4.8 ~ 5.0 ~ 5 DEG C and continue stirring 4 hours, purified water drip washing after filtering, vacuum-drying 16 hours at 50 DEG C, obtain off-white color solid (1130.1g, 71.5%), fusing point: 136.1 ~ 139.1 DEG C.
The preparation of Tirofiban hydrochloride 1
Compound 6 (500.0 grams, 1.1 moles) and 10% palladium charcoal (25.0 grams) are dissolved in acetic acid (5.0 liters, the weight of 5%), stirring reaction 6h under hydrogen pressure 1.50MPa and 60 DEG C condition.Filtration of catalyst, filtrate is concentrated into dry, adds acetic acid (500 milliliters) and water (500 milliliters), stir 1 hour in residuum, filters, obtains white solid (474.3 grams), fusing point: 221.0 ~ 223.0 DEG C.
Above-mentioned solid is dissolved in ethyl formate (5.0 liters), drips concentrated hydrochloric acid (150 milliliters), drip off rear stirred at ambient temperature 6 hours under stirring.Filter, filter cake is vacuum-drying 10 hours at 45 DEG C after ethyl acetate washing, obtains white solid 1 (512.4g, 95.1%), fusing point: 130.0 ~ 131.1 DEG C.
Case study on implementation 3
The preparation of N-normal-butyl alkylsulfonyl-TYR ethyl ester 5
Compound 4 (450.5 grams, 2.2 moles) be dissolved in 3 liters, acetone, add sodium bicarbonate (1.1 kilograms, 13.1 moles), normal-butyl SULPHURYL CHLORIDE (407 grams, 2.6 moles), stir at being warming up to 40 DEG C after 5 hours and filter, filtrate uses 1.0 mol/L dilute hydrochloric acid (750 milliliters), saturated aqueous common salt (750 milliliters), water (750 milliliter * 2) to wash successively, filter after anhydrous sodium sulfate drying, concentrated filtrate, residuum, through re crystallization from toluene, obtains off-white color pressed powder 5 (577.0 grams, yield is 81.4%).
The preparation of N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR 6
Compound 2(620.0 gram, 4.0 moles) join N, in N-dimethyl imide 5.6 liters, add sodium iodide (7.5 grams subsequently, 0.05 mole), room temperature vigorous stirring is after 4 hours, add compound 5 (1.18 kilograms, 3.6 moles), potassium hydroxide aqueous solution (4 mol/L are dripped under stirring, 2, 2 liters), react 15 hours at being warming up to 65 ~ 70 DEG C after dropwising, be chilled to room temperature after completion of the reaction, add water (6.0 liters) and isopropyl ether (4.0 liters), mechanical stirring 1 hour, 4.2 liters ~ 4.5 liters, the Glacial acetic acid of 50% is dripped in aqueous phase after separatory, measure pH value 4.8 ~ 5.0 ~ 5 DEG C and continue stirring 4 hours, purified water drip washing after filtering, vacuum-drying 16 hours at 50 DEG C, obtain off-white color solid (1290.2g, 82.1%), fusing point: 137.1 ~ 139.7 DEG C
The preparation of Tirofiban hydrochloride 1
Compound 6 (500.0 grams, 1.1 moles) and 10% palladium charcoal (25.0 grams) are dissolved in acetic acid (5.0 liters, the weight of 5%), stirring reaction 6h under hydrogen pressure 1.50MPa and 60 DEG C condition.Filtration of catalyst, filtrate is concentrated into dry, adds acetic acid (500 milliliters) and water (500 milliliters), stir 1 hour in residuum, filters, obtains white solid (475.0 grams), fusing point: 220.0 ~ 221.5 DEG C.
Above-mentioned solid is dissolved in ethyl formate (5.0 liters), drips concentrated hydrochloric acid (150 milliliters), drip off rear stirred at ambient temperature 6 hours under stirring.Filter, filter cake is vacuum-drying 10 hours at 45 DEG C after ethyl acetate washing, obtains white solid 1 (516.2g, 95.7%), fusing point: 130.0 ~ 131.0 DEG C.
Case study on implementation 4
The preparation of N-normal-butyl alkylsulfonyl-TYR ethyl ester 5
Compound 4 (450.5 grams, 2.2 moles) be dissolved in ethyl acetate 3 liters, add sodium bicarbonate (1.1 kilograms, 13.1 moles), normal-butyl SULPHURYL CHLORIDE (407 grams, 2.6 moles), stir at being warming up to 40 DEG C after 5 hours and filter, filtrate uses 1.0 mol/L dilute hydrochloric acid (750 milliliters), saturated aqueous common salt (750 milliliters), water (750 milliliter * 2) to wash successively, filter after anhydrous sodium sulfate drying, concentrated filtrate, residuum, through re crystallization from toluene, obtains off-white color pressed powder 5 (590.9 grams, yield is 83.4%).
The preparation of N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR 6
Compound 2(620.0 gram, 4.0 moles) join N, in N-dimethyl imide 5.6 liters, add sodium iodide (7.5 grams subsequently, 0.05 mole), room temperature vigorous stirring is after 4 hours, add compound 5 (1.18 kilograms, 3.6 moles), potassium hydroxide aqueous solution (4 mol/L are dripped under stirring, 2, 2 liters), react 15 hours at being warming up to 65 ~ 70 DEG C after dropwising, be chilled to room temperature after completion of the reaction, add water (6.0 liters) and isopropyl ether (4.0 liters), mechanical stirring 1 hour, 4.2 liters ~ 4.5 liters, the Glacial acetic acid of 50% is dripped in aqueous phase after separatory, measure pH value 4.8 ~ 5.0 ~ 5 DEG C and continue stirring 4 hours, purified water drip washing after filtering, vacuum-drying 16 hours at 50 DEG C, obtain off-white color solid (1327.7g, 84.5%), fusing point: 137.1 ~ 139.5 DEG C
The preparation of Tirofiban hydrochloride 1
Compound 6 (500.0 grams, 1.1 moles) and 10% palladium charcoal (25.0 grams) are dissolved in acetic acid (5.0 liters, the weight of 5%), stirring reaction 6h under hydrogen pressure 1.50MPa and 60 DEG C condition.Filtration of catalyst, filtrate is concentrated into dry, adds acetic acid (500 milliliters) and water (500 milliliters), stir 1 hour in residuum, filters, obtains white solid (474.1 grams), fusing point: 220.0 ~ 221.5 DEG C.
Above-mentioned solid is dissolved in ethyl formate (5.0 liters), drips concentrated hydrochloric acid (150 milliliters), drip off rear stirred at ambient temperature 6 hours under stirring.Filter, filter cake is vacuum-drying 10 hours at 45 DEG C after ethyl acetate washing, obtains white solid 1 (514.5g, 95.4%), fusing point: 130.0 ~ 131.0 DEG C.
Case study on implementation 5
The preparation of N-normal-butyl alkylsulfonyl-TYR ethyl ester 5
Compound 4 (450.5 grams, 2.2 moles) be dissolved in ethyl acetate 3 liters, add (1.8 kilograms, salt of wormwood, 13.1 moles), normal-butyl SULPHURYL CHLORIDE (407 grams, 2.6 moles), stir at being warming up to 40 DEG C after 5 hours and filter, filtrate uses 1.0 mol/L dilute hydrochloric acid (750 milliliters), saturated aqueous common salt (750 milliliters), water (750 milliliter * 2) to wash successively, filter after anhydrous sodium sulfate drying, concentrated filtrate, residuum, through re crystallization from toluene, obtains off-white color pressed powder 5 (595.9 grams, yield is 84.1%).
The preparation of N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR 6
Compound 2(620.0 gram, 4.0 moles) join N, in N-dimethyl imide 5.6 liters, add sodium iodide (7.5 grams subsequently, 0.05 mole), room temperature vigorous stirring is after 4 hours, add compound 5 (1.18 kilograms, 3.6 moles), potassium hydroxide aqueous solution (4 mol/L are dripped under stirring, 2, 2 liters), react 15 hours at being warming up to 65 ~ 70 DEG C after dropwising, be chilled to room temperature after completion of the reaction, add water (6.0 liters) and isopropyl ether (4.0 liters), mechanical stirring 1 hour, 4.2 liters ~ 4.5 liters, the Glacial acetic acid of 50% is dripped in aqueous phase after separatory, measure pH value 4.8 ~ 5.0 ~ 5 DEG C and continue stirring 4 hours, purified water drip washing after filtering, vacuum-drying 16 hours at 50 DEG C, obtain off-white color solid (1352.9g, 86.1%), fusing point: 137.2 ~ 139.2 DEG C
The preparation of Tirofiban hydrochloride 1
Compound 6 (500.0 grams, 1.1 moles) and Raney [Ni] (23.5 grams) are dissolved in ethanol (4.0 liters, the weight of 5%), stirring reaction 8h under hydrogen pressure 1.30MPa and 60 DEG C condition.Filtration of catalyst, filtrate is concentrated into dry, adds acetic acid (500 milliliters) and water (500 milliliters), stir 1 hour in residuum, filters, obtains white solid (466.1 grams), fusing point: 221.0 ~ 223.0 DEG C.
Above-mentioned solid is dissolved in ethyl formate (5.0 liters), drips concentrated hydrochloric acid (150 milliliters), drip off rear stirred at ambient temperature 6 hours under stirring.Filter, filter cake is vacuum-drying 10 hours at 45 DEG C after ethyl acetate washing, obtains white solid 1 (500.1g, 92.7%), fusing point: 130.1 ~ 132.1 DEG C.
Case study on implementation 6
The preparation of N-normal-butyl alkylsulfonyl-TYR ethyl ester 5
Compound 4 (450.5 grams, 2.2 moles) be dissolved in 3 liters, acetone, add sodium bicarbonate (1.1 kilograms, 13.1 moles), normal-butyl SULPHURYL CHLORIDE (407 grams, 2.6 moles), stir at being warming up to 40 DEG C after 5 hours and filter, filtrate uses 1.0 mol/L dilute hydrochloric acid (750 milliliters), saturated aqueous common salt (750 milliliters), water (750 milliliter * 2) to wash successively, filter after anhydrous sodium sulfate drying, concentrated filtrate, residuum, through re crystallization from toluene, obtains off-white color pressed powder 5 (589.8 grams, yield is 83.2%).
The preparation of N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR 6
Compound 2(620.0 gram, 4.0 moles) join in dimethyl sulfoxide (DMSO) 5.6 liters, add sodium iodide (7.5 grams subsequently, 0.05 mole), room temperature vigorous stirring is after 4 hours, add compound 5 (1.18 kilograms, 3.6 moles), aqueous sodium carbonate (5 mol/L are dripped under stirring, 3.0 liters), react 18 hours at being warming up to 65 ~ 70 DEG C after dropwising, be chilled to room temperature after completion of the reaction, add water (6.0 liters) and methyl tertiary butyl ether (5.0 liters), mechanical stirring 1 hour, 4.0 liters ~ 4.3 liters, the Glacial acetic acid of 50% is dripped in aqueous phase after separatory, measure pH value 4.8 ~ 5.0 ~ 5 DEG C and continue stirring 4 hours, purified water drip washing after filtering, vacuum-drying 16 hours at 50 DEG C, obtain off-white color solid (1171.1g, 74.1%), fusing point: 136.0 ~ 138.8 DEG C.
The preparation of Tirofiban hydrochloride 1
Compound 6 (500.0 grams, 1.1 moles) and Raney [Ni] (23.5 grams) are dissolved in ethanol (4.0 liters, the weight of 5%), stirring reaction 8h under hydrogen pressure 1.30MPa and 60 DEG C condition.Filtration of catalyst, filtrate is concentrated into dry, adds acetic acid (500 milliliters) and water (500 milliliters), stir 1 hour in residuum, filters, obtains white solid (468.3 grams), fusing point: 221.0 ~ 222.8 DEG C.
Above-mentioned solid is dissolved in ethyl formate (5.0 liters), drips concentrated hydrochloric acid (150 milliliters), drip off rear stirred at ambient temperature 6 hours under stirring.Filter, filter cake is vacuum-drying 10 hours at 45 DEG C after ethyl acetate washing, obtains white solid 1 (504.9g, 93.5%), fusing point: 130.1 ~ 131.8 DEG C.
Claims (12)
1. prepare a method for Tirofiban hydrochloride, it is characterized in that the method comprises the following steps:
A, 4-(4-pyridyl) Butyryl Chloride 2 " original position " are converted into 4-(4 pyridyl) butyl iodide 3
B, TYR ethyl ester 4 sulphonyl turn to N-normal-butyl alkylsulfonyl-TYR ethyl ester 5
C, 4-(4-piperidyl) butyl iodide 3 and N-normal-butyl alkylsulfonyl-TYR ethyl ester 5 condensation in the basic conditions, obtain compound 6
D, N-(fourth alkylsulfonyl)-O-(4-pyridine butyl)-TYR 6 is reduced into compound 7
E, compound 7 is converted into target product Tirofiban hydrochloride 1
2. the method for claim 1, it is characterized in that wherein iodination reagent used is NaI or KI in step a, reaction solvent is DMSO or DMF.
3. the method for claim 1, is characterized in that reaction solvent used in wherein step b is one or more in ester class, ketone.
4. the method as described in claims 1 to 3, is characterized in that reaction solvent used in wherein step b is one or more in ethyl acetate, methyl acetate, ethyl formate, acetone, butanone, methyl iso-butyl ketone (MIBK).
5. the method as described in claim as arbitrary in claims 1 to 3, is characterized in that the temperature of reaction of wherein step b is 20 DEG C ~ 80 DEG C.
6. the method as described in claim as arbitrary in claims 1 to 3, it is characterized in that wherein reactions steps b adds in alkaline hydrated oxide, alkali hydride or basic carbonate one or more, comprise sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, Quilonum Retard, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus.
7. the method for claim 1, is characterized in that the reaction solvent of wherein step c is one or more in DMSO, DMF.
8. the method for claim 1, is characterized in that the temperature of reaction of wherein step c is 0 DEG C ~ 80 DEG C.
9. as claimed in claim 7 or 8 method, is characterized in that basic cpd that wherein reactions steps c adds is one or more in metal hydroxides or metal alkaline compound.
10. the method for claim 1, is characterized in that the reductive agent adopted in wherein steps d is one or more in Pd/C, Raney [Ni], Na/EtOH.
11. methods as claimed in claim 9, is characterized in that being wherein react under the pressure of 0.1 ~ 5.0Mpa in steps d.
12. methods as described in claim 1 ~ 11, it is characterized in that wherein step a is replacement(metathesis)reaction, obtaining compound 3 is iodo thing, step b is acylation reaction, obtaining compound 5 is acylate, step c is condensation reaction, obtaining compound 7 is condensation product, steps d is reduction reaction, acquisition compound is reduzate, step e is salt-forming reaction, obtain compound 1 for target compound be Tirofiban hydrochloride, whole synthesis route with compound 2 for starting raw material, through iodo, acidylate, condensation, reduction, the synthesis techniques such as salify obtain target product Tirofiban hydrochloride.
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| CN108997198A (en) * | 2018-09-06 | 2018-12-14 | 无锡富泽药业有限公司 | A kind of preparation method of tirofiban hydrochloride |
| CN109608387A (en) * | 2019-01-02 | 2019-04-12 | 海门慧聚药业有限公司 | The preparation of tirofiban hydrochloride |
| CN112441962A (en) * | 2019-09-04 | 2021-03-05 | 武汉武药科技有限公司 | Tirofiban and purification method thereof |
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| CN108997198B (en) * | 2018-09-06 | 2021-10-12 | 无锡富泽药业有限公司 | Preparation method of tirofiban hydrochloride |
| CN109608387A (en) * | 2019-01-02 | 2019-04-12 | 海门慧聚药业有限公司 | The preparation of tirofiban hydrochloride |
| CN112441962A (en) * | 2019-09-04 | 2021-03-05 | 武汉武药科技有限公司 | Tirofiban and purification method thereof |
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