CN109608387A - The preparation of tirofiban hydrochloride - Google Patents
The preparation of tirofiban hydrochloride Download PDFInfo
- Publication number
- CN109608387A CN109608387A CN201910000573.7A CN201910000573A CN109608387A CN 109608387 A CN109608387 A CN 109608387A CN 201910000573 A CN201910000573 A CN 201910000573A CN 109608387 A CN109608387 A CN 109608387A
- Authority
- CN
- China
- Prior art keywords
- butyl
- formula
- normal
- sulfonyl
- alkynes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The method for preparing tirofiban hydrochloride the present invention relates to one.This method is using N- normal-butyl sulfonyl-L- tyrosine ester and 3- butyne-1-ol as starting material; O-3- alkynes butyl-N- normal-butyl sulfonyl-L- tyrosine ester is prepared by condensation reaction; then N- normal-butyl sulfonyl-O- (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- tyrosine ester is prepared by Sonogashira coupling reaction with 4- haloperidid again, the latter passes through hydrogenation again, hydrochloric acid completes the preparation of tirofiban hydrochloride at salt.
Description
Technical field
The present invention relates to the new preparation processes of tirofiban hydrochloride.
Background technique
Entitled (the N- normal-butyl sulphur of tirofiban hydrochloride (Tirofiban Hydrochloride Monohydrate) chemistry
Acyl group-O-4- (4- piperidyl) butyl)-L- tyrosine hydrochloride monohydrate is a kind of non-peptides blood platelet of invertibity
GPIIb/IIa receptor antagonist, by international pharmacy giant Merck company in the nineties in last century develop, and in May, 1998 at
Function is ratified to list by U.S. FDA, and the pdgf antagonist is on the states such as Switzerland, China, Germany and Holland are extensive at present
City uses.The medicine is suitable for unstable angina pectoris or non-q wave myocardial infarction patient, prevents cardiac ischemia event, while also fitting
Carry out patch resection in Coronary angioplasty or coronary artery for coronary ischemia syndrome patients, and prevention with through controlling coronary artery
Related heart ischemia complication is occluded suddenly.Tirofiban hydrochloride structural formula is as follows:
So far, chemists develop the synthetic route of a plurality of tirofiban hydrochloride:
Patent US750647 describes the original synthetic route of tirofiban hydrochloride, which goes out from 4- piperidines -2- ethyl alcohol
Hair reacts the synthesis for completing tirofiban hydrochloride, Swern oxidation, Wittig reaction, borane reduction involved in route etc. through 11 steps
Reaction, the route due to step is long, gross production rate is low etc. causing to be not easy industrial amplification production.
Patent CN1844099 discloses the new process for preparing tirofiban hydrochloride.The technique includes 4- (4- pyridyl group)-fourth
The reduction of base chlorine generates 4- (4- piperidyl) butyl chloride, and subsequent 4- (4- piperidyl) butyl chloride converted in-situ is 4- (4- piperidyl) fourth
Base iodine.Condensation prepares tirofiban certainly under alkaline condition for 4- (4- piperidyl) butyl iodide and N- butyl sulfonyl-L- tyrosine
By alkali, the latter obtains target product at salt again.Preparation of the route for starting material 4- (4- piperidyl) butyl chloride, patentee
Two lines are provided, are prepared first is that 4- (4- pyridyl group) butyl chloride is hydrogenated with Pd/C；Second is that 4- (4- pyridyl group) butyl chloride is used
Metallic sodium is restored in the case where ethyl alcohol does solvent condition.First route poor reproducibility；Article 2 route is due to that will use very
Active metallic sodium, safety issue are difficult to amplify.In addition critical component 4- (4- piperidyl) butyl chloride (iodine) is easy to happen certainly
Body intermolecular condensation, the patent equally exist the limitation of industry's enlarging production.
Merck house journal US5206373 (Tetrahedron, 1993,49,5767；Chinese patent CN1050832) make
It reacts to obtain N- with butyl sulfochlorides under BSTFA (bis- (trimethylsilyl) trifluoroacetamides of N, O-) effect with L- tyrosine
Butyl sulfonyl-L- tyrosine.N- butyl sulfonyl-L- tyrosine is under alkaline condition and in the condensation preparation of 4- pyridine butyl chloride
Mesosome N- normal-butyl sulfonyl-O- (4- (4- pyridyl group)-butyl)-L- tyrosine, the latter further it is hydrogenated, acidified and
The processes such as purification complete the preparation of tirofiban hydrochloride.The key point and patent US5206373 of Chinese patent CN1415606 is almost
Equally, it is using N- butyl sulfonyl-L- tyrosine and 4- pyridine butyl chloride in alkaline item that unique difference, which is patent US5206373,
It is condensed under part, and patent CN1415606 uses N- butyl sulfonyl-L- tyrosine methyl esters and 4- pyridine butyl chloride to exist
It is condensed under alkaline condition.These patents are directed to the preparation of intermediate 4- (4- pyridyl group)-butyl chloride, patent
US5206373 has used n-BuLi, need to react under -70 DEG C of low temperature and anhydrous condition, severe reaction conditions, actual industrial
Mass production difficulty is big；And patent CN1415606 is due to having used LiAlH4Reduction, is equally difficult to amplify production.These patents
Route is as follows:
Merck house journal CN1040534 then provides a more feasible method.This method key reaction is N- fourth
Base sulfonyl-L- tyrosine methyl esters and 4- pyridine butanol are issued in triphenylphosphine and diisopropyl azodiformate (DIAD) effect
Raw Mitsunobu reaction, prepares key intermediate N- normal-butyl sulfonyl-O- (4- (4- pyridyl group)-butyl)-L- tyrosine first
Ester, then the intermediate is piperidyl by hydrolysis of ester group, Pd/C/HOAc reduction pyridine groups, and last hydrochloric acid salt completes salt
The preparation of sour tirofiban.The route is relatively more suitable for industrialization, but starting material pyridine butanol cannot be still commercialized largely
Buying, and the technique for preparing pyridine butanol is related to using unworkable LiAlH4Reagent restores (CN1415606).Patent
CN1040534 correlation synthetic route is as follows:
Summary of the invention
The present invention it is newly developed go out a synthetic route for preparing tirofiban hydrochloride, which is not related to using being difficult to business
Change a large amount of buyings and expensive pyridine butanol, used cost of material is cheap, and is easy a large amount of buyings of commercialization.
Synthetic route of the invention is as follows:
The first step of the present invention is related to the condensation between N- normal-butyl sulfonyl-L- tyrosine ester (Formulas I) and 3- butyne-1-ol
Reaction generates O-3- alkynes butyl-N- normal-butyl sulfonyl-L- tyrosine ester (Formula II).
The condensation reaction that the reaction first step is related to refers to conventional Mitsunobu reaction.It is specifically included in Ph3P、n-Bu3P etc.
In the presence of and the condensing agents such as DIAD, DEAD in the presence of carry out Mitsunobu condensation reaction.
R in Formula I and Formula II is methyl, ethyl, isopropyl, n-propyl, normal-butyl.
Sonogashira coupling reaction of the second step between Formula II compound and 4- haloperidid (formula III) is reacted, it is raw
At N- normal-butyl sulfonyl-O- (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- tyrosine ester (formula IV).
Reacting metallic catalyst used in second step Sonogashira coupling reaction is Pd (PPh3)4、Pd(OAc)2、Pd
(PPh3)2Cl2、PdCl2、Pd2(dba)3·CHCl3、PdCl2(dppf)·CH2Cl2Deng the assembly respectively with CuI or CuCl
System.
X in compound formula III is Cl, Br, I.
R in compound formula IV is methyl, ethyl, isopropyl, n-propyl, normal-butyl.
Reacting third step is that hydrolysis of ester group reaction occurs under alkali effect for formula IV compound, generates N- normal-butyl sulfonyl-
O- (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- tyrosine (Formula V).
The alkali that reaction third step uses is LiOH, NaOH, KOH, CsOH.
Reacting the 4th step is Formula V compound under conditions of using acetic acid as solvent, is occurred under catalysts conditions containing Pd
Hydrogenation generates N- normal-butyl sulfonyl-O- (4- (piperidin-4-yl) butyl- 1- yl)-L- tyrosine (Formula IV).
Reacting catalyst containing Pd used in the 4th step is Pd/C, Pd (OH)2。
Reacting the 5th step is that hydrochloric acid is added into salt in Formula IV compound in the presence of solvent, completes the system of tirofiban hydrochloride
It is standby.
Specific embodiment
The present invention can be more specifically understood by the following examples, but it illustrates rather than the limitation present invention
Range.
Embodiment
1, O-3- alkynes butyl-N- normal-butyl sulfonyl-L- tyrosine ethyl ester (Formula II, R=Et) is prepared
2L reaction flask is equipped with magnetic agitation and thermometer.Under nitrogen protection, N- normal-butyl sulphonyl is added into reaction flask
Base-L- tyrosine ethyl ester (Formulas I, R=Et) (120g, 364.3mmol) and anhydrous THF (500mL), stirring make system in completely
Even solution.Then 3- butyne-1-ol (26.8g, 382.5mmol) and Ph are added into system3P(119.5g,456mmol)。
System is cooled to < 0 DEG C after addition, then by dropping funel be added into reaction system DEAD (76.0g,
436.4mmol).After addition, system warms naturally to room temperature reaction 12 hours, HPLC tracking reaction to N- normal-butyl sulphonyl
The basic fully reacting of base-L- tyrosine ethyl ester.After completion of the reaction, system removed under reduced pressure organic solvent in high vacuum conditions, so
H is added in backward reaction system2O (400mL), subsequent system is with dilute hydrochloric acid regulation system pH value between 6.0-7.0.System makes
It being extracted with ethyl acetate (3 × 400mL), merges organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate dries, filters,
Filtrate decompression removes solvent, and residue column chromatographic purifying obtains O-3- alkynes butyl-N- normal-butyl sulfonyl-L- tyrosine ethyl ester (formula
II, R=Et) (yellow oil, 118.2g, 85.1%).
2, N- normal-butyl sulfonyl-O- (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- tyrosine ethyl ester (formula IV, R=is prepared
Et)
By 4- bromopyridine (29.8g, 188.7mmol), triethylamine (20mL) and H2O (100mL) is added in reaction flask, is stirred
It mixes uniformly.Under nitrogen protection, successively into reaction flask be added LiCl (1.2g, 28.3mmol), CuI (1.5g, 7.88mmol) and
O-3- alkynes butyl-N- normal-butyl sulfonyl-L- tyrosine ethyl ester (Formula II, R=Et) (64.8g, 170mmol).System nitrogen is set
It changes three times, four (triphenyl phosphorus) palladiums (4.0g, 3.45mmol) is then added under nitrogen protection into reaction system.After addition
System is heated to reflux 4 hours.System is cooled to room temperature, filtering, and filtrate high vacuum vacuum distillation, residue column chromatographic purifying obtains N-
Normal-butyl sulfonyl-O- (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- tyrosine ethyl ester (formula IV, R=Et) (60.8g,
78.0%, yield is calculated based on Formula II compound).
3, N- normal-butyl sulfonyl-O- (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- tyrosine (Formula V) is prepared
Three mouthfuls of reaction flasks are equipped with magnetic agitation and thermometer.N- normal-butyl sulfonyl-O- (4- (pyrrole is added into reaction flask
Pyridine -4- base) butyl- 3- alkynes -1- base)-L- tyrosine ethyl ester (formula IV, R=Et) (58g, 126.5mmol), THF (300mL) and second
Alcohol (80mL).Then the H of LiOH (3.19g, 133mmol) is added in system stirring and dissolving after addition into reaction system2O
(80mL) solution.After addition, system, which is stirred at room temperature to TLC tracking initiation material formula IV, substantially completely to disappear.System is added
Dilute HCl adjusts pH value to 8-9, high vacuum removed under reduced pressure solvent, residue addition H2O (100mL) dilution, system use acetic acid second
Ester (100mL) extraction, removes organic phase, and water phase adjusts pH value to 5-6 using dilute HCl, then system with ethyl acetate (3 ×
It 100mL) extracts, anhydrous sodium sulfate dries, filters, and filtrate high vacuum removes solvent, and residue obtains N- using recrystallisation from isopropanol
Normal-butyl sulfonyl-O- (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- tyrosine (Formula V) (39.2g, 72%).
4, N- normal-butyl sulfonyl-O- (4- (piperidin-4-yl) butyl- 1- yl)-L- tyrosine (Formula IV) is prepared
N- normal-butyl sulfonyl-O- (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- network ammonia is added in 2L autoclave
Sour (Formula V) (35g, 81.3mmol) and acetic acid (400mL).Then, it will contain Pd/C's (5% contains Pd) (2.0g) under nitrogen protection
Dilute slurry of acetic acid (100mL) is added in autoclave.Autoclave is closed, after nitrogen displacement three times, reaction system is in hydrogen
Hydrogenation 5 hours is carried out under the conditions of pressure (3atm) and 60 DEG C.It is cooled to room temperature, system filtering, residue high vacuum removed under reduced pressure
Solvent (a small amount of acetic acid of system final residual does not need all de- dry), then to H is added in residue2O (400mL), room
Temperature is stirred overnight.Filtering, solid use H2O (200mL) washing, gained wet product are dried under reduced pressure to obtain N- normal-butyl sulfonyl-O- (4-
(piperidin-4-yl) butyl- 1- yl)-L- tyrosine (Formula IV) (31.6g, 88.2%).
5, tirofiban hydrochloride is prepared
It is equipped with magnetic agitation and thermometer in three neck round bottom flask, N- normal-butyl sulfonyl-O- is then added into reaction flask
(4- (piperidin-4-yl) butyl- 1- yl)-L- tyrosine (Formula IV) (25.0g, 56.7mmol) and isopropyl acetate (600mL).Carefully
Stirring solid into system is completely dissolved, and is then slowly added to dense HCl by dropping funel into reaction system at 20 DEG C
(9.5mL).Architecture heat preservation stirs 5 hours after addition, and then system filtered under nitrogen, obtained solid are different using acetic acid
Propyl ester washs (2 × 50mL).Obtained solid is dried under reduced pressure to obtain tirofiban hydrochloride monohydrate (25.9g, 92.5%).
Claims (15)
1. the method for preparing N- normal-butyl sulfonyl-O- (4- (piperidin-4-yl) butyl- 1- yl)-L- tyrosine (Formula IV), reaction equation
It is as follows:
2. having O-3- alkynes butyl-N- normal-butyl sulfonyl-L- tyrosine ester (Formula II) compound as shown in claim 1.
3. the preparation side with O-3- alkynes butyl-N- normal-butyl sulfonyl-L- tyrosine ester (Formula II) as shown in claim 1
Method, it is characterised in that the condensation reaction between N- normal-butyl sulfonyl-L- tyrosine ester (Formulas I) and 3- butyne-1-ol.
4. in claim 2, reacting used condensation reaction condition is routine Mitsunobu reaction condition.It is specifically included in
Ph3P、n-Bu3Mitsunobu condensation reaction is carried out in the presence of P etc. and in the presence of the condensing agents such as DIAD, DEAD.
5. in claim 3, the R in Formulas I and Formula II is methyl, ethyl, isopropyl, n-propyl, normal-butyl.
6. having N- normal-butyl sulfonyl-O- as shown in claim 1 (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- network
Propylhomoserin ester (formula IV) compound.
7. having N- normal-butyl sulfonyl-O- as shown in claim 1 (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- network
The preparation method of propylhomoserin ester (formula IV), it is characterised in that between the compound and 4- haloperidid (formula III) of Formula II structure
Sonogashira coupling reaction.
8. in claim 7, metallic catalyst used in Sonogashira coupling reaction is Pd (PPh3)4、Pd(OAc)2、Pd
(PPh3)2Cl2、PdCl2、Pd2(dba)3·CHCl3、PdCl2(dppf)·CH2Cl2Deng the assembly respectively with CuI or CuCl
System.
9. in claim 6, R is methyl, ethyl, isopropyl, n-propyl, normal-butyl in formula IV.
10. in claim 7, X is Cl, Br, I in formula III.
11. having N- normal-butyl sulfonyl-O- as shown in claim 1 (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- network
Propylhomoserin (Formula V) compound.
12. having N- normal-butyl sulfonyl-O- as shown in claim 1 (4- (pyridin-4-yl) butyl- 3- alkynes -1- base)-L- network
The preparation method of propylhomoserin (Formula V) compound, it is characterised in that hydrolysis of ester group reaction occurs under alkali effect for formula IV compound.
13. the alkali used in claim 12 includes LiOH, NaOH, KOH, CsOH.
14. having N- normal-butyl sulfonyl-O- as shown in claim 1 (4- (piperidin-4-yl) butyl- 1- yl)-L- tyrosine
The preparation method of (Formula IV), it is characterised in that Formula V compound is under conditions of using acetic acid as solvent, in catalysts conditions containing Pd
Lower generation hydrogenation.
15. the catalyst containing Pd used in claim 14 is Pd/C, Pd (OH)2。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910000573.7A CN109608387A (en) | 2019-01-02 | 2019-01-02 | The preparation of tirofiban hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910000573.7A CN109608387A (en) | 2019-01-02 | 2019-01-02 | The preparation of tirofiban hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109608387A true CN109608387A (en) | 2019-04-12 |
Family
ID=66015561
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910000573.7A Pending CN109608387A (en) | 2019-01-02 | 2019-01-02 | The preparation of tirofiban hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109608387A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112441962A (en) * | 2019-09-04 | 2021-03-05 | 武汉武药科技有限公司 | Tirofiban and purification method thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5206373A (en) * | 1992-02-28 | 1993-04-27 | Merck & Co., Inc. | Process for preparing fibrinogen receptor antagonists |
| CN1076442A (en) * | 1992-02-28 | 1993-09-22 | 麦克公司 | The method for preparing fibrinogen deceptor antagonists |
| CN1415606A (en) * | 2002-11-01 | 2003-05-07 | 北京天衡药物研究院 | Method of preparing compound of 0-substituted sulphonyl propylhomoserin class |
| CN1844099A (en) * | 2006-05-10 | 2006-10-11 | 鲁南制药集团股份有限公司 | Process for preparation of tirofiban hydrochloride |
| CN102241622A (en) * | 2010-05-13 | 2011-11-16 | 上海医药工业研究院 | Method for preparing tirofiban hydrochloride |
| CN102260208A (en) * | 2011-07-28 | 2011-11-30 | 海门慧聚药业有限公司 | New preparation process of 4-pyridine butanol |
| CN104447509A (en) * | 2013-09-18 | 2015-03-25 | 嘉实（湖南）医药科技有限公司 | Tirofiban hydrochloride preparation process |
| JP2017222611A (en) * | 2016-06-16 | 2017-12-21 | 学校法人上智学院 | Method for producing piperidine compound |
-
2019
- 2019-01-02 CN CN201910000573.7A patent/CN109608387A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5206373A (en) * | 1992-02-28 | 1993-04-27 | Merck & Co., Inc. | Process for preparing fibrinogen receptor antagonists |
| CN1076442A (en) * | 1992-02-28 | 1993-09-22 | 麦克公司 | The method for preparing fibrinogen deceptor antagonists |
| CN1415606A (en) * | 2002-11-01 | 2003-05-07 | 北京天衡药物研究院 | Method of preparing compound of 0-substituted sulphonyl propylhomoserin class |
| CN1844099A (en) * | 2006-05-10 | 2006-10-11 | 鲁南制药集团股份有限公司 | Process for preparation of tirofiban hydrochloride |
| CN102241622A (en) * | 2010-05-13 | 2011-11-16 | 上海医药工业研究院 | Method for preparing tirofiban hydrochloride |
| CN102260208A (en) * | 2011-07-28 | 2011-11-30 | 海门慧聚药业有限公司 | New preparation process of 4-pyridine butanol |
| CN104447509A (en) * | 2013-09-18 | 2015-03-25 | 嘉实（湖南）医药科技有限公司 | Tirofiban hydrochloride preparation process |
| JP2017222611A (en) * | 2016-06-16 | 2017-12-21 | 学校法人上智学院 | Method for producing piperidine compound |
Non-Patent Citations (5)
| Title |
|---|
| BEN CAPUANO ET AL.: "Synthesis and Preliminary Pharmacological Evaluation of 4-Arylalkyl Analogues of Clozapine. IV. The Effects of Aromaticity and Isosteric Replacement", 《AUST. J. CHEM.》 * |
| TOYONOBU USUKI AND AKIRA KOMATSU: "Preparation of monoalkylpiperidines via the mild hydrogenation of monoalkynylpyridines", 《TETRAHEDRON LETTERS》 * |
| ZHOU XU ET AL.: "Efficient One-Pot Multifunctionalization of Alkynes en Route to α-Alkoxyketones, α-Thioketones, andα-Thio Thioketals by using an Umpolung Strategy", 《CHEM. EUR. J.》 * |
| 刘超 等: "盐酸替罗非班的合成研究", 《精细化工中间体》 * |
| 叶家林 等: "盐酸替罗非班的合成", 《化学研究与应用》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112441962A (en) * | 2019-09-04 | 2021-03-05 | 武汉武药科技有限公司 | Tirofiban and purification method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111018767B (en) | Preparation method of D-proline derivative and intermediate thereof | |
| CN107011404B (en) | A method of using cholic acid as Material synthesis lithocholic acid | |
| CN106187808A (en) | The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate | |
| CN112679420A (en) | Preparation method of 2,5-dibromopyridine | |
| CN109608387A (en) | The preparation of tirofiban hydrochloride | |
| CN111233748B (en) | Synthesis of tirofiban hydrochloride | |
| CN106928222A (en) | A kind of preparation method of 3 alkyl Indoli zine derivatives | |
| KR102453655B1 (en) | Improved process for preparing acotiamide | |
| US10399992B2 (en) | Process for preparing AD-35 | |
| CN104628653B (en) | The method of synthesizing rosuvastatin spit of fland calcium key intermediate | |
| CN114539216A (en) | Preparation method of Vonoprazan | |
| CN105536873B (en) | A kind of composite catalyst and its application | |
| CN108864084B (en) | Apixaban related substances and preparation method thereof | |
| CN107674026B (en) | Preparation method of ruxolitinib intermediate (3R) -3- (4-bromo-1H-pyrazol-1-yl) -cyclopentyl propionitrile | |
| CN109384767A (en) | A kind of Preparation Method And Their Intermediate of pyridopyrimidines derivatives | |
| NO177567B (en) | Process for the synthesis of N-3- (1H-imidazol-1-yl) phenyl-4- (substituted) -2-pyrimidinamines | |
| CN105330690B (en) | A kind of synthetic method of pharmaceutical intermediate aryl ketones phosphonate compound | |
| CN104945434B (en) | (2 ﹣ bis- substitution phosphines phenyl) -1- alkyl-indols Phosphine ligands and its synthetic method and application | |
| KR20230026411A (en) | Method for producing aromatic ether compounds | |
| CN106588921A (en) | Synthetic method for 7-azaindole-3-methyl formate | |
| CN107629039B (en) | The preparation method and intermediate of deuterated acrylamide | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN107501171B (en) | Synthetic method of 2-chloro-3-pyridylaldehyde | |
| CN109384680A (en) | A kind of preparation method of flibanserin intermediate | |
| CN109400507A (en) | The synthesis of Ailamode intermediate impurities |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 226123 No. 18, Qinghua Road, Sanchang street, Haimen District, Nantong City, Jiangsu Province Applicant after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address before: 226123 No. 18, Qinghua Road, Sanchang street, Haimen City, Nantong City, Jiangsu Province Applicant before: WISDOM PHARMACEUTICAL Co.,Ltd. |
|
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190412 |