CN115448871A - Preparation method of tirofiban hydrochloride - Google Patents
Preparation method of tirofiban hydrochloride Download PDFInfo
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- CN115448871A CN115448871A CN202211054479.8A CN202211054479A CN115448871A CN 115448871 A CN115448871 A CN 115448871A CN 202211054479 A CN202211054479 A CN 202211054479A CN 115448871 A CN115448871 A CN 115448871A
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a preparation method of tirofiban hydrochloride. The method comprises the following steps: (1) Reacting a compound 1 (chemical name: 4- (2-oxoethyl) piperidine-1-carboxylic acid tert-butyl ester) with a compound 2 (chemical name: ethoxycarbonyl methylene triphenylphosphine) to obtain an intermediate compound 3; (2) carrying out Pd/C catalytic hydrogenation on the compound 3 to obtain an intermediate 4; (3) reducing the compound 4 by lithium aluminum hydride to obtain an intermediate 5; (4) Reacting the compound 5 with 4-methylbenzenesulfonyl chloride to obtain an intermediate 6; (5) Carrying out substitution reaction on the compound 6 and the compound 7 under an alkaline condition to obtain an intermediate 8; (6) Under the action of hydrochloric acid, the protective group of the intermediate 8 is removed to obtain tirofiban hydrochloride. The process route provided by the invention has the advantages that: the method has the advantages of low price and easy obtainment of raw materials, mild reaction conditions, simple and convenient operation, high yield, environmental friendliness and no need of heavy metal removal and detection on the raw material medicaments.
Description
Technical Field
The invention relates to the technical field of medicine manufacturing, and particularly relates to a preparation method of tirofiban hydrochloride.
Background
Tirofiban hydrochloride (english name: tirofiban hydrochloride) is an antiplatelet drug with the chemical name N- (N-butylsulfonyl) -O- [4- (4-piperidinyl) butyl ] -L-tyrosine hydrochloride, CAS accession number: 142373-60-2, the structural formula is shown as follows:
currently, there are two major synthetic routes for tirofiban hydrochloride. The first route is shown in Scheme 1: taking L-tyrosine as a raw material, carrying out ethylation to generate an intermediate 11, reacting the intermediate 11 with n-butylsulfonyl chloride to obtain a compound 12, carrying out Mitsunobu reaction on the compound 12 and a compound 13 to obtain an intermediate 14, and then carrying out hydrolysis, catalytic hydrogenation and salification to obtain tirofiban hydrochloride.
The route is long, although the final product is synthesized through six steps, the compound 13 is not cheap and easy to obtain, the synthesis needs 2-3 steps of reaction, and the reaction conditions are harsh; in the catalytic hydrogenation process, pressurization and heating are needed, so that potential safety hazards exist, and the requirement on equipment is high; pd/C catalytic hydrogenation is positioned in the penultimate step of the route, so that the risk of heavy metal residues in the final product is increased, the enterprise needs to remove and detect Pd residues, and the detection of palladium element is determined in the quality standard of the finished product, so that the production cost is increased.
The second route is shown in Scheme 2: similarly, L-tyrosine is used as a raw material and reacts with n-butylsulfonyl chloride to obtain an intermediate 19, then the intermediate 19 and a compound 18 are subjected to substitution reaction to obtain an intermediate 15, and the intermediate 15 is subjected to catalytic hydrogenation and salification to obtain tirofiban hydrochloride.
The raw materials used in the route are cheap and easy to obtain, the synthesis steps are shortened, and the obvious defects still exist: n-butyllithium is used in the preparation process of the intermediate 18, so that the reaction conditions are harsh, and the operation difficulty is increased; the L-tyrosine is not subjected to esterification protection in the route, so that the polarity of related intermediates is higher, reaction sites are increased, and more impurities are generated in the reaction process of compounds 18 and 19, which is not beneficial to separation and purification of products; the method still uses a catalytic hydrogenation method to reduce pyridine rings, needs heating and pressurizing, has potential safety hazards and has higher requirements on equipment; the Pd/C catalytic hydrogenation is also located in the penultimate step of the route, and the problems of heavy metal residue, removal and detection still exist.
Disclosure of Invention
In order to overcome the defects of the technical route, the invention provides a novel method for synthesizing tirofiban hydrochloride, which aims to use easily available raw materials and provide a synthetic route which is simple to operate, cheap and easily available in raw materials, mild in reaction conditions and free from heavy metal removal and detection on raw material medicines:
the method comprises the following steps:
s1: synthesis of Compound 3
Dissolving the compound 1 in an organic solvent, adding the compound 2, then stirring and reacting in a certain temperature range, detecting by TLC until the compound 1 completely reacts, adding water into the reaction liquid, performing liquid separation and extraction, removing the solvent under reduced pressure, adding a mixed solvent of petroleum ether and ethyl acetate in a certain proportion, performing suction filtration, and removing the solvent under reduced pressure to obtain the compound 3.
Wherein the organic solvent is one or more of dichloromethane, tetrahydrofuran, ethyl acetate and toluene, preferably dichloromethane; preferably, the molar ratio of the compound 1 to the compound 2 is 1.0; the reaction temperature is 25-80 ℃, preferably 40-55 ℃; in the purification process, the volume ratio of the petroleum ether to the ethyl acetate is 20.
S2: synthesis of Compound 4
Dissolving the compound 3 in an organic solvent, adding a catalyst palladium carbon, introducing hydrogen, stirring and reacting at a certain temperature, detecting by TLC (thin layer chromatography) until the compound 3 completely reacts, then filtering off the palladium carbon, and removing the solvent under reduced pressure to obtain a compound 4.
Wherein the organic solvent is one or more of methanol, ethanol, ethyl acetate and dichloromethane, preferably ethanol; the reaction temperature is 25 ℃ to 80 ℃, preferably 20 ℃ to 30 ℃.
S3: synthesis of Compound 5
Dissolving the compound 4 in an organic solvent, adding lithium aluminum hydride at 0 ℃, stirring at 25 ℃ for reaction, detecting by TLC until the compound 4 completely reacts, adding water and ethyl acetate into the reaction solution, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain the compound 5.
Wherein the organic solvent is one or more of tetrahydrofuran, 1, 4-dioxane and methyl tert-butyl ether, preferably tetrahydrofuran; the molar ratio of the compound 5 to the lithium aluminum hydride is 1.0-2.0, and preferably, the molar ratio of the compound 5 to the lithium aluminum hydride is 1.0.
S4: synthesis of Compound 6
Dissolving the compound 5 in an organic solvent, adding an organic base, adding 4-methylbenzenesulfonyl chloride at 0 ℃, stirring at 25 ℃ for reaction, detecting by TLC until the compound 5 completely reacts, adding water into a reaction liquid, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, removing the solvent under reduced pressure, and recrystallizing by using a mixed solvent of petroleum ether and ethyl acetate to obtain the compound 6.
Wherein the organic solvent is one or more of dichloromethane, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether and ethyl acetate, preferably dichloromethane; the organic base is one or more of triethylamine, N-diisopropylethylamine and pyridine, and triethylamine is preferred; the mol ratio of the compound 5, the 4-methylbenzenesulfonyl chloride and the triethylamine is 1.0-2.0, and the mol ratio of the compound 5, the 4-methylbenzenesulfonyl chloride and the triethylamine is preferably 1.0-1.2; in the recrystallization process, the volume ratio of the petroleum ether to the ethyl acetate is 30.
S5 Synthesis of Compound 8
Dissolving a compound 6 in an organic solvent, adding a compound 7, reacting in a certain temperature range under an alkaline condition, detecting by TLC until the compound 6 completely reacts, adding water and ethyl acetate into a reaction bottle, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and removing the solvent under reduced pressure to obtain an intermediate 8.
Wherein the organic solvent is one or more of acetonitrile, acetone, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide, and acetonitrile is preferred; the added alkali is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, N-diisopropylethylamine and triethylamine, preferably potassium carbonate; the molar ratio of the compound 6, the compound 7 and the potassium carbonate is 1.0-1.5, and preferably, the molar ratio of the compound 6, the compound 7 and the potassium carbonate is 1.0-1.1; the reaction temperature is 50-100 ℃, preferably 80-95 ℃.
S6: synthesis of Compound 9 (Tirofiban hydrochloride)
Dissolving the compound 8 in an organic solvent, adding concentrated hydrochloric acid, stirring at a certain temperature for reaction, detecting by TLC until the compound 8 completely reacts, performing suction filtration, drying a filter cake in vacuum, and recrystallizing by using ethanol to obtain the tirofiban hydrochloride.
Wherein the organic solvent is one or more of methanol, ethanol, isopropanol, 1, 4-dioxane and acetonitrile, preferably isopropanol; the reaction temperature is 0 ℃ to 50 ℃, preferably 15 ℃ to 25 ℃.
Advantageous effects
1. Aiming at various defects of the existing process route of tirofiban hydrochloride, the invention takes a compound 1 which is cheap and easy to obtain as a starting point, and invents a brand new process route, wherein the route not only avoids the catalysis of heavy metal Pd at the tail end of the process, but also avoids the reduction of pyridine ring by heating and pressure hydrogenation by directly introducing piperidine ring into the raw material; the invention provides a brand new synthesis method of tirofiban hydrochloride, the raw materials used in the method are cheap and easy to obtain, the route is short, the reaction condition is mild, heating and pressurized hydrogenation are not needed, and the method is more suitable for industrial production.
2. According to the method, the heavy metal Pd is used and is arranged in the second step, the heavy metal content of the intermediate 6 is less than 10ppM, so that Pd removal of raw material medicines and detection of palladium element in the quality standard of finished products are not needed, and the production cost is reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the experimental methods of the present invention are further described in detail by examples below.
The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically at the end of the reaction when starting material is lost.
Example 1:
embodiment 1 of the present invention provides a preparation method of an intermediate 3, and the synthetic route thereof is as follows:
the preparation method specifically comprises the following steps:
dissolving compound 1 (20g, 88mmol) in dichloromethane (250 mL), adding compound 2 (61.3g, 176mmol), then stirring at 45 ℃ for reaction for 4h, detecting compound 1 by TLC for complete reaction, adding water (100 mL) to the reaction solution, separating, extracting, removing dichloromethane under reduced pressure, adding petroleum ether (160 mL) and ethyl acetate (16 mL), stirring for 30min, filtering, and removing filtrate under reduced pressure to obtain compound 3.
By adopting the method, 20.4g of white solid is prepared, and the yield is 78%.
The identification of intermediate 3 obtained in this example gave the following results:
1 H NMR(300MHz,DMSO-d 6 )δ6.85(dt,J＝15.3Hz,7.5Hz,1H),5.90(d,J＝15.6Hz,1H),4.11(q,J＝7.1Hz,2H),3.91(d,J＝12.0Hz,2H),2.68(s,2H),2.14(m,2H),1.58(dd,J＝11.1Hz,3.9Hz,3H),1.39(s,9H),1.21(t,J＝7.14Hz,3H),1.00(m,2H).
example 2:
embodiment 2 of the present invention provides a method for preparing intermediate 3:
dissolving compound 1 (10g, 44mmol) in ethyl acetate (120 mL), adding compound 2 (30.6g, 88mmol), then stirring at 45 ℃ for reaction for 4h, detecting that compound 1 is completely reacted by TLC, adding water (50 mL) into the reaction solution, separating and extracting, removing dichloromethane under reduced pressure, adding petroleum ether (80 mL) and ethyl acetate (8 mL), stirring for 30min, filtering, and removing the filtrate under reduced pressure to obtain compound 3.
9g of a white solid was obtained in 69% yield.
Example 3:
embodiment 3 of the present invention provides a preparation method of an intermediate 4, and the synthetic route thereof is as follows:
the preparation method specifically comprises the following steps:
dissolving compound 3 (20g, 67.4mmol) in ethanol (100 mL), adding 10% wet Pd/C (0.5 g), carrying out catalytic hydrogenation reaction at 25 ℃, after 12h of reaction, detecting by TLC that compound 3 completely reacts, filtering to remove Pd/C, removing the solvent under reduced pressure, and concentrating to obtain light yellow liquid, namely compound 4.
The method is adopted to prepare 18.9g of light yellow liquid, and the yield is 94%.
The intermediate 4 prepared in this example was identified to obtain the following results:
1 H NMR(300MHz,CDCl 3 )δ4.13(q,J＝7.14Hz,2H),2.67(t,J＝12.5Hz,2H),2.24(t,J＝7.4Hz,4H),1.66(m,4H),1.46(s,9H),1.45(m,1H),1.26(m,5H),1.09(m,2H).
example 4:
embodiment 4 of the present invention provides a preparation method of an intermediate 5, and the synthetic route thereof is as follows:
compound 4 (18g, 60mmol) was dissolved in tetrahydrofuran (180 mL), lithium aluminum hydride (2.74, 72 mmol) was added at 0 ℃ followed by stirring at 25 ℃ for reaction for 3h, disappearance of compound 4 was detected by TLC, then water (50 mL) and ethyl acetate (50 mL) were added to the system, liquid-separation extraction was performed, the organic layer was dried over anhydrous sodium sulfate, suction filtration was performed, and the solvent was removed under reduced pressure to obtain compound 5.
The method is adopted to prepare 13.9g of light yellow liquid, and the yield is 90%.
The intermediate 5 prepared in this example was identified to obtain the following results:
1 H NMR(300MHz,DMSO-d 6 )δ4.70(s,1H),4.06～4.17(m，2H),3.65(t,J＝6.4Hz,2H),2.67(t,J＝12.4Hz,2H),1.68(m,6H),1.46(s,9H),1.38(m,3H)，1.28(m,2H)，1.06(m,2H).
example 5:
example 5 of the present invention provides a method for preparing intermediate 5:
compound 4 (18g, 60mmol) was dissolved in methyl t-butyl ether (180 mL), lithium aluminum hydride (2.74, 72 mmol) was added at 0 ℃, followed by stirring reaction at 25 ℃ for 3h, disappearance of compound 4 was detected by TLC, followed by addition of water (50 mL) and ethyl acetate (50 mL) to the system, liquid-separation extraction, drying of the organic layer with anhydrous sodium sulfate, suction filtration, and removal of the solvent under reduced pressure to give Compound 5.
The method is adopted to prepare 13.1g of light yellow liquid, and the yield is 85%.
Example 6:
embodiment 6 of the present invention provides a preparation method of intermediate 6, and the synthetic route is as follows:
dissolving compound 5 (22g, 85mmol) in dichloromethane (200 mL), adding triethylamine (13mL, 94mmol), subsequently adding 4-methylbenzenesulfonyl chloride (18g, 94mmol) at 0 ℃, stirring for 2h at 25 ℃ after the addition is finished, detecting the disappearance of compound 5 by TLC, adding water to the reaction solution, performing liquid separation extraction, drying the organic layer by using anhydrous sodium sulfate, performing suction filtration, removing the solvent under reduced pressure, adding petroleum ether (150 mL) and ethyl acetate (10 mL), and recrystallizing to obtain compound 6.
The method is adopted to prepare 32g of light yellow solid, the yield is 91 percent, and the IPC-MS measurement result shows that the Pd content in the compound 6 is less than 10ppm.
Example 7:
example 7 of the present invention provides a method of preparing intermediate 6:
compound 5 (20g, 78mmol) was dissolved in dichloromethane (200 mL), pyridine (6.9mL, 85mmol) was added, 4-methylbenzenesulfonyl chloride (169g, 85mmol) was then added at 0 ℃ and, after completion of the addition, stirring was carried out at 25 ℃ for 2h, disappearance of compound 5 was detected by TLC, water was added to the reaction solution, liquid-separation extraction was carried out, the organic layer was dried over anhydrous sodium sulfate, suction filtration was carried out, the solvent was removed under reduced pressure, and petroleum ether (140 mL) and ethyl acetate (9 mL) were added to the solution to carry out recrystallization, and Compound 6 was obtained.
28g of light yellow solid is prepared by the method, and the yield is 88%.
Example 8:
embodiment 8 of the present invention provides a preparation method of intermediate 8, which comprises the following synthetic route:
compound 6 (25g, 61mmol) and compound 7 (24g, 67mmol) were dissolved in acetonitrile (300 mL), anhydrous potassium carbonate (10g, 73mmol) was added, followed by stirring at 85 ℃ for reaction for 8h, and completion of compound 6 reaction was checked by TLC. Water (100 mL) and ethyl acetate (150 mL) were added to the reaction flask, followed by liquid-separation extraction, drying of the organic layer over anhydrous sodium sulfate, suction filtration, and removal of the solvent under reduced pressure to give intermediate 8.
The method is adopted to prepare 36g of light yellow liquid, and the yield is 99%.
The intermediate 8 obtained in this example was identified to obtain the following results:
1 H NMR(300MHz,CDCl 3 )δ7.16(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,2H),4.82(d,J＝9.3Hz,1H),4.06～4.22(m,3H)，3.93(t,J＝6.4Hz,2H),3.04(dd,J＝13.9Hz,5.7Hz,1H),2.93(dd,J＝13.9Hz,7.1Hz,1H),2.63～2.80(m,4H)，1.93(s,1H)，1.76(p,J＝6.8Hz,2H)，1.59～1.70(m,4H),1.46(d,J＝3.1Hz,18H),1.24～1.40(m,6H)，1.02～1.16(m,2H),0.88(t,J＝7.3Hz,3H).
example 9:
example 9 of the present invention provides a method for preparing intermediate 8:
compound 6 (20g, 49mmol) and compound 7 (19g, 53mmol) were dissolved in acetone (240 mL), anhydrous potassium carbonate (8g, 73mmol) was added, the reaction was stirred at 85 ℃ for 8h, and completion of compound 6 reaction was detected by TLC. Water (80 mL) and ethyl acetate (120 mL) were added to the reaction flask, followed by liquid-separation extraction, drying of the organic layer over anhydrous sodium sulfate, suction filtration, and removal of the solvent under reduced pressure to give intermediate 8.
28g of light yellow liquid is prepared by the method, and the yield is 97%.
Example 10:
the embodiment 10 of the invention provides a preparation method of tirofiban hydrochloride, which comprises the following synthetic route:
compound 8 (50g, 84mmol) was dissolved in isopropanol (200 mL), concentrated hydrochloric acid (40 mL) was added at 0 deg.C, followed by stirring at 20 deg.C for 2h, and disappearance of compound 8 was detected by TLC. And (4) carrying out suction filtration, drying a filter cake in vacuum, and recrystallizing by using ethanol to obtain the tirofiban hydrochloride.
The method is adopted to prepare 36g of white solid tirofiban hydrochloride, the yield is 90 percent, and the purity is more than 99.8 percent.
The tirofiban hydrochloride prepared in the example was identified, and the following results were obtained:
1 H NMR(300MHz,D 2 O)δ7.16(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,2H),4.04(dd,J＝10.7Hz,4.3Hz,1H),3.94(t,J＝6.3Hz,2H),3.26(d,J＝12.8Hz,2H),3.11(dd,J＝14.1Hz,4.2Hz,1H),2.82(td,J＝12.8Hz,2.4Hz,2H)，2.66(dd,J＝15.2Hz,10.7Hz,H)，2.48～2.59(m,2H)，1.81(d,J＝14.1Hz,2H),1.63(p,J＝6.7Hz,2H)，1.46(s,1H),1.27～1.40(m,3H)，1.23(t,J＝6.2Hz,4H),1.03(s,3H),0.63(t,J＝7.1Hz,3H).
the above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (8)
1. A method for preparing tirofiban hydrochloride is characterized by adopting the following technical route:
the method comprises the following operation steps:
s1: synthesis of Compound 3
Dissolving the compound 1 in an organic solvent, adding the compound 2, stirring for reaction until the compound 1 completely reacts, adding water into a reaction liquid, separating and extracting, removing the solvent, adding a mixed solvent of petroleum ether and ethyl acetate, performing suction filtration, and removing the solvent to obtain a compound 3;
s2: synthesis of Compound 4
Dissolving a compound 3 in an organic solvent, adding a catalyst Pd/C, introducing hydrogen, stirring for reaction until the compound 3 completely reacts, filtering off the Pd/C, and removing the solvent under reduced pressure to obtain a compound 4;
s3: synthesis of Compound 5
Dissolving the compound 4 in an organic solvent, adding lithium aluminum hydride at 0 ℃, stirring at 25 ℃ for reaction until the compound 4 completely reacts, adding water and ethyl acetate into a reaction solution, separating liquid for extraction, drying an organic layer, performing suction filtration, and removing the solvent under reduced pressure to obtain a compound 5;
s4: synthesis of Compound 6
Dissolving a compound 5 in an organic solvent, adding an organic base, adding 4-methylbenzenesulfonyl chloride at 0 ℃, stirring at 25 ℃ for reaction, detecting by TLC until the compound 5 completely reacts, adding water into a reaction liquid, separating and extracting, drying an organic layer, performing suction filtration, removing the solvent under reduced pressure, and recrystallizing by using a mixed solvent of petroleum ether and ethyl acetate to obtain a compound 6;
s5 Synthesis of Compound 8
Dissolving a compound 6 in an organic solvent, adding a compound 7, reacting under an alkaline condition until the compound 6 completely reacts, adding water and ethyl acetate into a reaction bottle, performing liquid separation extraction, drying an organic layer, performing suction filtration, and removing the solvent under reduced pressure to obtain an intermediate 8;
s6: synthesis of Compound 9
Dissolving the compound 8 in an organic solvent, adding concentrated hydrochloric acid, stirring for reaction until the compound 8 completely reacts, performing suction filtration, drying a filter cake in vacuum, and recrystallizing to obtain a compound 9, namely tirofiban hydrochloride 9.
2. A process for the preparation of tirofiban hydrochloride according to claim 1,
the method comprises the following operation steps:
s1: synthesis of Compound 3
Dissolving the compound 1 in an organic solvent, adding the compound 2, stirring for reaction, detecting by TLC until the compound 1 completely reacts, adding water into a reaction solution, performing liquid separation and extraction, removing the solvent under reduced pressure, adding a mixed solvent of petroleum ether and ethyl acetate, performing suction filtration, and removing the solvent under reduced pressure to obtain a compound 3;
s2: synthesis of Compound 4
Dissolving the compound 3 in an organic solvent, adding a catalyst Pd/C, introducing hydrogen, stirring for reaction, detecting by TLC (thin layer chromatography) until the compound 3 completely reacts, filtering off Pd/C, and removing the solvent under reduced pressure to obtain a compound 4;
s3: synthesis of Compound 5
Dissolving a compound 4 in an organic solvent, adding lithium aluminum hydride at 0 ℃, stirring at 25 ℃ for reaction, detecting by TLC until the compound 4 completely reacts, adding water and ethyl acetate into a reaction solution, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain a compound 5;
s4: synthesis of Compound 6
Dissolving a compound 5 in an organic solvent, adding an organic base, adding 4-methylbenzenesulfonyl chloride at 0 ℃, stirring at 25 ℃ for reaction, detecting by TLC until the compound 5 completely reacts, adding water into a reaction liquid, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, removing the solvent by reducing pressure, and recrystallizing by using a mixed solvent of petroleum ether and ethyl acetate to obtain a compound 6;
s5 Synthesis of Compound 8
Dissolving a compound 6 in an organic solvent, adding a compound 7, reacting under an alkaline condition, detecting by TLC (thin layer chromatography) until the compound 6 completely reacts, adding water and ethyl acetate into a reaction bottle, performing liquid-separation extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain an intermediate 8;
s6: synthesis of Compound 9
Dissolving the compound 8 in an organic solvent, adding concentrated hydrochloric acid, then stirring for reaction, detecting by TLC until the compound 8 completely reacts, performing suction filtration, drying a filter cake in vacuum, and then recrystallizing by using ethanol to obtain a compound 9, namely tirofiban hydrochloride.
3. The method for synthesizing tirofiban hydrochloride according to claim 2, wherein in step S1, the organic solvent is one or more of dichloromethane, tetrahydrofuran, ethyl acetate and toluene; the mol ratio of the compound 1 to the compound 2 is 1.0; the reaction temperature is 25-80 ℃; in the purification process, the volume ratio of the petroleum ether to the ethyl acetate is 20.
4. The tirofiban hydrochloride synthesis method according to claim 2, wherein in step S2, the organic solvent is one or more of methanol, ethanol, ethyl acetate and dichloromethane; the reaction temperature is 25-80 ℃.
5. The method for synthesizing tirofiban hydrochloride according to claim 2, wherein in step S3, the organic solvent is one or more of tetrahydrofuran, 1, 4-dioxane and methyl tert-butyl ether; the molar ratio of the compound 5 to the lithium aluminum hydride is 1.0 to 2.0.
6. The method for synthesizing tirofiban hydrochloride according to claim 2, wherein in step S4, the organic solvent is one or more of dichloromethane, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether and ethyl acetate; the organic base is one or more of triethylamine, N-diisopropylethylamine and pyridine; the mol ratio of the compound 5, the 4-methylbenzenesulfonyl chloride and the triethylamine is 1.0-2.0; in the recrystallization process, the volume ratio of the petroleum ether to the ethyl acetate is 30.
7. The method for synthesizing tirofiban hydrochloride according to claim 2, wherein in step S5, the organic solvent is one or more of acetonitrile, acetone, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide; the added alkali is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, N-diisopropylethylamine and triethylamine; the molar ratio of the compound 6 to the compound 7 to the potassium carbonate is 1.0-1.5; the reaction temperature is 50-100 ℃.
8. The method for synthesizing tirofiban hydrochloride according to claim 2, wherein in step S6, the organic solvent is one or more of methanol, ethanol, isopropanol, 1, 4-dioxane and acetonitrile; the reaction temperature is 0-50 ℃.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1060096A (en) * | 1990-09-27 | 1992-04-08 | 麦克公司 | Fibrinogen receptor anlagonists |
| WO2001002386A1 (en) * | 1999-07-01 | 2001-01-11 | Mediolanum Farmaceutici S.P.A. | SELECTIVE M2 MUSCARINIC RECEPTOR ANTAGONISTS HAVING 5H-DIBENZ[b,f]AZEPINE STRUCTURE |
| US6194435B1 (en) * | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
| WO2011055770A1 (en) * | 2009-11-06 | 2011-05-12 | 武田薬品工業株式会社 | Fused heterocyclic compound |
| CN102459209A (en) * | 2009-04-16 | 2012-05-16 | 武田药品工业株式会社 | Derivatives of n-acyl-n'-phenylpiperazine useful (inter alia) for the prophylaxis or treatment of diabetes |
| US20190185452A1 (en) * | 2016-08-05 | 2019-06-20 | Centre Hospitalier Universitaire Vaudois Chuv | Piperidine derivatives for use in the treatment of pancreatic cancer |
| CN111718228A (en) * | 2020-07-30 | 2020-09-29 | 兰州大学 | Method for synthesizing carboxylic acid for prolonging two carbon chains by olefin in one step |
-
2022
- 2022-08-30 CN CN202211054479.8A patent/CN115448871B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1060096A (en) * | 1990-09-27 | 1992-04-08 | 麦克公司 | Fibrinogen receptor anlagonists |
| US6194435B1 (en) * | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
| WO2001002386A1 (en) * | 1999-07-01 | 2001-01-11 | Mediolanum Farmaceutici S.P.A. | SELECTIVE M2 MUSCARINIC RECEPTOR ANTAGONISTS HAVING 5H-DIBENZ[b,f]AZEPINE STRUCTURE |
| CN102459209A (en) * | 2009-04-16 | 2012-05-16 | 武田药品工业株式会社 | Derivatives of n-acyl-n'-phenylpiperazine useful (inter alia) for the prophylaxis or treatment of diabetes |
| WO2011055770A1 (en) * | 2009-11-06 | 2011-05-12 | 武田薬品工業株式会社 | Fused heterocyclic compound |
| US20190185452A1 (en) * | 2016-08-05 | 2019-06-20 | Centre Hospitalier Universitaire Vaudois Chuv | Piperidine derivatives for use in the treatment of pancreatic cancer |
| CN111718228A (en) * | 2020-07-30 | 2020-09-29 | 兰州大学 | Method for synthesizing carboxylic acid for prolonging two carbon chains by olefin in one step |
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