CN115772116A - Tirofiban intermediate compound - Google Patents
Tirofiban intermediate compound Download PDFInfo
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- CN115772116A CN115772116A CN202111052992.9A CN202111052992A CN115772116A CN 115772116 A CN115772116 A CN 115772116A CN 202111052992 A CN202111052992 A CN 202111052992A CN 115772116 A CN115772116 A CN 115772116A
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Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a tirofiban intermediate compound. The invention takes 4-pyridine butanol and p-toluene sulfonyl chloride as starting materials to react to obtain a new intermediate compound of tirofiban. Meanwhile, the invention provides a method for preparing a tirofiban key intermediate (S) -2- (butylsulfonylamino) -3- (4- (4- (pyridine-4-yl) butoxy) phenyl) propionic acid by reacting the new intermediate compound with N-N-butylsulfonyl-L-tyrosine ethyl ester. The new intermediate provided by the invention is simple in synthesis method, short in synthesis route, high in yield, mild in reaction condition and stable in process when used for preparing tirofiban, and is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a tirofiban intermediate compound.
Background
Tirofiban hydrochloride (tirofiban hydrochloride) with the chemical name of N- (butylsulfonyl) -O- [4- (4-pyridyl) butyl ] -L-tyrosine hydrochloride is developed by Merck company, is the first non-peptide platelet surface Glycoprotein (GP) IIb/IIIa receptor antagonist on the market, and has the advantages of high efficiency, high selectivity, reversibility and the like. The medicine is firstly marketed in the United states in 5 months in 1998, is a domestic only platelet model GPIIb/IIIa receptor antagonist in 2004, is clinically used for treating acute coronary syndromes including unstable angina or patients without Q-wave myocardial infarction and patients undergoing percutaneous transluminal coronary angioplasty or atherectomy, has unique action mechanism, definite clinical curative effect and good safety, and is a therapeutic medicine with great development prospect. Molecular weight: 495.08, CAS registry No. 150915-40-5, structural formula as follows:
the currently reported synthesis processes for tirofiban mainly include the following two processes:
the method comprises the following steps: tetrahedron,1993,49;5767-5776, it is reported that n-butyl piperidine derivatives are used as substrates, condensed with L-tyrosine derivatives to form tirofiban skeleton, and then correspondingly deprotected and salified to obtain the target product:
in the method, the piperidine derivative serving as a reaction substrate is generally obtained by catalytic hydrogenation of a pyridine derivative, N-protected piperidine butanol is usually adopted, the required reaction steps are more, the operation is complex, and the industrialization is difficult to realize; or a high-activity substrate is adopted, and the required operating conditions are harsh due to high activity of the substrate, such as absolute anhydrous light protection, and the industrialization is not facilitated.
The second method comprises the following steps: the synthesis [ J ] of Tirofiban hydrochloride, chemical research and application of phyllaline and the like, 2012,024 (005): 821-824, wherein L-tyrosine is used as a raw material, and Tirofiban hydrochloride is obtained by 6 steps of esterification, sulfonylation, mitsunobu reaction, hydrolysis, catalytic hydrogenation, salt formation and the like:
in the method, triphenylphosphine is needed in the Mitsunobu reaction, the generated triphenylphosphine oxide is difficult to remove and has certain harm to the environment, and the total yield of the reaction is only 33 percent, which is not beneficial to industrial production.
To circumvent the Mitsunobu reaction, the synthesis of tirofiban hydrochloride by zheng yong et al [ J ]. Journal of chinese medical industry, 2012 (06): 408-410. The preparation of compound V by condensation of compound 6 with compound IV was reported as follows:
however, this reaction produces disubstituted impurities, which are difficult to remove in subsequent purification steps:
in view of the problems existing in the existing preparation of the intermediate compound (S) -2- (butylsulfonamido) -3- (4- (4- (pyridine-4-yl) butoxy) phenyl) propionic acid of tirofiban, the research and the search of a method which has the advantages of mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost and is suitable for industrially producing the intermediate compound (S) -2- (butylsulfonamido) -3- (4- (pyridine-4-yl) butoxy) phenyl) propionic acid of tirofiban is a problem to be solved at present.
Disclosure of Invention
In order to overcome the defects of the prior art and search for a better method for preparing a tirofiban intermediate (S) -2- (butylsulfonamido) -3- (4- (4- (pyridine-4-yl) butoxy) phenyl) propionic acid, the invention provides a novel tirofiban intermediate compound and a novel method for preparing (S) -2- (butylsulfonamido) -3- (4- (4- (pyridine-4-yl) butoxy) phenyl) propionic acid by using the novel intermediate, and a target product prepared by the method has the characteristics of higher purity and yield, mild reaction conditions, simple and convenient operation process and lower production cost.
The specific technical content of the invention is as follows:
the invention provides a new tirofiban intermediate compound in a first aspect, which has a structure shown as a formula III:
the second aspect of the invention provides a preparation method of the tirofiban intermediate compound III: a preparation method of a tirofiban intermediate compound III comprises the following steps: adding a compound II, alkali A and a catalyst into an organic solvent A, stirring, adding p-toluenesulfonyl chloride, reacting at room temperature until the reaction is finished to obtain a compound III:
preferably, the base is selected from one of triethylamine, diisopropylethylamine, sodium methoxide and sodium hydride, wherein triethylamine is particularly preferred.
Preferably, the catalyst is selected from one of 4-dimethylamino pyridine, 3, 5-dimethyl pyridine and 3-amino pyridine, wherein the 4-dimethylamino pyridine is particularly preferred.
Preferably, the organic solvent A is selected from one or a combination of dichloromethane, tetrahydrofuran, chloroform and acetonitrile.
Preferably, the feeding molar ratio of the compound II, the paratoluensulfonyl chloride, the base A and the catalyst is 1: 1.0-2.0: 1.8 to 2.5, preferably 1: .
In a preferred scheme, after the reaction is finished, post-treatment is needed, and the method comprises the following specific steps: after the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture, the aqueous phase was separated and removed, the aqueous phase was extracted with dichloromethane, the organic phases were combined, the organic phase was washed with water and a saturated saline solution once, respectively, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove the drying agent, concentrating under reduced pressure to remove the solvent by evaporation, and recrystallizing the residual product with toluene to obtain the compound III.
In a third aspect, the present invention provides a process for the preparation of tirofiban key intermediate compound (S) -2- (butylsulfonamido) -3- (4- (4- (pyridin-4-yl) butoxy) phenyl) propanoic acid from the new intermediate compound III:
a method for preparing a tirofiban intermediate compound (S) -2- (butylsulfonylamino) -3- (4- (4- (pyridin-4-yl) butoxy) phenyl) propanoic acid, comprising the steps of: adding a compound IV and an alkali B into a single-neck flask at room temperature, adding an organic solvent B, stirring at low temperature, adding a compound III, continuing to react at constant temperature, after detection reaction is finished, adding a saturated ammonium chloride aqueous solution into a reaction solution for dilution, separating an organic phase, extracting a water phase with diethyl ether, combining the organic phases, washing with salt, drying and then evaporating the organic phase, adding an obtained product into a tetrahydrofuran and methanol organic solution, dropwise adding an alkali C solution, and reacting at room temperature until the reaction is finished to obtain a compound V.
Preferably, the base B is selected from one of potassium tert-butoxide, sodium hydroxide and sodium hydride, and particularly preferred is potassium tert-butoxide.
Preferably, the organic solvent B is one selected from dried diethyl ether, tetrahydrofuran, acetonitrile and dichloromethane.
Preferably, the base C is selected from one of lithium hydroxide, sodium hydride, and potassium carbonate, with lithium hydroxide being particularly preferred.
Preferably, the feeding molar ratio of the compound IV, the compound III, the base B and the base C is as follows: 1.0-2.0: 1.1:3.0:1.2.
preferably, the temperature is controlled to be-5 ℃ after the organic solvent B is added.
In a preferred scheme, after the reaction is finished, post-treatment is required, and the method comprises the following specific steps: adding 1M acid into the reaction solution to adjust the pH to be = 8-9, distilling off the solvent under reduced pressure, adding water and ethyl acetate, adjusting the pH to be = 5-6 by using 0.5M diluted hydrochloric acid, extracting the ethyl acetate, drying the ethyl acetate by using anhydrous sodium sulfate, filtering, distilling off the solvent from the filtrate under reduced pressure, and recrystallizing the crude product by using isopropanol to obtain the compound V.
Compared with the prior art, the invention has the following technical effects:
1. provides a new tirofiban intermediate compound, simultaneously provides a method for preparing a tirofiban key intermediate (S) -2- (butylsulfonylamino) -3- (4- (4- (pyridine-4-yl) butoxy) phenyl) propionic acid by utilizing the new intermediate simply, conveniently and efficiently, and the whole synthesis method has simple and convenient operation and high reaction yield;
2. the tirofiban prepared by the new intermediate can effectively avoid etherification reaction and does not generate disubstituted impurities;
3. the (S) -2- (butylsulfonylamino) -3- (4- (4- (pyridine-4-yl) butoxy) phenyl) propionic acid obtained by the technology has higher purity and yield, and is suitable for industrial amplification production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
The structure of the compound obtained by the invention is confirmed:
HPLC peak area normalization:
a chromatographic column: YMC-Triart C 18 Columns (4.6 mm. Times.250mm, 5 μm);
mobile phase: acetonitrile: water (70: 30);
column temperature: 30 ℃;
detection wavelength: 220nm;
flow rate: 1.0ml/min;
sample injection amount: 10 mul;
retention time: and (3) 18.5min.
High resolution mass spectrum of compound III: ESI-HRMS: m/z =306.1082[ 2 ], [ M + H ]] + , 1 H-NMR(400MHz,DMSO-d6):8.65(s,1H),8.55(s,1H),7.76(s,1H),7.75(s,1H),7.46(s,1H),7.45(s,1H),7.23(s,1H),7.22(s,1H),4.02(t,2H),3.402(t,2H),2.43(s,3H),1.52-1.60(m,4H)； 13 C-NMR(400MHz,DMSO-d6):151.6,149.2,149.1,144.4,140.3,130.5,130.4,128.3,128.2,123.6,123.5,69.9,35.7,28.8,28.2,21.3
Characterization of compound V:
HPLC peak area normalization method:
a chromatographic column: YMC-Triart C 18 Columns (4.6 mm. Times.250mm, 5 μm);
mobile phase: a is a buffer solution (0.79 g of disodium hydrogen phosphate and 2.46g of sodium dihydrogen phosphate are taken, water is added to 1000 ml) methanol (95: 5), B is acetonitrile, and gradient elution is carried out (0-20min, B20% -35%, 20-40min, B80%, 40-50min, B80% -20%);
column temperature: 35 ℃;
detection wavelength: 230nm;
flow rate: 1.5ml/min;
sample injection amount: 10 mu l of the mixture;
retention time: and (3) 18.8min.
ESI-HRMS(m/z)：457.1878[M+Na] + .mp 137～138℃℃； 1 H-NMR(400MHz,CDCl 3 )δ:8.41(d,2H),7.35(d,2H),7.17(d,2H),6.83(d,2H),4.95(s,1H),4.08(q,1H),3.99(t,2H),3.30(dd,1H),2.74-2.78(m,4H),2.63(t,2H),1.82-1.83(m,2H)，1.44-1.46(m,2H)，1.21-1.23(m,2H),0.81(t,3H)； 13 C-NMR(100MHz,CDCl 3 )δ:174.7,156.5,151.6,149.2,149.1,129.5,129.4,128.2,123.7,123.6,114.4,114.3,68.7,61.3,60.1,35.7,35.6,29.2,29.1,21.6,21.0,13.8.
Preparation of Compound III
Example 1
Compound II (Shanghai Kai, chemical science and technology Co., ltd., 98%,30.24g,0.20 mol), triethylamine (40.48g, 0.40mol), 4-dimethylaminopyridine (3.67g, 0.03mol) and dry dichloromethane (100 mL) were added to a single-neck flask, stirred and dissolved, reacted at room temperature for 15 minutes, and then p-toluenesulfonyl chloride (50.71g, 0.27mol) was added thereto, and the mixture was reacted at constant temperature for 4 hours. After the reaction, a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, the aqueous phase was separated and removed, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, the organic phase was washed with water and saturated saline solution once, respectively, the organic phase was dried with anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by reduced pressure concentration, and the remaining product was recrystallized from toluene (100 mL) to obtain a white solid powder III with a yield of 98.4% and an HPLC purity of 99.92%.
Example 2
A single-neck flask was charged with Compound II (98%, 30.24g, 0.20mol; shanghai Kai, chemical technology Co., ltd.), diisopropylethylamine (51.70g, 0.40mol), 4-dimethylaminopyridine (3.67g, 0.03mol) and dry chloroform (100 mL) and dissolved by stirring, reacted at room temperature for 15 minutes, then, p-toluenesulfonyl chloride (38.13g, 0.20mol) was added thereto, and reacted at a constant temperature for 4 hours. After the reaction, a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, the aqueous phase was separated and removed, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, the organic phase was washed with water and saturated saline solution once, respectively, the organic phase was dried with anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by reduced pressure concentration, and the remaining product was recrystallized from toluene (100 mL) to obtain a white solid powder III with a yield of 94.3% and an HPLC purity of 99.55%.
Example 3
Compound II (98%, 30.24g,0.20mol, khaikai chemical Co., ltd.), sodium potassium alkoxide (21.62g, 0.40mol), 4-dimethylaminopyridine (3.67g, 0.03mol) and dry acetonitrile (100 mL) were charged into a single-neck flask, and dissolved with stirring, reacted at room temperature for 15 minutes, then p-toluenesulfonyl chloride (76.26g, 0.40mol) was added thereto, and the mixture was reacted at a constant temperature for 4 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, liquid separation was performed to remove the aqueous phase, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, the organic phase was washed with water and saturated brine once, the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the remaining product was recrystallized from toluene (100 mL) to obtain a white solid powder III with a yield of 94.8% and an HPLC purity of 99.48%.
Example 4
A single-neck flask was charged with Compound II (Shanghai Kai, chemical science and technology Co., ltd., 98%,30.24g,0.20 mol), sodium hydride (9.60g, 0.40mol), 4-dimethylaminopyridine (4.89g, 0.04mol) and dry tetrahydrofuran (100 mL) and dissolved by stirring, reacted at room temperature for 15 minutes, then added with p-toluenesulfonyl chloride (50.71g, 0.27mol), and reacted at constant temperature for 4 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, the aqueous phase was separated and removed, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, the organic phase was washed with water and saturated saline solution once, respectively, the organic phase was dried with anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by reduced pressure concentration, and the remaining product was recrystallized from toluene (100 mL) to obtain a white solid powder III with a yield of 93.9% and an HPLC purity of 99.45%.
Example 5
A single-neck flask was charged with Compound II (Shanghai Kai, chemical science and technology Co., ltd., 98%,30.24g, 0.20mol), diisopropylethylamine (51.70g, 0.40mol), 4-dimethylaminopyridine (2.44g, 0.02mol) and dry dichloromethane (100 mL) and dissolved with stirring, reacted at room temperature for 15 minutes, then added with p-toluenesulfonyl chloride (50.71g, 0.27mol), and reacted at constant temperature for 4 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, liquid separation was performed to remove the aqueous phase, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, the organic phase was washed with water and saturated brine once, the organic phase was dried with anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the remaining product was recrystallized from toluene (100 mL) to obtain a white solid powder III with a yield of 94.5% and an HPLC purity of 99.32%.
Example 6
Compound II (Shanghai Kai, chemical science and technology Co., ltd., 98%,30.24g,0.20 mol), triethylamine (36.43g, 0.36mol), 3, 5-lutidine (3.21g, 0.03mol) and dry tetrahydrofuran (100 mL) were added to a single-neck flask, stirred and dissolved, reacted at room temperature for 15 minutes, and then p-toluenesulfonyl chloride (50.71g, 0.27mol) was added thereto, and reacted at constant temperature for 4 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, the aqueous phase was separated and removed, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, the organic phase was washed with water and saturated saline solution once, respectively, the organic phase was dried with anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the remaining product was recrystallized from toluene (100 mL) to obtain a white solid powder III with a yield of 94.4% and an HPLC purity of 99.54%.
Example 7
Compound II (Shanghai Kai, chemical science and technology Co., ltd., 98%,30.24g,0.20 mol), triethylamine (50.60g, 0.5 mol), 3-aminopyridine (2.82g, 0.03mol) and dry dichloromethane (100 mL) were added to a single-neck flask, and the mixture was dissolved with stirring, reacted at room temperature for 15 minutes, and then p-toluenesulfonyl chloride (50.71g, 0.27mol) was added thereto, and reacted at constant temperature for 4 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, liquid separation was performed to remove the aqueous phase, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, the organic phase was washed with water and saturated brine once, the organic phase was dried with anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the remaining product was recrystallized from toluene (100 mL) to obtain a white solid powder III with a yield of 95.5% and an HPLC purity of 99.45%.
Example 8
Compound II (Shanghai Kai, chemical science and technology Co., ltd., 98%,30.24g, 0.20mol), triethylamine (30.36g, 0.3mol), 4-dimethylaminopyridine (1.95g, 0.016mol) and dry dichloromethane (100 mL) were charged into a single-neck flask, stirred and dissolved, reacted at room temperature for 15 minutes, and then p-toluenesulfonyl chloride (50.71g, 0.27mol) was added thereto, and the reaction was carried out at a constant temperature for 4 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, liquid separation was performed to remove the aqueous phase, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, the organic phase was washed with water and saturated brine once, the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the remaining product was recrystallized from toluene (100 mL) to obtain a white solid powder III with a yield of 88.9% and an HPLC purity of 98.85%.
Example 9
Compound II (Shanghai Kai, chemical science and technology Co., ltd., 98%,30.24g,0.20 mol), triethylamine (54.64g, 0.54mol), pyridine (3.48g, 0.044 mol) and dry dichloromethane (100 mL) were added to a single-neck flask, stirred and dissolved, reacted at room temperature for 15 minutes, and then p-toluenesulfonyl chloride (83.88g, 0.44mol) was added thereto, and reacted at constant temperature for 4 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, liquid separation was performed to remove the aqueous phase, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, the organic phase was washed with water and saturated brine once, the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the remaining product was recrystallized from toluene (100 mL) to obtain a white solid powder III with a yield of 86.3% and an HPLC purity of 97.55%.
Preparation of Compound V
Example 10
Compound IV (32.94g, 0.10mol), potassium tert-butoxide (33.66g, 0.30mol) and dry ether (200 mL) were charged into a single-neck flask, and stirred at 0 ℃ for 30 minutes, followed by addition of compound III (33.56g, 0.111mol), followed by stirring at constant temperature for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, the aqueous phase was extracted with ether (200 mL. Times.3), the organic phases were combined, the organic phase was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated by concentration under reduced pressure to give a yellow liquid, which was added with tetrahydrofuran (200 mL), methanol (70 mL), and an aqueous solution of lithium hydroxide (5.03g, 0.12mol, dissolved in 70mL of water) dropwise, followed by reaction overnight. With 1 mol. L -1 Adjusting the pH to 8 to 9 with an acid, removing the solvent by evaporation under reduced pressure, adding water (70 mL), washing with ethyl acetate (100 mL), and then washing with 0.5mol · L -1 Adjusting the pH value to be 5-6 by dilute hydrochloric acid, extracting by ethyl acetate (100 mL multiplied by 3), drying by anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and recrystallizing a crude product by isopropanol (100 mL) to obtain a beige solid compound V, wherein the yield is 98.9 percent and the HPLC purity is 99.80 percent.
Example 11
Compound IV (32.94g, 0.10 mol), sodium t-butoxide (38.83g, 0.30mol) and dry ether (200 mL) were added to a single-neck flask, and after stirring at 5 ℃ for 30 minutes and compound III (30.51g, 0.10 mol) were added, the mixture was stirred at constant temperature for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, the aqueous phase was extracted with ether (200 mL. Times.3), the organic phases were combined, the organic phase was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated by concentration under reduced pressure to give a yellow liquid, which was added with tetrahydrofuran (200 mL), methanol (70 mL), and an aqueous solution of lithium hydroxide (5.03g, 0.12mol, dissolved in 70mL of water) dropwise, followed by reaction overnight. With 1 mol. L -1 Adjusting pH to 8-9 with acid, removing the solvent by evaporation under reduced pressure, adding water (70 mL), washing with ethyl acetate (100 mL), and then washing with 0.5 mol. L -1 Adjusting the pH value to be 5-6 by dilute hydrochloric acid, extracting by ethyl acetate (100 mL multiplied by 3), drying by anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and recrystallizing the crude product by isopropanol (100 mL) to obtain a beige solid compound V, wherein the yield is 94.3%, and the HPLC purity is 99.56%.
Example 12
Compound IV (32.94g, 0.10 mol), sodium hydroxide (12.00g, 0.30mol) and dry ether (200 mL) were added to a single-neck flask, and stirred at 5 ℃ for 30 minutes, followed by addition of compound III (61.02g, 0.20mol), followed by stirring at constant temperature for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, the aqueous phase was extracted with diethyl ether (200 mL. Times.3), the organic phases were combined, the organic phase was washed with water and saturated brine once, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated by concentration under reduced pressure to give a yellow liquid, which was added with tetrahydrofuran (200 mL), methanol (70 mL), and an aqueous solution of lithium hydroxide (5.03g, 0.12mol, dissolved in 70mL of water) dropwise, followed by reaction overnight. With 1 mol. L -1 Adjusting pH to 8-9 with acid, removing the solvent by evaporation under reduced pressure, adding water (70 mL), washing with ethyl acetate (100 mL), and then washing with 0.5 mol. L -1 Adjusting the pH value to 5-6 with dilute hydrochloric acid, extracting with ethyl acetate (100 mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and recrystallizing the crude product with isopropanol (100 mL) to obtain a beige solid compound V, wherein the yield is 95.2%, and the HPLC purity is 99.42%.
Example 13
Compound IV (32.94g, 0.10 mol), sodium hydride (6.0 g, 0.25mol) and dry tetrahydrofuran (200 mL) were charged into a single-neck flask, and stirred at 0 ℃ for 30 minutes, followed by addition of compound III (33.56g, 0.11mol), and after completion of the addition, stirring was carried out at constant temperature for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, the aqueous phase was extracted with ether (200 mL. Times.3), the organic phases were combined, the organic phase was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, evaporating to remove solvent to obtain yellow liquid, adding tetrahydrofuran (200 mL), methanol (70 mL), and dropwise adding hydrogen and oxygenAn aqueous solution of sodium chloride (4.0 g,0.10mol, dissolved in 70mL of water) was reacted overnight. With 1 mol. L -1 Adjusting pH to 8-9 with acid, removing the solvent by evaporation under reduced pressure, adding water (70 mL), washing with ethyl acetate (100 mL), and then washing with 0.5 mol. L -1 Adjusting the pH value to be 5-6 by dilute hydrochloric acid, extracting by ethyl acetate (100 mL multiplied by 3), drying by anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and recrystallizing the crude product by isopropanol (100 mL) to obtain a beige solid compound V, wherein the yield is 94.1 percent, and the HPLC purity is 99.51 percent.
Example 14
Compound IV (32.94g, 0.10mol), potassium tert-butoxide (14.69g, 0.35mol) and dry dichloromethane (200 mL) were charged in a single-neck flask, and stirred at 5 ℃ for 30 minutes, followed by addition of compound III (33.56g, 0.11mol), and after completion of the addition, the mixture was stirred at constant temperature for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, the aqueous phase was extracted with diethyl ether (200 mL. Times.3), the organic phases were combined, the organic phase was washed with water and saturated brine once, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated by concentration under reduced pressure to give a yellow liquid, which was added with tetrahydrofuran (200 mL), methanol (70 mL), and an aqueous solution of potassium carbonate (27.64g, 0.20mol, dissolved in 70mL of water) dropwise, followed by reaction overnight. With 1 mol. L -1 Adjusting pH to 8-9 with acid, removing the solvent by evaporation under reduced pressure, adding water (70 mL), washing with ethyl acetate (100 mL), and then washing with 0.5 mol. L -1 Adjusting the pH value to 5-6 with dilute hydrochloric acid, extracting with ethyl acetate (100 mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and recrystallizing the crude product with isopropanol (100 mL) to obtain a beige solid compound V, wherein the yield is 95.2%, and the HPLC purity is 99.40%.
Example 15
Compound IV (32.94g, 0.10 mol), potassium tert-butoxide (41.52g, 0.37mol) and dry dichloromethane (200 mL) were added to a single-neck flask, and stirred at-8 ℃ for 30 minutes, followed by addition of compound III (67.12g, 0.22mol), and after completion of the addition, the mixture was stirred at constant temperature for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, the aqueous phase was extracted with diethyl ether (200 mL. Times.3), the organic phases were combined, the organic phase was washed with water and saturated brine once, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, and reducing pressureThe solvent was evaporated by concentration to give a yellow liquid, which was added with tetrahydrofuran (200 mL), methanol (70 mL), and an aqueous solution of sodium hydride (5.28g, 0.22mol, dissolved in 70mL of water) dropwise and reacted overnight. With 1 mol. L -1 Adjusting pH to 8-9 with acid, removing the solvent by evaporation under reduced pressure, adding water (70 mL), washing with ethyl acetate (100 mL), and then washing with 0.5 mol. L -1 Adjusting the pH value to be 5-6 by dilute hydrochloric acid, extracting by ethyl acetate (100 mL multiplied by 3), drying by anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and recrystallizing the crude product by isopropanol (100 mL) to obtain a beige solid compound V, wherein the yield is 88.2 percent, and the HPLC purity is 98.70 percent.
Claims (10)
1. A tirofiban intermediate compound is characterized in that the structure is shown as formula III:
2. a process for the preparation of a tirofiban intermediate compound according to claim 1, comprising the steps of:
adding a compound II, alkali A and a catalyst into an organic solvent A, stirring, adding p-toluenesulfonyl chloride, reacting at room temperature until the reaction is finished to obtain a compound III:
3. the method according to claim 2, wherein the base is one selected from triethylamine, diisopropylethylamine, sodium potassium alkoxide, and sodium hydride.
4. The method of claim 2, wherein the catalyst is selected from the group consisting of 4-dimethylaminopyridine, pyridine, 3, 5-lutidine, and 3-aminopyridine.
5. The preparation method according to claim 2, wherein the organic solvent A is selected from one or a combination of dichloromethane, tetrahydrofuran, chloroform and acetonitrile.
6. The preparation method according to claim 2, wherein the feeding molar ratio of the compound II, the p-toluenesulfonyl chloride, the base A and the catalyst is 1: 1.0-2.0: 1.8-2.5.
7. Use of a tirofiban intermediate compound according to claim 1 for the preparation of a tirofiban key intermediate compound.
8. Use of a gimeracil intermediate compound according to claim 7 for the preparation of a gimeracil key intermediate compound, comprising the steps of: adding a compound IV and an alkali B into a single-neck flask at room temperature, adding an organic solvent B, stirring at low temperature, adding a compound III, continuously reacting at constant temperature, after the detection reaction is finished, adding a saturated ammonium chloride aqueous solution into the reaction solution for dilution, separating an organic phase, extracting a water phase with diethyl ether, combining the organic phases, washing the organic phase with water, washing with salt, drying, evaporating, adding the obtained product into a tetrahydrofuran and methanol organic solution, dropwise adding an alkali C solution, and reacting at room temperature until the reaction is finished to obtain a compound V:
9. the use according to claim 7, wherein the base B is selected from one of potassium tert-butoxide, sodium hydroxide and sodium hydride; the alkali C is selected from one of lithium hydroxide, sodium hydride and potassium carbonate; the organic solvent B is selected from one of dry diethyl ether, tetrahydrofuran, acetonitrile and dichloromethane; after the organic solvent B is added, the temperature is controlled to be-5 ℃.
10. The use according to claim 7, wherein the compound IV, the compound III, the base B and the base C are fed in a molar ratio of: 1.0-2.0.
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