A tirofiban intermediate compound and preparation method thereof

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology, and in particular to a tirofiban intermediate compound and a preparation method thereof. The present invention uses 4-pyridine butanol and p-toluenesulfonyl chloride as starting materials to react and obtain a new tirofiban intermediate compound. At the same time, the present invention provides a new intermediate compound and N-n-butylsulfonyl-L-tyrosine ethyl ester to react and prepare a key tirofiban intermediate (S)-2-(butylsulfonylamino)-3-(4-(4-(pyridine-4-yl)butoxy)phenyl)propionic acid (ester), and the intermediate is further reacted to obtain tirofiban hydrochloride. The new intermediate synthesis method provided by the present invention is simple, and the new intermediate is used to prepare a short synthetic route for tirofiban, with high yield, mild reaction conditions, stable process, and is suitable for a large number of industrialized production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a tirofiban intermediate compound and a preparation method thereof. Background Art

[0002] Tirofiban hydrochloride, chemically known as N-(butylsulfonyl)-O-[4-(4-pyridyl)butyl]-L-tyrosine hydrochloride, is the first non-peptide platelet surface glycoprotein (GP) IIb / IIIa receptor antagonist developed by Merck and is currently the only platelet-based GP IIb / IIIa receptor antagonist in China. It is clinically used to treat acute coronary syndromes, including patients with unstable angina or non-Q-wave myocardial infarction, as well as patients undergoing percutaneous transluminal coronary angioplasty or atherectomy. This drug has a unique mechanism of action, is highly selective and specific for platelet GP IIb / IIIa receptors, reversibly inhibits platelet aggregation, and has a short half-life, no antigenicity, no adverse reactions, definite clinical efficacy, and a good safety profile. It is a highly promising therapeutic drug. The structural formula is as follows:

[0003]

[0004] Most existing processes for the synthesis of tirofiban use n-butylpiperidine (pyridine) derivatives as substrates, which are condensed with L-tyrosine derivatives to form a tirofiban skeleton, and then undergo corresponding deprotection and salt formation to obtain the target product.

[0005] For example, the U.S. patent application US5206373 and the literature Synthesis of Tirofiban Hydrochloride [J]. Chinese Journal of Pharmaceutical Industry, 2012, 43(6): 408-410. It was reported that 4-methylpyridine was used as a raw material and anhydrous tetrahydrofuran was used as a reaction solvent. Under the condition of n-butyl lithium, 1-chloro-3-bromopropane was reacted to synthesize 4-(4-pyridyl)-chlorobutane hydrochloride. At the same time, L-tyrosine was used as a raw material. In the presence of bis(trimethylsilyl)trifluoroacetamide (BSTFA) and pyridine ring Under the influence of the environment, it reacts with 1-butanesulfonyl chloride to generate N-butanesulfonyl-L-tyrosine. N-butanesulfonyl-L-tyrosine in dimethyl sulfoxide reacts with 4-(4-pyridyl)-chlorobutane hydrochloride under the action of potassium hydride to synthesize N-butanesulfonyl-O-(4-pyridyl)butyl-L-tyrosine. Then, glacial acetic acid is used as solvent and palladium carbon is used as catalyst to carry out high-pressure catalytic hydrogenation to obtain the compound N-butanesulfonyl-O-4-(4-piperidyl)butyl-L-tyrosine. The compound is salified with hydrochloric acid to prepare tirofiban hydrochloride:

[0006]

[0007] The literature Tetrahedron, 1993, 49; 5767-5776. reported that n-butylpiperidine derivatives were used as substrates to condense with L-tyrosine derivatives to form the tirofiban skeleton, and then the target product was obtained through corresponding deprotection and salt formation:

[0008]

[0009] The above process was studied and it was found that when n-butylpiperidine (pyridine) derivatives were condensed with L-tyrosine derivatives to form the tirofiban skeleton, disubstituted impurities were generated, and these impurities were difficult to remove in the subsequent purification steps:

[0010]

[0011] Ye Jialin et al. synthesized tirofiban hydrochloride [J]. Chemical Research and Application, 2012, 024(005): 821-824. Using L-tyrosine as raw material, tirofiban hydrochloride was obtained through 6 steps of esterification, sulfonylation, mitsunobu reaction, hydrolysis, catalytic hydrogenation, and salt formation:

[0012]

[0013] In this method, the Mitsunobu reaction requires the use of triphenylphosphine. The generated triphenylphosphine oxide is difficult to remove and has certain environmental hazards. In addition, the overall yield of the reaction is only 33%, which is not conducive to industrial production.

[0014] In view of the above problems in the current preparation of tirofiban, it is currently necessary to find a method for the industrial production of the tirofiban intermediate compound (S)-2-(butylsulfonylamino)-3-(4-(4-(pyridin-4-yl)butoxy)phenyl)propionic acid (ester) with mild reaction conditions, simple operation process, high product yield, high purity and low production cost. Summary of the Invention

[0015] In order to overcome the defects of the existing technology and find a better method for preparing tirofiban, the present invention provides a new tirofiban intermediate compound and a new method for preparing tirofiban hydrochloride using the new intermediate. The target product prepared by this method has high purity and yield, and the reaction conditions are mild, the operation process is simple, and the production cost is lower.

[0016] The specific technical contents of the present invention are as follows:

[0017] The first aspect of the present invention provides a new tirofiban intermediate compound, the structure of which is shown in Formula III:

[0018]

[0019] The second aspect of the present invention provides a method for preparing the tirofiban intermediate compound III. The method comprises the following steps: adding compound II, base A, and a catalyst to an organic solvent A, adding p-toluenesulfonyl chloride with stirring, and reacting at room temperature until the reaction is complete to obtain compound III:

[0020]

[0021] Preferably, the base A is selected from one of triethylamine, diisopropylethylamine, sodium methoxide, and sodium hydride, among which triethylamine is particularly preferred.

[0022] Preferably, the catalyst is selected from one of 4-dimethylaminopyridine, pyridine, 3,5-lutidine, and 3-aminopyridine, among which 4-dimethylaminopyridine is particularly preferred.

[0023] Preferably, the organic solvent A is selected from one of dichloromethane, chloroform, acetonitrile or a combination thereof.

[0024] Preferably, the molar ratio of compound II, p-toluenesulfonyl chloride, base A, and catalyst is 1:2.5-3.5:3.5-4.5:0.01-0.1, preferably 1:3.0:4.0:0.015:.

[0025] In a preferred embodiment, post-treatment is required after the reaction is completed. The specific steps are as follows: after the reaction is completed, saturated aqueous ammonium chloride solution is added to the reaction solution, the aqueous phase is separated and removed, the aqueous phase is extracted with dichloromethane, the organic phases are combined, the organic phases are washed once with water and once with saturated brine, and the organic phases are dried over anhydrous sodium sulfate. The desiccant is removed by filtration, the solvent is evaporated under reduced pressure, and the remaining product is recrystallized from toluene to obtain Compound III.

[0026] The third aspect of the present invention provides a method for preparing tirofiban hydrochloride using the new intermediate compound III:

[0027]

[0028] A method for preparing tirofiban comprises the following steps:

[0029] Step 1): Add compound IV and base B to a single-necked flask at room temperature, add organic solvent B and stir at low temperature, add compound III, and continue the reaction at constant temperature to obtain compound V;

[0030] Step 2): Compound V is added to a mixture of tetrahydrofuran and methanol, and lithium hydroxide is added and stirred for reaction. After the reaction is completed, the pH of the reaction solution is adjusted and then recrystallized from isopropanol. The obtained intermediate is directly added with ethyl acetate and hydrochloric acid without separation to obtain tirofiban hydrochloride.

[0031] Preferably, the base B in step 1) is selected from potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, and sodium hydride, with potassium tert-butoxide being particularly preferred.

[0032] Preferably, the organic solvent B in step 1) is selected from one of dry ether, tetrahydrofuran, acetonitrile and dichloromethane.

[0033] Preferably, in step 1), the molar ratio of compound IV, compound III, and base B is 1:1.0-2.0:2.5-3.5:, with 1:1.1:3.0 being particularly preferred.

[0034] Preferably, in step 1), the temperature is controlled at -5°C to 5°C after adding the organic solvent B.

[0035] Preferably, in step 2), the molar ratio of compound V to lithium hydroxide is 1:1.20, with 1:1.2 being particularly preferred.

[0036] In a preferred embodiment, after completion of the reaction in step 1), post-treatment is required. Specifically, the steps include diluting with saturated aqueous ammonium chloride, separating the organic phase, extracting the aqueous phase with diethyl ether, combining the organic phases, washing the organic phases once with water and once with saturated brine, and drying the organic phases over anhydrous sodium sulfate. The desiccant is removed by filtration, and the solvent is evaporated under reduced pressure to obtain Compound V.

[0037] In a preferred embodiment, after the reaction of adding lithium hydroxide in step 2) is completed, post-treatment is required, which specifically comprises the following steps: adjusting the pH to 8-9 with dilute hydrochloric acid, removing the solvent under reduced pressure, adding water, washing with ethyl acetate, adjusting the pH to 5-6 with dilute hydrochloric acid, extracting with ethyl acetate, drying over anhydrous sodium sulfate, filtering, removing the solvent from the filtrate under reduced pressure, and recrystallizing the crude product with isopropanol and adding ethyl acetate and hydrochloric acid.

[0038] Compared with the prior art, the technical effects achieved by the present invention are:

[0039] 1. Provides a new tirofiban intermediate compound and a simple and efficient method for preparing tirofiban using the new intermediate. The entire synthetic method is simple to operate and has a high reaction yield;

[0040] 2. The use of this new intermediate in the preparation of tirofiban can effectively avoid etherification reactions and produce no disubstituted impurities;

[0041] 3. The intermediate compound V obtained by this technology has high purity and yield, and is suitable for industrial scale-up production. DETAILED DESCRIPTION

[0042] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0043] The structure of the compound obtained by the present invention is confirmed:

[0044]

[0045] HPLC peak area normalization method:

[0046] Chromatographic column: YMC-Triart C 18 Column (4.6 mm × 250 mm, 5 μm);

[0047] Mobile phase: Mobile phase A is a buffer solution (take 0.79g of disodium hydrogen phosphate and 2.46g of sodium dihydrogen phosphate, add water to 1000ml): methanol (95:5), B is acetonitrile

[0048] Gradient elution: (0-20 min: B 20%-35%, 20-40 min: B 80%, 40-50 min: B 80%-20%);

[0049] Column temperature: 40°C;

[0050] Detection wavelength: 230nm;

[0051] Flow rate: 1.5 ml / min;

[0052] Injection volume: 10 μl;

[0053] Retention time: 16.8min.

[0054] High-resolution mass spectrum of compound III: ESI-HRMS: m / z = 645.8365 [M+Na] + , 1H-NMR(400MHz, CDCl3)δ:7.65(d,2H),7.45(d,2H),7.34(br,1H),7.13(d,2H),6.86(d,2H) ,4.11(q,2H),4.06(t,2H),3.81(d,1H),3.39(t,2H),3.33(t,2H),3.21(t,2H),3.17(d,1H) ,2.92(d,1H),2.43(s,3H),1.75-1.79(m,2H),1.60-1.62(m,2H),1.53-1.58(dt,2H),1.38- 1.42(m,1H),1.33(dt,2H),1.28-1.31(m,4H),1.21(t,3H),1.18-1.20(m,2H),0.89(t,3H); 13 C-NMR (100MHz, CDCl3) δ:171.5,156.6,143.3,137.6,129.4,129.3,129.2,129.1,128.2,128.1,128.0,114.4,1 14.3,68.7,61.3,60.1,59.1,47.0,46.9,35.9,33.0,29.9,28.9,28.7,21.8,21.6,21.3,21.0,19.3,14.1,13.8.

[0055]

[0056] HPLC peak area normalization method:

[0057] Chromatographic column: YMC-Triart C 18 Column (4.6 mm × 250 mm, 5 μm);

[0058] Mobile phase: A is a buffer solution (take 0.79g of disodium hydrogen phosphate and 2.46g of sodium dihydrogen phosphate, add water to 1000ml): methanol (95:5), B is acetonitrile;

[0059] Gradient elution: 0-20 min: B 20%-35%, 20-40 min: B 80%, 40-50 min: B 80%-40%;

[0060] Column temperature: 40°C;

[0061] Detection wavelength: 230nm;

[0062] Flow rate: 1.5 ml / min;

[0063] Injection volume: 10 μl;

[0064] Retention time: 16.8min.

[0065] ESI-HRMS(m / z):645.8365[M+Na] + .mp 157~158℃; 1 H-NMR(400MHz, CDCl3)δ:7.65(d,2H),7.45(d,2H),7.34(br,1H),7.13(d,2H),6.86(d,2H) ,4.11(q,2H),4.06(t,2H),3.81(d,1H),3.39(t,2H),3.33(t,2H),3.21(t,2H),3.17(d,1H) ,2.92(d,1H),2.43(s,3H),1.75-1.79(m,2H),1.60-1.62(m,2H),1.53-1.58(dt,2H),1.38- 1.42(m,1H),1.33(dt,2H),1.28-1.31(m,4H),1.21(t,3H),1.18-1.20(m,2H),0.89(t,3H); 13 C-NMR (100MHz, CDCl3) δ:171.5,156.6,143.3,137.6,129.4,129.3,129.2,129.1,128.2,128.1,128.0,114.4,1 14.3,68.7,61.3,60.1,59.1,47.0,46.9,35.9,33.0,29.9,28.9,28.7,21.8,21.6,21.3,21.0,19.3,14.1,13.8.

[0066]

[0067] Characterization of Compound I:

[0068] HPLC peak area normalization method:

[0069] Chromatographic column: YMC-Triart C 18 Column (4.6 mm × 250 mm, 5 μm);

[0070] Mobile phase: A is a buffer solution (take 0.79g of disodium hydrogen phosphate and 2.46g of sodium dihydrogen phosphate, add water to 1000ml): methanol (95:5), B is acetonitrile;

[0071] Gradient elution: 0-15 min: B 30%-50%, 15-40 min: B 50%, 40-45 min: B 50%-30%;

[0072] Column temperature: 35°C;

[0073] Detection wavelength: 230nm;

[0074] Flow rate: 1.5 ml / min;

[0075] Injection volume: 10 μl;

[0076] Retention time: 12.2min.

[0077] ESI-HRMS (m / z): 441.6023 [M+H] + .mp 131~132℃; 1 H-NMR(400MHz,CD3OD)δ:7.18(d,2H),6.88(d,2H),3.97-4.08(m,1H),3.94(t,2H),3.29-3.34(m,5H),2.87(dd,1H),2. 75-2.79(m,2H),2.67-2.70(m,1H),2.63(t,2H),1.98-2.01(m,2H),1.75-1.78(m,2H),1.20-1.52(m,11H),0.86(t,3H); 13 C-NMR(100MHz,CD3OD)δ:174.7,156.6,129.5,129.4,128.2,114.4,114.3,68. 7,61.3,60.1,47.3,47.2,35.6,33.0,32.5,32.3,29.9,21.8,21.6,19.3,13.8.

[0078] Preparation of Compound III

[0079] Example 1

[0080] Compound II (31.45 g, 0.20 mol), triethylamine (80.92 g, 0.80 mol), 4-dimethylaminopyridine (3.67 g, 0.03 mol) and dry dichloromethane (200 mL) were added to a single-necked flask and stirred to dissolve. After reacting at room temperature for 15 minutes, p-toluenesulfonyl chloride (114.39 g, 0.60 mol) was added and the reaction was continued at constant temperature for 4 hours. After the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, the aqueous phase was separated and removed, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The remaining product was recrystallized from toluene (200 mL) to obtain a white solid powder with a yield of 98.4% and an HPLC purity of 99.92%.

[0081] Example 2

[0082] Compound II (31.45 g, 0.20 mol), diisopropylethylamine (103.4 g, 0.80 mol), 4-dimethylaminopyridine (3.67 g, 0.03 mol) and dry chloroform (300 mL) were added to a single-necked flask and stirred to dissolve. After reacting at room temperature for 15 minutes, p-toluenesulfonyl chloride (95.28 g, 0.50 mol) was added and the reaction was continued at constant temperature for 4 hours. After the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, the aqueous phase was separated and removed, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The remaining product was recrystallized from toluene (200 mL) to obtain a white solid powder III with a yield of 94.3% and an HPLC purity of 99.55%.

[0083] Example 3

[0084] Compound II (31.45 g, 0.20 mol), sodium methoxide (43.20 g, 0.80 mol), 4-dimethylaminopyridine (3.67 g, 0.03 mol) and dry acetonitrile (300 mL) were added to a single-necked flask and stirred to dissolve. After reacting at room temperature for 15 minutes, p-toluenesulfonyl chloride (133.39 g, 0.7 mol) was added and the reaction was continued at constant temperature for 4 hours. After the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, the aqueous phase was separated and removed, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The remaining product was recrystallized from toluene (200 mL) to obtain a white solid powder III with a yield of 94.8% and an HPLC purity of 99.48%.

[0085] Example 4

[0086] Compound II (31.45 g, 0.20 mol), sodium hydride (19.20 g, 0.80 mol), 4-dimethylaminopyridine (2.44 g, 0.02 mol) and dry acetonitrile (200 mL) were added to a single-necked flask and stirred to dissolve. After reacting at room temperature for 15 minutes, p-toluenesulfonyl chloride (114.33 g, 0.6 mol) was added and the reaction was continued at constant temperature for 4 hours. After the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, the aqueous phase was separated and removed, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The remaining product was recrystallized from toluene (200 mL) to obtain a white solid powder III with a yield of 93.9% and an HPLC purity of 99.45%.

[0087] Example 5

[0088] Compound II (31.45 g, 0.20 mol), diisopropylethylamine (103.4 g, 0.80 mol), 4-dimethylaminopyridine (0.38 g, 2.0 mmol) and dry dichloromethane (200 mL) were added to a single-necked flask and stirred to dissolve. After reacting at room temperature for 15 minutes, p-toluenesulfonyl chloride (114.33 g, 0.6 mol) was added and the reaction was continued at constant temperature for 4 hours. After the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, the aqueous phase was separated and removed, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The remaining product was recrystallized from toluene (100 mL) to obtain white solid powder III with a yield of 94.5% and an HPLC purity of 99.32%.

[0089] Example 6

[0090] Compound II (31.45 g, 0.20 mol), triethylamine (70.83 g, 0.7 mol), 3,5-lutidine (3.21 g, 0.03 mol), and dry dichloromethane (200 mL) were added to a single-necked flask and stirred to dissolve. After reacting at room temperature for 15 minutes, p-toluenesulfonyl chloride (114.33 g, 0.6 mol) was added and the reaction was continued at constant temperature for 4 hours. After the reaction, saturated aqueous ammonium chloride (100 mL) was added to the reaction solution, the aqueous phase was separated and removed, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The remaining product was recrystallized from toluene (200 mL) to obtain a white solid powder III with a yield of 94.4% and an HPLC purity of 99.54%.

[0091] Example 7

[0092] Compound II (31.45 g, 0.20 mol), triethylamine (91.07 g, 0.9 mol), 3-aminopyridine (2.82 g, 0.03 mol) and dry dichloromethane (200 mL) were added to a single-necked flask and stirred to dissolve. After reacting at room temperature for 15 minutes, p-toluenesulfonyl chloride (114.33 g, 0.6 mol) was added and the reaction was continued at constant temperature for 4 hours. After the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, the aqueous phase was separated and removed, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The remaining product was recrystallized from toluene (200 mL) to obtain a white solid powder III with a yield of 95.5% and an HPLC purity of 99.45%.

[0093] Example 8

[0094] Compound II (31.45 g, 0.20 mol), triethylamine (60.71 g, 0.6 mol), 4-dimethylaminopyridine (0.22 g, 1.8 mmol) and dry dichloromethane (200 mL) were added to a single-necked flask and stirred to dissolve. After reacting at room temperature for 15 minutes, p-toluenesulfonyl chloride (83.85 g, 0.44 mol) was added and the reaction was continued at constant temperature for 4 hours. After the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, the aqueous phase was separated and removed, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The remaining product was recrystallized from toluene (200 mL) to obtain a white solid powder III with a yield of 88.9% and an HPLC purity of 98.85%.

[0095] Example 9

[0096] Compound II (31.45 g, 0.20 mol), triethylamine (97.14 g, 0.96 mol), pyridine (1.90 g, 0.024 mol) and dry dichloromethane (300 mL) were added to a single-necked flask and stirred to dissolve. After reacting at room temperature for 15 minutes, p-toluenesulfonyl chloride (141.01 g, 0.74 mol) was added and the reaction was continued at constant temperature for 4 hours. After the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, the aqueous phase was separated and removed, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. 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%.

[0097] Preparation of Compound V

[0098] Example 10

[0099] Compound IV (32.94 g, 0.10 mol), potassium tert-butoxide (33.66 g, 0.30 mol) and dry ether (200 mL) were added to a single-necked flask and stirred at 0°C for 30 minutes. Compound III (51.17 g, 0.11 mol) was added and stirred at constant temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, and the aqueous phase was extracted with ether (200 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure to obtain a beige solid compound V with a yield of 98.9% and an HPLC purity of 99.80%.

[0100] Example 11

[0101] Compound IV (32.94 g, 0.10 mol), sodium tert-butoxide (38.83 g, 0.30 mol) and dry ether (200 mL) were added to a single-necked flask and stirred at -5°C for 30 minutes. Compound III (46.51 g, 0.10 mol) was added and stirred at constant temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, and the aqueous phase was extracted with ether (200 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure to obtain a yellow solid compound V with a yield of 94.3% and an HPLC purity of 99.56%.

[0102] Example 12

[0103] Compound IV (32.94 g, 0.10 mol), sodium hydroxide (12.00 g, 0.30 mol) and dry ether (200 mL) were added to a single-necked flask and stirred at 5°C for 30 minutes. Compound III (93.03 g, 0.20 mol) was added and stirred at constant temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, and the aqueous phase was extracted with ether (200 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure to obtain a yellow solid compound V with a yield of 95.2% and an HPLC purity of 99.42%.

[0104] Example 13

[0105] Compound IV (32.94 g, 0.10 mol), sodium hydride (6.0 g, 0.25 mol), and dry tetrahydrofuran (200 mL) were added to a single-necked flask and stirred at 0°C for 30 minutes. Compound III (51.17 g, 0.11 mol) was added and stirred at constant temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride (250 mL) was added to dilute the mixture, the organic phase was separated, and the aqueous phase was extracted with ether (200 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to obtain Compound V as a yellow solid with a yield of 94.1% and an HPLC purity of 99.51%.

[0106] Example 14

[0107] Compound IV (32.94 g, 0.10 mol), potassium tert-butoxide (14.69 g, 0.35 mol) and dry dichloromethane (200 mL) were added to a single-necked flask and stirred at 5°C for 30 minutes. Compound III (51.17 g, 0.11 mol) was added and stirred at constant temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, and the aqueous phase was extracted with ether (200 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure to obtain a yellow solid compound V with a yield of 95.2% and an HPLC purity of 99.40%.

[0108] Example 15

[0109] Compound IV (32.94 g, 0.10 mol), potassium tert-butoxide (41.52 g, 0.37 mol) and dry dichloromethane (200 mL) were added to a single-necked flask and stirred at -8°C for 30 minutes. Compound III (102.33 g, 0.22 mol) was added and stirred at constant temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (250 mL) was added to dilute the mixture, the organic phase was separated, and the aqueous phase was extracted with ether (200 mL × 3). The organic phases were combined and washed once with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure to obtain yellow solid compound V with a yield of 88.2% and an HPLC purity of 98.70%.

[0110] Preparation of Tirofiban Hydrochloride

[0111] Compound V (62.23 g, 0.10 mol), tetrahydrofuran (200 mL), methanol (70 mL) were added to a single-necked flask, and an aqueous solution of lithium hydroxide (5.03 g, 0.12 mol, dissolved in 70 mL of water) was added dropwise, and the reaction was allowed to proceed overnight. -1 Adjust pH to 8-9 with acid, remove the solvent under reduced pressure, add water (70 mL), wash with ethyl acetate (100 mL), and then use 0.5 mol·L -1 The pH was adjusted to 5-6 with dilute hydrochloric acid, extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was recrystallized from isopropanol (100 mL) to obtain a beige solid compound. The beige solid was added with isopropyl acetate (125 mL), and concentrated hydrochloric acid (6 mL) was slowly added dropwise under stirring at room temperature. The reaction was carried out at a constant temperature for 5 hours, filtered, and dried to obtain tirofiban hydrochloride with a yield of 98.9% and an HPLC purity of 99.80%.

[0112] Comparative Example

[0113] 4-(4-Chlorobutyl)pyridine hydrochloride (155.0 g, 1.0 mol), N-(butanesulfonyl)-L-tyrosine (273.6 g, 0.9 mol), and potassium iodide (1.7 g, 10 mmol) were dissolved in DMSO (1.4 L). 4 mol / L potassium hydroxide solution (550 ml) was added dropwise with stirring. After complete addition, the reaction mixture was stirred at 65°C for 12 hours. After cooling to room temperature, water (1.5 L) and methyl tert-butyl ether (800 ml) were added to the reaction mixture. After stirring, the mixture separated. 50% acetic acid (approximately 130 ml) was slowly added dropwise to the aqueous layer to adjust the pH to 4.8. The mixture was stirred at room temperature for 5 hours, filtered, and the filter cake was washed with water (500 ml) to obtain Compound V as an off-white solid with an mp of 138-140°C, a yield of 70.2%, and an HPLC purity of 95.35%.

Claims

1. A tirofiban intermediate compound, characterized in that: Its structure is shown in Formula III:

2. A method for preparing the tirofiban intermediate compound according to claim 1, characterized in that: The steps include: Compound II, base A, and catalyst are added to organic solvent A, p-toluenesulfonyl chloride is added with stirring, and the mixture is reacted at room temperature until the reaction is complete to obtain compound III:

3. The preparation method according to claim 2, characterized in that The base A is selected from one of triethylamine, diisopropylethylamine, potassium sodium alkoxide and sodium hydride.

4. The preparation method according to claim 2, characterized in that The catalyst is selected from one of 4-dimethylaminopyridine, pyridine, 3,5-lutidine and 3-aminopyridine.

5. The preparation method according to claim 2, characterized in that The organic solvent A is selected from one of dichloromethane, tetrahydrofuran, chloroform, acetonitrile or a combination thereof.

6. The preparation method according to claim 2, characterized in that The molar ratio of compound II, p-toluenesulfonyl chloride, base A and catalyst is 1:1.0-2.0:1.8-2.5:0.01-0.

1.

7. Use of the tirofiban intermediate compound according to claim 1 for preparing tirofiban hydrochloride.

8. Use of the tirofiban intermediate compound for tirofiban hydrochloride according to claim 7, characterized in that: The steps include: Step 1): Add compound IV and base B to a single-necked flask at room temperature, add organic solvent B and stir at low temperature, add compound III, and continue the reaction at constant temperature to obtain compound V; Step 2): Compound V is added to a mixture of tetrahydrofuran and methanol, and lithium hydroxide is added and stirred for reaction. After the reaction is completed, the pH of the reaction solution is adjusted and recrystallized from isopropanol. The obtained intermediate is directly added to ethyl acetate and hydrochloric acid without separation and stirred for reaction to obtain tirofiban hydrochloride: The synthetic route is as follows:

9. The use according to claim 8, characterized in that The base B is selected from one of potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, and sodium hydride; the organic solvent B is selected from one of dry ether, tetrahydrofuran, acetonitrile, and dichloromethane; and the temperature is controlled at -5°C to 5°C after the organic solvent B is added.

10. The use according to claim 8, characterized in that The molar ratio of compound IV, compound III and base B is 1:1.0-2.0:2.5-3.5; the molar ratio of compound V and lithium hydroxide is 1:1.20.

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