CN116041249A - Preparation method of tirofiban hydrochloride - Google Patents
Preparation method of tirofiban hydrochloride Download PDFInfo
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- CN116041249A CN116041249A CN202310136300.1A CN202310136300A CN116041249A CN 116041249 A CN116041249 A CN 116041249A CN 202310136300 A CN202310136300 A CN 202310136300A CN 116041249 A CN116041249 A CN 116041249A
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- tirofiban
- reaction
- solvent
- catalyst
- hydrochloride
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- 229960004929 tirofiban hydrochloride Drugs 0.000 title claims abstract description 25
- HWAAPJPFZPHHBC-FGJQBABTSA-N tirofiban hydrochloride Chemical compound O.Cl.C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 HWAAPJPFZPHHBC-FGJQBABTSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 34
- 239000003054 catalyst Substances 0.000 claims abstract description 25
- 229960003425 tirofiban Drugs 0.000 claims abstract description 22
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 claims abstract description 22
- CIPSBYICMDRGKQ-UHFFFAOYSA-N 4-(4-chlorobutyl)pyridine;hydrochloride Chemical compound Cl.ClCCCCC1=CC=NC=C1 CIPSBYICMDRGKQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 238000006482 condensation reaction Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000006722 reduction reaction Methods 0.000 claims abstract description 12
- VCKJOKXXEIQENI-LBPRGKRZSA-N (2s)-2-(butylsulfonylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound CCCCS(=O)(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 VCKJOKXXEIQENI-LBPRGKRZSA-N 0.000 claims abstract description 11
- 239000007868 Raney catalyst Substances 0.000 claims abstract description 9
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 229960000583 acetic acid Drugs 0.000 claims description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- 235000009518 sodium iodide Nutrition 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 208000001778 Coronary Occlusion Diseases 0.000 description 1
- 206010011086 Coronary artery occlusion Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Abstract
The invention belongs to the technical field of medicine synthesis, and provides a preparation method of tirofiban hydrochloride, wherein 4- (4-pyridyl) butyl chloride hydrochloride, N- (butylsulfonyl) -L-tyrosine, alkali and a catalyst are subjected to condensation reaction in a solvent to obtain an intermediate; mixing the intermediate, the catalyst and the solvent for reduction reaction to obtain tirofiban; and (3) carrying out salt forming reaction on tirofiban, ethyl acetate and hydrochloric acid to obtain the tirofiban hydrochloride. The method selects specific alkali in the condensation reaction to reduce the content of isomers in the intermediate, thereby improving the yield of the intermediate and reducing the difficulty of product separation; in the reduction reaction, raney nickel is selected as a catalyst for reaction, so that the reaction requirement is reduced, and the reaction progress is quickened. The preparation method provided by the invention has low process requirements, high yield up to 98.6%, stable quality and suitability for industrial production, and is a simple and efficient preparation method of tirofiban hydrochloride.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of tirofiban hydrochloride.
Background
Tirofiban hydrochloride is a clinically commonly used cardiac medicament and is suitable for unstable angina or non-Q wave myocardial infarction symptoms. Tirofiban hydrochloride can prevent heart ischemia and is also suitable for coronary angioplasty or plaque excision in coronary ischemic syndrome patients to prevent heart ischemia complications related to sudden coronary occlusion. In clinical manifestations, tirofiban hydrochloride not only has good treatment effect, but also has lighter adverse reaction, and becomes a conventional drug in myocardial infarction treatment. However, the synthesis time is long and the yield is low in the synthesis process of tirofiban hydrochloride, so that the medicine is limited in use. Therefore, it is an urgent problem to be solved to improve the preparation method of tirofiban hydrochloride and thereby obtain higher yields.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of tirofiban hydrochloride.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of tirofiban hydrochloride, which comprises the following steps:
(1) 4- (4-pyridyl) butyl chloride hydrochloride, N- (butylsulfonyl) -L-tyrosine, alkali and a catalyst are subjected to condensation reaction in a solvent to obtain an intermediate;
(2) Mixing the intermediate, the catalyst and the solvent for reduction reaction to obtain tirofiban;
(3) And (3) carrying out salt forming reaction on tirofiban, ethyl acetate and hydrochloric acid to obtain the tirofiban hydrochloride.
Preferably, the molar ratio of 4- (4-pyridyl) butyl chloride hydrochloride to N- (butylsulfonyl) -L-tyrosine in the step (1) is 0.8-1.2: 0.8 to 1.2;
the alkali is potassium tert-butoxide, and the molar ratio of the 4- (4-pyridyl) butyl chloride hydrochloride to the alkali is 1:1.5 to 2.
Preferably, the catalyst in the step (1) is potassium iodide and/or sodium iodide;
the molar ratio of the 4- (4-pyridyl) butyl chloride hydrochloride to the catalyst is 1:0.6 to 0.8;
the solvent is dimethyl sulfoxide and/or N, N-dimethylformamide;
the molar volume ratio of the 4- (4-pyridyl) butyl chloride hydrochloride to the solvent is 1mol: 3-4L.
Preferably, the temperature of the condensation reaction in the step (1) is 50 to 70 ℃ and the time is 8 to 10 hours.
Preferably, in the step (2), the catalyst is raney nickel, and the solvent is glacial acetic acid.
Preferably, in the step (2), the mass ratio of the intermediate to the catalyst is 8-10: 1.
preferably, the mass ratio of the intermediate to the solvent in the step (2) is 1:5.4 to 6.6.
Preferably, the temperature of the reduction reaction in the step (2) is 120 to 140 ℃ and the time is 6 to 8 hours.
Preferably, in the step (3), the mass-volume ratio of tirofiban to ethyl acetate is 1g: 15-20 mL;
the concentration of the hydrochloric acid is 7-8 mol/L;
the mass volume ratio of tirofiban to hydrochloric acid is 1g: 0.3-0.5 mL.
Preferably, the salt-forming reaction in step (3) is carried out at a temperature of 20 to 30 ℃ for a time of 5 to 7 hours.
The invention provides a preparation method of tirofiban hydrochloride, 4- (4-pyridyl) butyl chloride hydrochloride, N- (butylsulfonyl) -L-tyrosine, alkali and a catalyst are subjected to condensation reaction in a solvent to obtain an intermediate; mixing the intermediate, the catalyst and the solvent for reduction reaction to obtain tirofiban; and (3) carrying out salt forming reaction on tirofiban, ethyl acetate and hydrochloric acid to obtain the tirofiban hydrochloride. According to the invention, the specific alkali is selected in the condensation reaction, so that the content of isomers in the intermediate can be reduced, thereby improving the yield of the intermediate and reducing the difficulty of product separation; in the reduction reaction, raney nickel is selected as a catalyst for reaction, so that the reaction requirement is reduced, and the reaction progress is quickened. The preparation method provided by the invention has the advantages of low process requirement, high yield and stable quality, and is suitable for industrial production.
Detailed Description
The invention provides a preparation method of tirofiban hydrochloride, which comprises the following steps:
(1) 4- (4-pyridyl) butyl chloride hydrochloride, N- (butylsulfonyl) -L-tyrosine, alkali and a catalyst are subjected to condensation reaction in a solvent to obtain an intermediate;
(2) Mixing the intermediate, the catalyst and the solvent for reduction reaction to obtain tirofiban;
(3) And (3) carrying out salt forming reaction on tirofiban, ethyl acetate and hydrochloric acid to obtain the tirofiban hydrochloride.
In the present invention, the molar ratio of 4- (4-pyridyl) butyl chloride hydrochloride to N- (butylsulfonyl) -L-tyrosine in step (1) is preferably 0.8 to 1.2:0.8 to 1.2, more preferably 0.9 to 1.1:0.9 to 1.1, more preferably 0.95 to 1.05:0.95 to 1.05.
In the present invention, the base is preferably potassium t-butoxide, and the molar ratio of the 4- (4-pyridyl) butyl chloride hydrochloride to the base is preferably 1:1.5 to 2, more preferably 1:1.6 to 1.9, more preferably 1:1.7 to 1.8.
In the present invention, the catalyst in step (1) is preferably potassium iodide and/or sodium iodide.
In the present invention, the molar ratio of the 4- (4-pyridyl) butyl chloride hydrochloride to the catalyst is preferably 1:0.6 to 0.8, more preferably 1:0.65 to 0.75, more preferably 1:0.68 to 0.72.
In the present invention, the solvent is preferably dimethyl sulfoxide and/or N, N-dimethylformamide.
In the present invention, the molar volume ratio of the 4- (4-pyridyl) butyl chloride hydrochloride and the solvent is preferably 1mol:3 to 4L, more preferably 1mol:3.2 to 3.8L, more preferably 1mol: 3.4-3.6L.
In the present invention, the temperature of the condensation reaction in step (1) is preferably 50 to 70 ℃, more preferably 55 to 65 ℃, still more preferably 58 to 62 ℃; the time is preferably 8 to 10 hours, more preferably 8.5 to 9.5 hours, and still more preferably 8.6 to 9.4 hours.
In the present invention, after the condensation reaction in the step (1), the solvent is distilled off under reduced pressure, and the pH is adjusted with hydrochloric acid, wherein the pH is preferably 2 to 3, more preferably 2.2 to 2.8, and even more preferably 2.4 to 2.6; then extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an intermediate.
In the present invention, the catalyst in step (2) is preferably raney nickel and the solvent is preferably glacial acetic acid.
In the present invention, the mass ratio of the intermediate to the catalyst in step (2) is preferably 8 to 10:1, more preferably 8.5 to 9.5:1, more preferably 8.8 to 9.2:1.
in the present invention, the mass ratio of the intermediate to the solvent in step (2) is preferably 1:5.4 to 6.6, more preferably 1:5.6 to 6.4, more preferably 1:5.8 to 6.2.
In the present invention, the temperature of the reduction reaction in the step (2) is preferably 120 to 140 ℃, more preferably 125 to 135 ℃, still more preferably 128 to 132 ℃; the time is preferably 6 to 8 hours, more preferably 6.5 to 7.5 hours, and still more preferably 6.8 to 7.2 hours.
In the invention, impurities are removed by filtration after the reduction reaction in the step (2), the filtrate is decompressed and distilled to remove the solvent, and acetic acid and water are added, wherein the volume mass ratio of the acetic acid to the intermediate in the step (2) is preferably 0.8-1.2 mL:0.8 to 1.2g, more preferably 0.9 to 1.1mL:0.9 to 1.1g, more preferably 0.95 to 1.05mL: 0.95-1.05 g; the volume ratio of acetic acid to water is preferably 1:10 to 12, more preferably 1:10.5 to 11.5, more preferably 1:10.8 to 11.2; stirring is performed for a period of preferably 2 to 4 hours, more preferably 2.5 to 3.5 hours, and still more preferably 2.8 to 3.2 hours; the rotation speed is preferably 100 to 200rpm, more preferably 120 to 180rpm, and still more preferably 140 to 160rpm; and filtering after stirring to obtain white solid, namely tirofiban.
In the present invention, the mass-to-volume ratio of tirofiban to ethyl acetate in step (3) is preferably 1g:15 to 20mL, more preferably 1g:16 to 19mL, more preferably 1g: 17-18 mL.
In the present invention, the concentration of the hydrochloric acid is preferably 7 to 8mol/L, more preferably 7.2 to 7.8mol/L, and still more preferably 7.4 to 7.6mol/L.
In the invention, the mass-volume ratio of the tirofiban to the hydrochloric acid is preferably 1g:0.3 to 0.5mL, more preferably 1g:0.35 to 0.45mL, more preferably 1g: 0.38-0.42 mL.
In the present invention, the temperature of the salt forming reaction in the step (3) is preferably 20 to 30 ℃, more preferably 22 to 28 ℃, still more preferably 24 to 26 ℃; the time is preferably 5 to 7 hours, more preferably 5.5 to 6.5 hours, and still more preferably 5.8 to 6.2 hours.
In the present invention, the salt-forming reaction in the step (3) is carried out in a stirring state, and the stirring speed is preferably 100 to 150rpm, more preferably 110 to 140rpm, still more preferably 120 to 130rpm.
In the invention, after the reaction in the step (3), filtering, washing with ethyl acetate and drying to obtain a white solid, namely tirofiban hydrochloride.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
1mol of 4- (4-pyridyl) butyl chloride hydrochloride, 1mol of N- (butylsulfonyl) -L-tyrosine, 1.8mol of potassium tert-butoxide and 0.65mol of potassium iodide are dissolved in 3.5L of dimethyl sulfoxide, the reaction temperature is controlled to be 60 ℃ for 9 hours, the solvent is distilled off under reduced pressure after the reaction is finished, the pH is regulated to 3 by hydrochloric acid, the organic phases are extracted and combined by ethyl acetate, the organic phases are dried by anhydrous sodium sulfate, and the solvent is distilled off again under reduced pressure to obtain an intermediate (308.8 g, 78.6%).
100g of the prepared intermediate is taken, 10g of Raney nickel is placed in 540g of glacial acetic acid to react for 7h at 130 ℃, impurities are removed by filtration after the reaction is finished, the filtrate is decompressed and distilled to remove the solvent, 100mL of acetic acid and 1000mL of water are added, stirring is carried out for 3h at 150rpm, and white solid (96.1 g, 96.1%) is obtained by filtration, namely tirofiban.
50g of prepared tirofiban and 900mL of ethyl acetate are mixed, 20mL of hydrochloric acid with the concentration of 7.5mol/L is added dropwise, after all the dropwise addition is finished, the reaction is carried out for 6 hours at the temperature of 25 ℃ and the rpm of 130rpm, and after the reaction is finished, the mixture is washed and dried by using ethyl acetate, so that white solid (55.2 g, 98.6%) is obtained, namely tirofiban hydrochloride.
Example 2
0.5mol of 4- (4-pyridyl) butyl chloride hydrochloride, 0.55mol of N- (butylsulfonyl) -L-tyrosine, 1mol of potassium tert-butoxide and 0.35mol of sodium iodide are dissolved in 2L of N, N-dimethylformamide, the reaction is carried out at 50 ℃ for 9.5h, the solvent is distilled off under reduced pressure after the reaction is finished, the pH is adjusted to 2.5 by hydrochloric acid, the organic phases are extracted and combined, dried over anhydrous sodium sulfate, and the solvent is distilled off again under reduced pressure to obtain an intermediate (154.7 g, 79.2%).
50g of the prepared intermediate is taken, 5.6g of Raney nickel is placed in 300g of glacial acetic acid to react for 8 hours at 125 ℃, impurities are removed by filtration after the reaction is finished, the filtrate is decompressed and distilled to remove the solvent, 50mL of acetic acid and 600mL of water are added, stirring is carried out for 4 hours at 180rpm, and white solid (48.95 g, 95.8%) is obtained by filtration, namely tirofiban.
Mixing 40g of prepared tirofiban and 640mL of ethyl acetate, then dropwise adding 16mL of hydrochloric acid with the concentration of 8mol/L, reacting for 7h at the temperature of 30 ℃ and the speed of 150rpm after all dropwise adding, and washing and drying with ethyl acetate after the reaction is finished to obtain white solid (43 g, 98.3%) which is tirofiban hydrochloride.
Example 3
0.1mol of 4- (4-pyridyl) butyl chloride hydrochloride, 0.09mol of N- (butylsulfonyl) -L-tyrosine, 0.16mol of potassium tert-butoxide and 0.065mol of potassium iodide are dissolved in 0.3L of dimethyl sulfoxide, the reaction temperature is controlled to 65 ℃ for 8 hours, the solvent is distilled off under reduced pressure after the reaction is finished, the pH is regulated to 3 by hydrochloric acid, the organic phases are combined by extraction with ethyl acetate, the mixture is dried by anhydrous sodium sulfate, and the solvent is distilled off again under reduced pressure to obtain an intermediate (31.4 g, 80.1%).
25g of the prepared intermediate is taken, 2.5g of Raney nickel is placed in 150g of glacial acetic acid, the reaction is carried out for 6.5h at 130 ℃, impurities are removed by filtration after the reaction is finished, the filtrate is decompressed and distilled to remove the solvent, 25mL of acetic acid and 275mL of water are added, stirring is carried out for 3h at 140rpm, and white solid (24.4 g, 96.1%) is obtained by filtration.
20g of prepared tirofiban and 360mL of ethyl acetate are mixed, 7mL of hydrochloric acid with the concentration of 7.5mol/L is added dropwise, after all the dropwise addition is finished, the reaction is carried out for 5.5 hours at the temperature of 23 ℃ and the rpm of 120rpm, and after the reaction is finished, the mixture is washed and dried by the ethyl acetate, so that white solid (21.4 g, 98.5%) is obtained, namely tirofiban hydrochloride.
According to the embodiment, the invention provides the preparation method of tirofiban hydrochloride, and the specific alkali is selected in the condensation reaction, so that the content of isomers in the intermediate can be reduced, the yield of the intermediate is improved, and the difficulty in separating products is reduced; in the reduction reaction, raney nickel is selected as a catalyst for reaction, so that the reaction requirement is reduced, and the reaction progress is quickened. The yield of the preparation method provided by the invention is as high as 98.6%, and the preparation method is simple and efficient.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The preparation method of tirofiban hydrochloride is characterized by comprising the following steps:
(1) 4- (4-pyridyl) butyl chloride hydrochloride, N- (butylsulfonyl) -L-tyrosine, alkali and a catalyst are subjected to condensation reaction in a solvent to obtain an intermediate;
(2) Mixing the intermediate, the catalyst and the solvent for reduction reaction to obtain tirofiban;
(3) And (3) carrying out salt forming reaction on tirofiban, ethyl acetate and hydrochloric acid to obtain the tirofiban hydrochloride.
2. The process according to claim 1, wherein the molar ratio of 4- (4-pyridyl) butyl chloride hydrochloride to N- (butylsulfonyl) -L-tyrosine in step (1) is 0.8 to 1.2:0.8 to 1.2;
the alkali is potassium tert-butoxide, and the molar ratio of the 4- (4-pyridyl) butyl chloride hydrochloride to the alkali is 1:1.5 to 2.
3. The process according to claim 1 or 2, wherein the catalyst in step (1) is potassium iodide and/or sodium iodide;
the molar ratio of the 4- (4-pyridyl) butyl chloride hydrochloride to the catalyst is 1:0.6 to 0.8;
the solvent is dimethyl sulfoxide and/or N, N-dimethylformamide;
the molar volume ratio of the 4- (4-pyridyl) butyl chloride hydrochloride to the solvent is 1mol: 3-4L.
4. The process according to claim 3, wherein the condensation reaction in step (1) is carried out at a temperature of 50 to 70℃for a period of 8 to 10 hours.
5. The process according to claim 1 or 4, wherein the catalyst in step (2) is Raney nickel and the solvent is glacial acetic acid.
6. The preparation method according to claim 5, wherein the mass ratio of the intermediate to the catalyst in the step (2) is 8 to 10:1.
7. the process according to claim 6, wherein the mass ratio of the intermediate to the solvent in step (2) is 1:5.4 to 6.6.
8. The method according to claim 1, 6 or 7, wherein the reduction reaction in step (2) is carried out at a temperature of 120 to 140℃for a period of 6 to 8 hours.
9. The method of claim 8, wherein the mass to volume ratio of tirofiban to ethyl acetate in step (3) is 1g: 15-20 mL;
the concentration of the hydrochloric acid is 7-8 mol/L;
the mass volume ratio of tirofiban to hydrochloric acid is 1g: 0.3-0.5 mL.
10. The process according to claim 1 or 9, wherein the salt-forming reaction in step (3) is carried out at a temperature of 20 to 30 ℃ for a period of 5 to 7 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310136300.1A CN116041249A (en) | 2023-02-20 | 2023-02-20 | Preparation method of tirofiban hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310136300.1A CN116041249A (en) | 2023-02-20 | 2023-02-20 | Preparation method of tirofiban hydrochloride |
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| Publication Number | Publication Date |
|---|---|
| CN116041249A true CN116041249A (en) | 2023-05-02 |
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|---|---|---|---|
| CN202310136300.1A Pending CN116041249A (en) | 2023-02-20 | 2023-02-20 | Preparation method of tirofiban hydrochloride |
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| Country | Link |
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- 2023-02-20 CN CN202310136300.1A patent/CN116041249A/en active Pending
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