CN112851485B - Preparation method of ticagrelor key intermediate - Google Patents
Preparation method of ticagrelor key intermediate Download PDFInfo
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
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Abstract
The invention relates to the technical field of medicines, in particular to a preparation method of a ticagrelor key intermediate, which comprises the following steps: dissolving a compound shown in a formula I and 3, 4-difluoroiodobenzene in a solvent, adding a catalyst, a first ligand, a second ligand, an acid and a metal salt catalyst, and heating for reaction to obtain a compound shown in a formula II; dissolving the compound of the formula II and alkali in a solvent, stirring for reaction, dropwise adding bromine, continuing to react after the dropwise adding is finished, adding sodium thiosulfate, and obtaining the compound of the formula III after the reaction is finished. The preparation method of the ticagrelor chiral intermediate provided by the invention is short and novel in route, mild in reaction conditions, economic and effective, and higher in yield than the existing preparation method, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of a ticagrelor key intermediate.
Background
Ticagrelor, developed by AstraZeneca (AstraZeneca), was FDA approved in 2011 at 20/7 for reducing the incidence of thrombotic events in patients with Acute Coronary Syndrome (ACS). It is a novel, selective anticoagulant, and is the first reversible binding P2Y12 adenosine diphosphate receptor (ADP) antagonist, can act on purine 2 receptor subtype P2Y12 on Vascular Smooth Muscle Cells (VSMC) reversibly, has obvious inhibition effect on platelet aggregation caused by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease. Ticagrelor (or ticagrelor) was sold under the trade name of dilinda in 2012 and had acquired an imported drug license issued by the national food and drug administration (SFDA), meaning that this drug for patients with Acute Coronary Syndrome (ACS) has been approved for formal marketing in china. (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine is used as a key intermediate for synthesizing ticagrelor, so that the development of a method for preparing high-enantiopure cyclopropylamine suitable for industrial production is particularly important.
Patent WO2011017108A discloses a process for the preparation of ticagrelor, which is synthesized as follows:
the route is long in steps and expensive in raw materials; the recovery of chiral auxiliary groups is difficult, and the atom economy is poor; diazomethane is generated in the reaction process, and has strong stimulation effect on respiratory tract and inhibition effect on central nervous system. Acute poisoning causes severe irritable cough, dyspnea and chest pain. It is accompanied by symptoms such as fatigue, weakness, emesis, cold sweat, rapid and weak pulse, etc. Patients with severe symptoms of pneumonia, pulmonary edema, shock, coma and even death; is not suitable for industrial production.
Patent WO2012001531A discloses a process for the preparation of ticagrelor, which is synthesized as follows:
the route has longer steps; the first Wittig reaction produces triphenylphosphine oxide, which has poor atom economy and is difficult to purify; the carbene addition uses a more expensive ruthenium catalyst, so the cost is higher; is not suitable for industrial production.
Patent US20080132719A discloses a process for the preparation of ticagrelor, the synthetic route of which is as follows:
the CBS catalyst is used in the route, so that the cost is high; dimethyl sulfide has bad smell, and its vapor and air can form explosive mixture, and it is easy to burn and explode when it meets open fire and high heat, and it is decomposed by high heat to produce toxic sulfide smoke. The fuel can react with an oxidant strongly, and reacts with water, water vapor and acids to generate toxic and inflammable gas, the vapor is heavier than air and can be diffused to a far place at a lower part and can be ignited and reburnt when meeting a fire source; sodium hydride has irritation to eyes and respiratory tract, skin directly contacts to cause burn, chemical reaction activity is very high, the sodium hydride can spontaneously combust in humid air, heat or contact with moisture and acid to release heat and hydrogen to initiate combustion and explosion, the sodium hydride can strongly react with an oxidant to initiate combustion or explosion, and hydroxide is generated when the sodium hydride meets moisture and water, so that the corrosivity is very strong; is not suitable for industrial production.
In conclusion, the prior art generally faces the problems of long reaction route, low yield, poor atom economy, environmental unfriendliness, difficult control of chiral purity and the like, and is not suitable for industrial production. In view of the promising pharmaceutical prospect of ticagrelor, there is a need to develop an economical and safe preparation method.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the preparation method of the chiral intermediate of the Gracilostazol has the advantages of few reaction steps, high yield and mild reaction conditions.
The technical scheme for solving the technical problems is as follows:
a preparation method of a ticagrelor chiral intermediate comprises the following steps:
(1) dissolving a compound shown in a formula I and 3, 4-difluoroiodobenzene in a solvent, adding a catalyst, a first ligand, a second ligand, an acid and a metal salt catalyst, and heating for reaction to obtain a compound shown in a formula II;
(2) dissolving a compound shown in a formula II and alkali in a solvent, stirring for reaction, dropwise adding bromine, continuing to react after dropwise adding, adding sodium thiosulfate, and obtaining a compound shown in a formula III after the reaction is finished;
preferably, the catalyst in step (1) is selected from palladium catalysts.
Further, the palladium catalyst in the step (1) is selected from palladium acetate, palladium chloride or tetrakis (triphenylphosphine) palladium.
Preferably, in step (1), the first ligand is selected from chiral amino acids, and the second ligand is selected from pyridine derivatives.
Further, the chiral amino acid in the step (1) is selected from L-proline, L-phenylalanine, L-valine and D-cyclopentyl glycine.
Further, the pyridine derivative in the step (1) is selected from the group consisting of 2-hydroxypyridine, 2-hydroxy-5-chloropyridine, 2-hydroxy-5-nitropyridine and 2-hydroxy-5-trifluoromethylpyridine.
Preferably, the metal salt catalyst in step (1) is selected from silver salts or copper salts, and the specific silver salt is selected from silver carbonate, silver acetate or silver phosphate; the copper salt is selected from cupric chloride, ketone bromide, cuprous chloride, cuprous bromide or cupric acetate.
Preferably, the acid in step (1) is an inorganic acid or an organic acid, and specifically, the inorganic acid may be selected from hydrochloric acid, phosphoric acid or sulfuric acid; the organic acid may be selected from acetic acid, trifluoroacetic acid or tartaric acid.
Preferably, the molar ratio of the compound of formula I in step (1), 3, 4-difluoroiodobenzene, catalyst, first ligand, second ligand, acid, metal salt catalyst is 1: 0.5-1: 0.01-0.2: 0.01-0.2: 0.01-0.2: 0.5-10: 0.1 to 1.
Further, the molar ratio of the compound of formula I in the step (1), 3, 4-difluoroiodobenzene, the catalyst, the first ligand, the second ligand, the acid and the metal salt catalyst is 1: 0.5-0.8: 0.01-0.1: 0.01-0.1: 0.01-0.1: 0.5-2: 0.2 to 1.
Further, the molar ratio of the compound of formula I in the step (1), 3, 4-difluoroiodobenzene, the catalyst, the first ligand, the second ligand, the acid and the metal salt catalyst is 1: 0.5-0.75: 0.01-0.05: 0.05-0.1: 0.02-0.1: 0.75-2: 0.2 to 0.5.
Preferably, the solvent in step (1) is selected from C1～4One or more of alcohol, chloroalkane, ether solvents, acetonitrile or formamide solvents.
Preferably, the base in step (2) is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.
Preferably, sodium thiosulfate is also added in the step (2) to reduce residual Br2。
Preferably, the compound of formula II in step (2), a base, Br2And sodium thiosulfate in a molar ratio of 1: 4-20: 3-10: 0.5 to 10.
Further, in the step (2), a compound of formula II, alkali and Br2And sodium thiosulfate in a molar ratio of 1: 4-8: 3-6: 2 to 4.
In step (1), the first ligand and the second ligand participate in the intermediate state reaction together, and the possible reaction process is shown in the above reaction formula.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The preparation method of the ticagrelor chiral intermediate provided by the invention has the advantages that the reaction steps are greatly shortened, the yield is high, the raw materials are cheap and easy to obtain, the traditional coupling reaction is replaced by the carbon-hydrogen bond activation reaction, the step of preparing a metal reagent or a boric acid reagent is avoided, the atom economy is high, the labor and raw material cost is effectively reduced, and the preparation method is suitable for industrial production; in addition, due to the rigid structure of the three-membered ring, only a homeotropic transition state can be generated under the action of the chiral ligand, and a cis-product is generated with high selectivity. Due to the fact that the steric hindrance of the three-membered ring cis-form product is large, the three-membered ring cis-form product can be completely converted into a thermodynamically stable trans-form structure under the alkaline condition by combining the special property of carbonyl enol interconversion, and material loss and cost pressure caused by post-resolution are effectively avoided. Meanwhile, one pot completes the haloform reaction, and the functional group conversion is efficiently realized. The method has the advantages of short and novel route, mild reaction conditions, economy and effectiveness, higher yield than the existing preparation method, and suitability for large-scale industrial production.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
the compound of the formula I is subjected to coupling reaction to obtain a compound of a formula II
Cyclopropylmethyl ketone (1.68g,20mmol), palladium acetate (0.22g,1mmol), L-valine (0.23g,2mmol), 2-hydroxy-5-nitropyridine (0.28g,2mmol), 3, 4-difluoroiodobenzene (2.40g,10mmol), trifluoroacetic acid (1.71g,15mmol), and silver phosphate (2.76g,10mmol) were added to 25mL of isopropanol, heated to reflux, incubated overnight, and TLC detected complete conversion of the starting material. Adding appropriate amount of silica gel, concentrating under reduced pressure at 45 deg.C to dryness, and performing column chromatography to obtain compound of formula II 1.70g with purity of 98.5% by HPLC, yield of 85.0%, and ee value of more than 99%.1H NMR(500MHz,CDCl3)δ7.03(ddd,J＝8.9,7.5,5.6Hz,1H),6.99-6.92(m,1H),6.89(dddd,J＝7.6,5.7,2.0,1.0Hz,1H),2.60-2.51(m,1H),2.36(q,J＝7.0Hz,1H),2.19(s,3H),1.71(td,J＝7.0,5.0Hz,1H),1.39(td,J＝6.9,4.9Hz,1H).
Example 2:
cyclopropylmethyl ketone (1.68g,20mmol), tetrakis (triphenylphosphine) palladium (0.23g,0.2mmol), L-proline (0.12g,1mmol), 2-hydroxy-5-trifluoromethylpyridine (0.06g,0.4mmol), 3, 4-difluoroiodobenzene (3.60g,15mmol), trifluoroacetic acid (4.56g,40mmol), and silver acetate (0.47g,4mmol) were added to 30mL acetonitrile, heated to reflux, reacted overnight with TLC to detect complete conversion of the starting material. Adding appropriate amount of silica gel, concentrating under reduced pressure at 45 deg.C to dryness, and performing column chromatography to obtain compound of formula II 1.67g with purity of 97.6% by HPLC, yield of 83.0%, and ee value of more than 99%.
Example 3:
the compound of the formula II is prepared into the compound of the formula III by a one-pot method of configuration inversion and haloform reaction
The compound of formula II (1.96g,10mmol) was dissolved in 10mL1, 4-dioxane, aqueous sodium hydroxide (5mL,80mmol) was added, the temperature was raised to 40 deg.C, the mixture was kept under stirring overnight, and the configuration was monitored by TLC to be completely inverted. Cooling to 0-5 deg.C, slowly adding dropwise bromine (6.39g,40mmol), and controlling temperature to be not more than 5 deg.C; after dripping, the temperature is kept for reaction for 6h, sodium thiosulfate (3.16g,20mmol) is added, stirring is carried out for 30min at room temperature, and the pH of the reaction solution is adjusted to 3-4 by 2N hydrochloric acid. Extracting with 10mL of 3 ethyl acetate, separating layers, washing the ethyl acetate layer with 10mL of 2 water, drying the organic layer with anhydrous sodium sulfate, filtering, adding a proper amount of silica gel into the filtrate, concentrating under reduced pressure at 45 ℃ until the mixture is dried, and carrying out column chromatography to obtain 1.94g of the compound shown in the formula III, wherein the purity is 97.2% by HPLC (high performance liquid chromatography), the yield is 95.3%, and the ee value is more than 99%.
1H NMR(500MHz,CDCl3)δ10.08(s,1H),7.06(dd,J＝18.3,8.5Hz,1H),6.97-6.77(m,2H),2.61-2.46(m,1H),1.85(dt,J＝8.9,4.6Hz,1H),1.66(dt,J＝9.7,5.0Hz,1H),1.41-1.25(m,1H).
Example 4:
the compound of formula II (1.96g,10mmol) was dissolved in 15mL of 1, 4-dioxane, aqueous potassium hydroxide (5mL,30mmol) was added, the temperature was raised to 40 deg.C, the mixture was kept warm and stirred overnight, and the configuration was monitored by TLC to be completely inverted. Cooling to 0-5 deg.C, slowly adding dropwise bromine (9.59g,60mmol), and controlling temperature to be not more than 5 deg.C; after dripping, the temperature is kept for reaction for 6h, sodium thiosulfate (6.32g,40mmol) is added, stirring is carried out for 30min at room temperature, and the pH of the reaction solution is adjusted to 3-4 by 2N hydrochloric acid. Extracting with 10mL of 3 ethyl acetate, separating layers, washing the ethyl acetate layer with 10mL of 2 water, drying the organic layer with anhydrous sodium sulfate, filtering, adding a proper amount of silica gel into the filtrate, concentrating under reduced pressure at 45 ℃ until the mixture is dried, and carrying out column chromatography to obtain 1.93g of the compound shown in the formula III, wherein the purity is 97.0% by HPLC (high performance liquid chromatography), the yield is 94.6%, and the ee value is more than 99%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (2)
1. A preparation method of a ticagrelor chiral intermediate is characterized by comprising the following steps:
(1) dissolving a compound shown in a formula I and 3, 4-difluoroiodobenzene in a solvent, adding a catalyst, a first ligand, a second ligand, an acid and a metal salt catalyst, and heating for reaction to obtain a compound shown in a formula II;
the catalyst is a palladium catalyst; the palladium catalyst is selected from palladium acetate, palladium chloride or tetrakis (triphenylphosphine) palladium;
the first ligand is selected from chiral amino acid, and the second ligand is selected from pyridine derivative; the chiral amino acid is selected from L-proline or L-valine; the pyridine derivative is selected from 2-hydroxypyridine, 2-hydroxy-5-chloropyridine, 2-hydroxy-5-nitropyridine and 2-hydroxy-5-trifluoromethylpyridine;
the metal salt catalyst is selected from silver salts selected from silver carbonate, silver acetate or silver phosphate;
the acid is selected from trifluoroacetic acid;
the molar ratio of the compound of the formula I, 3, 4-difluoroiodobenzene, the catalyst, the first ligand, the second ligand, the acid and the metal salt catalyst is 1: 0.5-0.75: 0.01-0.05: 0.05-0.1: 0.02-0.1: 0.75-2: 0.2 to 0.5;
the solvent is selected from C1~4One or more of an alcohol or acetonitrile solvent;
(2) dissolving the compound of formula II and alkali in solvent, stirring for reaction, and dripping Br2Continuing the reaction after dripping to obtain a compound shown in the formula III;
2. the process for preparing chiral intermediates of ticagrelor according to claim 1, wherein the compound of formula II, base and Br in step (2)2In a molar ratio of 1: 4-20: 3 to 10.
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