CN111072467A

CN111072467A - Preparation method of ticagrelor key intermediate

Info

Publication number: CN111072467A
Application number: CN201911256003.0A
Authority: CN
Inventors: 张云然; 孙光祥; 王兵; 孙海江; 俞风山; 周文
Original assignee: Changzhou Pharmaceutical Factory
Current assignee: Changzhou Pharmaceutical Factory
Priority date: 2019-12-10
Filing date: 2019-12-10
Publication date: 2020-04-28
Anticipated expiration: 2039-12-10
Also published as: CN111072467B

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a ticagrelor key intermediate.

Description

Preparation method of ticagrelor key intermediate

Technical Field

The invention relates to the technical field of medicines, in particular to a preparation method of a compound shown in a formula II, which can be used for preparing ticagrelor.

Background

Ticagrelor, developed by astrikang (AstraZeneca), was FDA approved at 7/20 days 2011 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 has 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. The (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 the high-enantiopure cyclopropaneamine suitable for industrial production is particularly important.

Patent WO2011017108 discloses a preparation method of ticagrelor, and a synthetic route of the ticagrelor is 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 WO2012001531 also discloses a preparation method of ticagrelor, and the synthetic route is 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 US20080132719 also discloses a preparation method 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 good medicinal prospect of ticagrelor, an economical and safe preparation method needs to be developed.

Disclosure of Invention

The invention relates to a preparation method of a key intermediate of ticagrelor. Cheap and easily available cyclopropane formic acid is used as a raw material, a compound in a formula II is obtained through a coupling reaction, and a compound in a formula III is obtained through a rearrangement reaction and a salt-forming one-pot method. The structure is shown as the following formula:

(1) the compound of the formula I is subjected to coupling reaction to obtain a compound of a formula II

Dissolving a compound shown in a formula I and 3, 4-difluoroiodobenzene in a first solvent, adding a palladium catalyst, a ligand, a first type of alkali and a metal salt catalyst, heating for reaction, adding water for treatment after the reaction is finished, adjusting the pH value to be acidic, adding a second solvent for extraction, adding a second type of alkali into a second solvent extraction liquid, heating until the reaction is finished, adjusting the pH value to be acidic, and performing post-treatment to obtain a compound shown in a formula II;

according to an embodiment, the compound of formula 1 is used in an amount of 1: 1-2, the reaction temperature is from room temperature to the reflux stability of the solvent, and the dosage of the compound shown in the formula 1 and the 3, 4-difluoroiodobenzene is preferably 1: 1.5-2;

the first solvent is selected from C1-C4 alcohol, chloroalkane, ether solvent, acetonitrile, formamide solvent or mixed solvent thereof, such as: dichloromethane, 1, 2-dichloroethane, chloroform, methanol, ethanol, tert-butanol, DMF, preferably the first solvent is chloroform, N-dimethylformamide;

the palladium catalyst is selected from palladium acetate, palladium chloride or palladium tetratriphenylphosphine, the dosage of the compound shown in the formula I and the catalyst is 1-20%, and the dosage of the palladium catalyst is preferably 1-10%;

the ligand is a chiral amino acid derivative, the chiral amino acid derivative is selected from proline, phenylalanine, valine and pyroglutamic acid, preferably Boc-L-valine, the dosage of the compound of the formula I and the ligand is 1-20%, and the dosage of the compound of the formula I and the ligand is preferably 1-10%;

the first type of base is an inorganic base, an organic base, such as: the inorganic base is selected from sodium carbonate, sodium bicarbonate and potassium carbonate, the organic base is selected from pyridine and triethylamine, the molar ratio of the compound in the formula I to the first type of base is 1: 1-2, and the preferred base is sodium carbonate and sodium bicarbonate;

the metal salt catalyst is selected from silver salt and copper salt, the molar ratio of the compound shown in the formula I to the metal salt catalyst is 1: 1-4, the silver salt is further selected from silver carbonate and silver acetate, and the copper salt is cupric chloride, ketone bromide, cuprous chloride, cuprous bromide and cupric acetate;

the second solvent is selected from a chloroalkane solvent, an aromatic solvent, an ether solvent or a mixed solvent thereof, and is further selected from dichloromethane, chloroform, methyltetrahydrofuran, toluene, xylene or a mixed solvent thereof, and the preferred second solvent is toluene and xylene;

the second type of base is selected from organic bases, for example: pyridine, triethylamine, sodium tert-butoxide, potassium tert-butoxide and NaH, wherein the molar ratio of the compound of formula I to the second type of base is 1: 1-3, the base is further selected from sodium tert-butoxide, potassium tert-butoxide or sodium methoxide, and the molar ratio of the compound of formula I to the second type of base is 1: 2;

the pH of the acetic acid is adjusted to 1 to 5, and more preferably 3 to 4.

(2) The compound of formula II is subjected to rearrangement reaction and salifying one-pot method to prepare the compound of formula III

The rearrangement and resolution of the compound of the formula II specifically comprises the following steps: nitridizing a compound of a formula II, heating and rearranging, mixing a rearranged product with acid, reacting at 75-85 ℃, salifying with R-mandelic acid, and performing chiral resolution;

azidation of a compound of formula II comprises: after reacting the compound shown in the formula II with thionyl chloride, adding an azide compound, a phase transfer catalyst and sodium carbonate for reaction, wherein preferably, the azide compound can be sodium azide, and the phase transfer catalyst can be tetrabutylammonium bromide;

further, azidation of the compound of formula II comprises: dissolving the compound shown in the formula II in toluene, adding a drop of pyridine, adding thionyl chloride, heating to 68-72 ℃, reacting for 2.5-3.5 hours under the condition of heat preservation, adding thionyl chloride, and continuing to react for 0.8-1.2 hours under the condition of heat preservation. Evaporating the reaction solution to dryness, dissolving the residue in toluene, cooling to-5-2 ℃, and adding sodium azide, tetrabutylammonium bromide and sodium carbonate to react for 1.5-2.5 hours;

according to some embodiments, the azide product is diluted with water, the layers are separated, and the organic layer is washed with saturated sodium chloride to remove residual salts in the organic phase;

according to some embodiments, the heating rearrangement is to react the azide product at 90-110 ℃ for 50-70 min. Specifically, in some embodiments, the heating rearrangement is to heat toluene to 100 ℃, and the toluene is dripped into an organic phase which is layered and washed after azidation to carry out rearrangement reaction to generate isocyanate;

according to some embodiments, the step of mixing the rearranged product with acid, reacting at 75-85 ℃, salifying with R-mandelic acid, and performing chiral resolution comprises: and dropwise adding the generated isocyanate solution into a hydrochloric acid solution, controlling the temperature at 75-85 ℃, and reacting for 60-70 min. Adding water, cooling to 25 deg.C, and layering. And adjusting the pH of the water layer which is hydrolyzed under acidic condition and dissolved with salt to 10-12 by using a sodium hydroxide solution, extracting by using ethyl acetate, and washing the ethyl acetate layer by using water after layering. And dissolving R-mandelic acid in ethyl acetate, mixing with the washed ethyl acetate layer, controlling the temperature to be 16-19 ℃, stirring for reacting for 2.5-3.5 hours, performing suction filtration, washing a filter cake with ethyl acetate, and drying at low temperature to obtain the compound shown in the formula III. Preferably, the low-temperature drying temperature is 38-42 ℃;

according to some embodiments, the compound of formula II is rearranged, resolved, and specifically includes:

firstly, dissolving a compound shown in a formula II in toluene, adding a drop of pyridine, adding thionyl chloride, heating to 68-72 ℃, carrying out heat preservation reaction for 2.5-3.5 hours, then adding thionyl chloride, continuing the heat preservation reaction for 0.8-1.2 hours, evaporating the reaction solution to dryness, dissolving the residue in toluene, cooling to-5-2 ℃, adding sodium azide, tetrabutylammonium bromide and sodium carbonate, carrying out reaction for 1.5-2.5 hours, adding water to dilute the azide product, layering, and washing an organic layer by saturated sodium chloride;

secondly, heating toluene to 100 ℃, dropwise adding the toluene to the organic phase which is layered and washed after azidation, and carrying out rearrangement reaction to generate isocyanate;

then, dropwise adding the generated isocyanate solution into a hydrochloric acid solution, controlling the temperature at 75-85 ℃, reacting for 60-70 min, adding water, cooling to 25 ℃, layering, adjusting the pH of a water layer dissolved with salt after hydrolysis under an acidic condition to 10-12 by using a sodium hydroxide solution, extracting by using ethyl acetate, washing an ethyl acetate layer by using water after layering, dissolving R-mandelic acid in ethyl acetate, mixing with the washed ethyl acetate layer, controlling the temperature at 16-19 ℃, stirring for reacting for 2.5-3.5 hours, performing suction filtration, washing a filter cake by using ethyl acetate, and drying at a low temperature to obtain the compound of the formula III.

Compared with the prior art, the invention is improved as follows:

1. 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 method is suitable for industrial production;

2. the rigidity of the ternary ring structure is very high, and under the action of a chiral ligand, only a homeotropic transition state can be generated, and a cis-form product is generated with high selectivity; by utilizing the special property of carbonyl enol interconversion, heating is carried out under the alkaline condition, the carbonyl enol interconversion is completely converted into a thermodynamically stable trans-structure, the chiral purity can reach more than 98 percent, and the material loss and the cost pressure caused by the post-resolution are effectively avoided;

3. the two-step product can remove impurities in a salifying mode, has good crystallinity, replaces column chromatography with recrystallization, greatly saves cost, improves product quality and is suitable for industrial production;

in conclusion, the whole route designed by the invention is short and novel, the reaction condition is mild, the method is economic and effective, the yield is higher than that of the existing preparation method, and the method is suitable for large-scale industrial production.

Drawings

FIG. 1 is a NMR spectrum of a compound of formula II.

FIG. 2 is a NMR spectrum of a compound of formula III.

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

8.6g cyclopropanecarboxylic acid, 2.25g palladium acetate, 2.17g Boc-L-valine, 36.0g 3, 4-difluoroiodobenzene, 15.9g sodium carbonate, 3.0g silver carbonate were added to 130mL chloroform, refluxed overnight, and TLC checked for complete conversion of starting material. Adding 130mL of water, stirring, layering, adjusting the pH of a water layer to 3-4 by using acetic acid, extracting by using 50mL of toluene multiplied by 3, combining organic layers, adding 19.2g of sodium tert-butoxide, carrying out reflux reaction for 8 hours, cooling to room temperature, adjusting the pH to 3-4 by using acetic acid, washing by using water, spinning a toluene layer, and recrystallizing residues by using ethyl acetate and n-hexane to obtain 15.4g of white solid, wherein the yield is 78%, and the ee value is more than 98%.¹H NMR (500 MHz, CDCl3) δ 10.08(s, 1H), 7.06 (dd, J = 18.3, 8.5 Hz, 1H), 6.97 – 6.77 (m, 2H), 2.61 – 2.46(m, 1H), 1.85 (dt, J = 8.9, 4.6 Hz, 1H), 1.66 (dt, J = 9.7, 5.0 Hz, 1H), 1.41– 1.25 (m, 1H)。

Example 2

The compound of formula II is subjected to rearrangement reaction and salifying one-pot method to prepare the compound of formula III

Dissolving 3.45g of the compound of the formula II in 15mL of toluene, adding one drop of pyridine, adding 2.3g of thionyl chloride, heating to 70 ℃, preserving heat for three hours, supplementing 0.5g of thionyl chloride, preserving heat againAnd (4) 1 h. The reaction was evaporated to dryness and the thionyl chloride residue was taken up with 15g x 3 toluene. The residue was dissolved in 10mL of toluene, cooled to 0 ℃ and then incubated for 2h with 1.24g of sodium azide, 0.056g of tetrabutylammonium bromide and 0.922g of sodium carbonate in 6.2g of water. Diluting with 3.8g of water, separating the layers, washing the organic layer with 3.8g of water and 3.8mL of saturated sodium chloride, and keeping the temperature at 3 ℃ for later use. 6g of toluene is heated to 100 ℃, the solution to be used is dripped, and the temperature is kept for 1 hour after dripping. The temperature is reduced to 20 ℃. The above solution was added dropwise to 18.2g of 3M HCl solution, the temperature was controlled at 80 ℃ and the reaction was carried out for 65 min. 34g of water was added thereto, and the reaction solution was cooled to 25 ℃ to separate layers. The aqueous layer was adjusted to pH 12 with 3.8g 45% sodium hydroxide solution, extracted with 31g ethyl acetate, the layers were separated and the ethyl acetate layer was washed with 13.7mL 2 water for use. 2.26 gR-mandelic acid was dissolved in 45.3mL of ethyl acetate and added dropwise to the above solution to be used, with the temperature controlled at 17 ℃. After dropping, stirring for 3h at 25 ℃, filtering, washing the filter cake with 13.8g of ethyl acetate, drying at 40 ℃ to obtain 4.54g of the compound shown in the formula III, wherein the yield is 82 percent, and the ee value is more than 99.9 percent.¹H NMR (500 MHz, DMSO) δ 7.40(d, J = 7.5 Hz, 2H), 7.29 (ddd, J = 18.9, 12.8, 8.1 Hz, 3H), 7.22 – 7.08 (m,2H), 7.00 – 6.91 (m, 1H), 4.67 (s, 1H), 2.66 (dt, J = 7.9, 4.1 Hz, 1H), 2.23(ddd, J = 9.7, 6.2, 3.5 Hz, 1H), 1.33 – 1.20 (m, 1H), 1.13 (dt, J = 12.7, 6.2Hz, 1H).

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

1. A process for the preparation of a compound of formula II, characterized by the steps of:

dissolving a compound shown in a formula I and 3, 4-difluoroiodobenzene in a first solvent, adding a palladium catalyst, a ligand, a first type of alkali and a metal salt catalyst, heating for reaction, adding water for treatment after the reaction is finished, adjusting the pH value to be acidic, adding a second solvent for extraction, adding a second type of alkali into a second solvent extraction liquid, heating until the reaction is finished, adjusting the pH value to be acidic, and performing post-treatment to obtain a compound shown in a formula II.

2. A process for the preparation of a compound of formula II according to claim 1, characterized in that: the dosage of the compound shown in the formula 1 and the 3, 4-difluoroiodobenzene is 1 (1-2), the reaction temperature is room temperature until the solvent is stable in reflux, and the first solvent is selected from C1-C4 alcohol, chloroalkane, ether solvents, acetonitrile, formamide solvents or mixed solvents thereof.

3. A process for the preparation of a compound of formula II according to claim 1, characterized in that: the palladium catalyst is selected from palladium acetate, palladium chloride or palladium tetratriphenylphosphine, and the dosage of the compound shown in the formula I and the catalyst is 1-10%.

4. A process for the preparation of a compound of formula II according to claim 1, characterized in that: the ligand is a chiral amino acid derivative, and the dosage of the compound shown in the formula I and the ligand is 1-20%.

5. A process for the preparation of a compound of formula II according to claim 4, characterized in that: the chiral amino acid derivative is selected from proline, phenylalanine, valine and pyroglutamic acid, and the dosage of the compound shown in the formula I and the ligand is 1-10%.

6. A process for the preparation of a compound of formula II according to claim 1, characterized in that: the first type of alkali is inorganic alkali or organic alkali, wherein the molar ratio of the compound in the formula I to the first type of alkali is 1 (1-2).

7. A process for the preparation of a compound of formula II according to claim 1, characterized in that: the metal salt catalyst is selected from silver salt and copper salt, and the molar ratio of the compound shown in the formula I to the metal salt catalyst is 1 (1-4).

8. A process for the preparation of a compound of formula II according to claim 7, characterized in that: the silver salt is selected from silver carbonate and silver acetate, and the copper salt is selected from copper chloride, ketone bromide, cuprous chloride, cuprous bromide and copper acetate.

9. A process for the preparation of a compound of formula II according to claim 1, characterized in that: the second solvent is selected from a chloroalkane solvent, an aromatic solvent, an ether solvent or a mixed solvent thereof.

10. A process for the preparation of a compound of formula II according to claim 9, characterized in that: the second solvent is selected from dichloromethane, chloroform, methyltetrahydrofuran, toluene and xylene.

11. A process for the preparation of a compound of formula II according to claim 1, characterized in that: the second type of alkali is selected from organic alkali, and the molar ratio of the compound shown in the formula I to the second type of alkali is 1 (1-3).

12. A process for the preparation of a compound of formula II according to claim 11, characterized in that: the organic base is selected from sodium tert-butoxide, potassium tert-butoxide or sodium methoxide, and the molar ratio of the compound shown in the formula I to the second type of base is 1 (1-2).

13. A process for the preparation of a compound of formula II according to any one of claims 1 to 12, characterized in that: adjusting pH to 3-4.